Development and Testing of a
Protocol for Computational Prediction of
1H and 13C NMR Chemical Shifts
and
Thermochemistry and Reaction Analysis
of Benzyne Formation and Trapping
A THESIS
SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL
OF THE UNIVERSITY OF MINNESOTA
BY
Daniel Joshua Marell
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
FOR THE DEGREE OF
MASTER OF SCIENCE
Thomas R. Hoye
January, 2013
© Daniel Joshua Marell 2013
ALL RIGHTS RESERVED
Acknowledgments
I first would like to thank my adviser, Dr. Thomas Hoye. Tom fostered an environment to
explore the chemistry interesting to me, and provided an open door for discussion whenever
the need arose. Throughout my time in his group, I have learned to appreciate thoughtful
consideration of the facts and careful analysis of details, skills critical to any future endeavor.
Within the Hoye group, I wish to thank particularly Susan Brown for the great friendship
that has grown out of my time spent here. A constant source of laughs and advice, Susan
provided a listening ear, insightful feedback and everything in between. I would also like
to thank Patrick Willoughby who provided a great working environment when I switched
offices. His attention to detail was always welcome, especially for my thesis and his wealth
of knowledge provided numerous discussion that grew my understanding of chemistry on a
daily basis. I’d also like to thank Drs. Susanna Emond and Aman Kulshretha, collaborators
and friends, who made the analysis of biorenewable lactones the most enjoyable experience
possible. With my colleagues above and Enver Izgu, Dawen Niu, Dr. Matthew Jansma,
Tao Wang, Julian Lo, Adam Wohl, Andrew Michel, Junhua Chen, Sean Ross, Brian Woods,
and Andrew Mullins I thank them for their encouragement and friendship.
Dr. Christopher Cramer was the source of many thoughtful discussions and advice as
I transitioned to a computational chemistry project, and I thank him for allowing me to
participate in his group meetings this past spring semester. The ability to learn and interact
with the members of a computational group provided numerous benefits throughout my
research.
I would also like to thank the Minnesota Supercomputing Institute for the computational
resources provided.
I also owe gratitude to those in my personal life that provided unwavering support. My
parents, Ellyn and Michael, for fostering an environment of learning and exploration at
home, which I know resulted in my growth into chemistry. To my brother Noah, so highly
motivated and who has inspired me strive for the next goal ahead. I also thank my extended
i
family who I am fortunate to have a close relationship with for their support and interest
in my studies.
The single person who has acted as my biggest fan and supporter these past years has
been my partner, Philip. Full of endless friendship, support, wisdom, and love, he provided
a place of great calm even during the most trying moments of my research program. His
constant encouragement to push for the goals I most desire, always sound advice, and his
example of hard work and dedication were crucial to my completion of this program. This
would not have been possible without him.
ii
Abstract
Elucidating structures of novel compounds and investigation of new reactions are two
tasks that experimental organic chemists address on a frequent basis. The pursuit of these
objectives can be rigorous and time-consuming. Of the methods employed in elucidating
the structure of novel compounds, nuclear magnetic resonance (NMR) is by far the most
widely applied. Investigation into new reactions may require any number of techniques to
understand the reaction scope, kinetics, optimal conditions, mechanisms, etc. In both cases,
the use of computational methods is well-suited to augment the experimentalist’s data to
guide and understand the system being investigated.
A protocol for facilitating computational prediction of NMR chemical shifts was de-
veloped. Application to a set of natural products previously evaluated against computed
NMR shifts, showed improved accuracy, through analysis of the corrected mean-absolute
error (CMAE). The protocol was further employed successfully to aid in analysis of exper-
imental spectra for compounds synthesized by collaborators where multiple diastereomers
were possible. Graphing templates were also created to allow for rapid inspection of possible
structures without more in-depth statistical analysis.
Thermodynamic and mechanistic analysis on the formation and reaction of benzyne was
also performed. Thermodynamic restrictions on the ring-size of fused benzynocycloalkanes
were investigated. Additionally, analysis of the energetics and transition state geometries
for small-molecule trapping (both intra and intermolecular) of benzyne are discussed.
iii
Table of Contents
Acknowledgments i
Abstract iii
Table of Contents iv
List of Tables vi
List of Figures vii
List of Schemes viii
Acronyms ix
1 Introduction 1
1.1 Background of Computational Chemistry . . . . . . . . . . . . . . . . . . 1
1.2 Theory of Computing NMR Chemical Shifts . . . . . . . . . . . . . . . . . 3
1.3 Calculation of Thermodynamic Quantities by DFT . . . . . . . . . . . . . 5
1.4 Methods for Locating a Transition State . . . . . . . . . . . . . . . . . . . 6
1.5 Solvation Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2 Developing a Protocol for Facile Computation of NMR Chemical Shifts 9
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.2 The Process of Calculating NMR Chemical Shifts . . . . . . . . . . . . . . 9
2.2.1 Specific Implementation for Calculating NMR Chemical Shifts . . 10
2.3 Examining Optimization Protocols . . . . . . . . . . . . . . . . . . . . . . 11
2.4 Methods of Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.4.1 Statistical Analysis Methods . . . . . . . . . . . . . . . . . . . . . 14
2.4.2 Qualitative Graphical Analysis . . . . . . . . . . . . . . . . . . . . 18
2.5 Comparison of our Protocol with a Previously Computed Natural Product 20
2.6 Evaluating Stereoisomers of Bioderived Lactones . . . . . . . . . . . . . . 23
2.6.1 Lactones Derived from β-pinene: A Small Molecule Test Case . . . 25
2.6.2 Lactones From Menthone and Carvone: Pairs of Diastereomers . . 29
2.7 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
iv
3 Examining Thermodynamics of Benzyne Formation and Reaction 40
3.1 Introduction to Benzyne: Structure, Formation and Reactivity . . . . . . 40
3.1.1 The Structure of Benzyne . . . . . . . . . . . . . . . . . . . . . . . 40
3.1.2 Reactivity of Benzyne . . . . . . . . . . . . . . . . . . . . . . . . . 41
3.1.3 Synthesis of Benzyne . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.2 Ring-Size Restrictions on Fused Benzynocycloalkane Formation . . . . . . 45
3.3 Thermodynamics and Transition States of Intermolecular Trapping . . . . 49
3.3.1 Transition State Analysis of Benzodioxole Carbene Formation . . . 52
3.3.2 Generation of N-heterocyclic Carbenes by Benzyne Trapping . . . 54
3.4 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
References 61
Scripts and Utilities 65
A-1 Maestro Scripts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
A-1.1 write-g09-inputs-default.py . . . . . . . . . . . . . . . . . . . . . . 65
A-1.2 write-g09-inputs-calcFCcalcall.py . . . . . . . . . . . . . . . . . . . 69
A-2 NMR Scripts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
A-2.1 nmr-data compilation.py . . . . . . . . . . . . . . . . . . . . . . . . 74
Supporting Information 80
S-I Calculated Geometries, Energies and NMR Shielding Tensors for Com-
pounds with Computed NMR Shifts . . . . . . . . . . . . . . . . . . . . . 80
S-II Calculated and Experimental NMR Chemical Shifts . . . . . . . . . . . . 180
S-III Calculated Geometries and Free Energies for Benzyne, Related Compounds
and Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
v
List of Tables
2.1 Optimization Procedures and Effect on Calculation Time . . . . . . . . . . . 12
2.2 Example MAE and CMAE Analysis of cis-Carvomenthone (201a) . . . . . . 16
2.3 Example Mismatched MAE and CMAE Analysis of Carvomenthone (201) . . 17
2.4 Impact of Uncertain Shifts on MAE and CMAE Results . . . . . . . . . . . . 18
2.5 Comparison of Our Protocol and Goodman’s on Computed Nankakurine Shifts 22
2.6 Statistical Matching Parameters of Computed Shifts of β-Pinene Lactones . . 26
2.7 Accuracy of 1H Computation for Bridging Methyl and Methylenes . . . . . . 27
2.8 Calculated CMAE Values for Normal Carvomenthide . . . . . . . . . . . . . . 37
2.9 Calculated CMAE Values for Abnormal Carvomenthide . . . . . . . . . . . . 39
3.1 Calculated ∆G Values for Benzynocycloalkane Formation From a Triyne . . . 46
3.2 Bond Lengths for 311b and 314 . . . . . . . . . . . . . . . . . . . . . . . . . 48
3.3 Bond Lengths for 315 and 316 . . . . . . . . . . . . . . . . . . . . . . . . . . 49
vi
List of Figures
1.1 Number of Publications Listing DFT as a Topic . . . . . . . . . . . . . . . . 3
2.1 Structure and Numbering of cis-carvomenthone (201a) . . . . . . . . . . . . 16
2.2 Example of a Stacked Graphical Comparison . . . . . . . . . . . . . . . . . . 19
2.3 Nankakurine Natural Product Used to Test NMR Computation . . . . . . . . 20
2.4 Conformers of Nankakurine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2.5 Set of Bio-derived Lactones Synthesized . . . . . . . . . . . . . . . . . . . . . 24
2.6 Selected Interatomic Distances of Protons in β-Pinene Normal Lactone . . . . 28
2.7 Lactones Derived from Menthone and Carvomenthone . . . . . . . . . . . . . 30
2.8 Diastereomers and Numbering Scheme of Normal Menthide . . . . . . . . . . 31
2.9 Lowest Energy Conformer of Normal cis-Carvomenthide . . . . . . . . . . . . 34
2.10 Conformational Prefernce and Support NMR Assignments of Abnormal cis-
Carvomenthide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
2.11 Diastereomers and Numbering Scheme for Normal Carvomenthide . . . . . . 36
2.12 Diastereomers and Numbering Scheme for Abnormal Carvomenthide . . . . . 38
3.1 Isomers of Benzyne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3.2 Various Representations of Benzyne . . . . . . . . . . . . . . . . . . . . . . . 41
3.3 Overlap of the p Orbitals in Benzyne’s Triple Bond . . . . . . . . . . . . . . . 42
3.4 Small Molecule Traps and Corresponding Products with Benzyne . . . . . . . 50
3.5 Calculated Free Energy Difference of Trapping Products . . . . . . . . . . . . 51
3.6 Transition State Leading to Formation of Benzodioxole Carbene . . . . . . . 52
3.7 IRC Plot for the Formation of Benzodioxole Carbene . . . . . . . . . . . . . . 53
3.8 Transition State For Proton Transfer From Zwitterionic Intermediate to Benzyne 55
3.9 Zwitterionic Intermediate on to NHC Formation, Prior to Proton Transfer . . 56
3.10 IRC Plot for Proton Transfer Step of NHC Formation . . . . . . . . . . . . . 58
3.11 Free Energy Diagram of NHC Formation by Benzyne Trapping . . . . . . . . 59
vii
List of Schemes
2.1 Synthesis of Normal and Abnormal β-pinene Lactones from Nopinone . . . . 25
2.2 Synthesis of Carvomenthides from Carvone . . . . . . . . . . . . . . . . . . . 33
3.1 1,2-Elimination of an Arene to form an Aryne . . . . . . . . . . . . . . . . . . 43
3.2 Cyclization of a Linear Tetrayne to a Benzenoid . . . . . . . . . . . . . . . . 43
3.3 Mechanism of Benzenoid Formation from Linear Tetrayne . . . . . . . . . . . 44
3.4 Model to Examine Thermodynamics of Benzynocycloalkane Formation . . . . 45
3.5 Analogous Model Benzynocycloalkane Formation without Extra “Tail” . . . . 46
3.6 Ring-Opening of Benzynocyclobutane to a Diene . . . . . . . . . . . . . . . . 47
3.7 Ring-Opening of Benzocyclobutane to a Diene . . . . . . . . . . . . . . . . . 48
3.8 Generation of NHC Through Hydrogen Abstraction By Benzyne . . . . . . . 54
3.9 NHC Generation By Benzyne Through Zwitterionic Intermediate . . . . . . . 55
viii
Acronyms
AO atomic orbital
BSSE basis set superposition error
CMAE corrected mean-absolute error
CPCM conductor-like polarizable continuum model
CSA chemical shift anisotropy
CSGT continuous set of gauge transformations
DFT density functional theory
GIAO gauge-independent atomic orbital
HDDA hexadehydro-Diels-Alder
HF Hartree-Fock
IEFPCM integral equation-formalism polarizable continuum model
IGAIM individual gauges for atoms in molecules
IRC intrinsic reaction coordinate
MAE mean-absolute error
MC/MM Monte-Carlo/multiple minimum
m-CPBA meta-chloroperoxybenzoic acid
MM molecular mechanics
MPLC medium-pressure liquid chromatography
NHC N-heterocylic carbene
NMR nuclear magnetic resonance
NOE nuclear Overhauser effect
PES potential energy surface
QST quadratic synchronous transit
ROTEP ring opening transesterification polymerization
SCF self-consistent field
STQN synchronous transit-guided quasi-Newton
TFA trifluoroacetic acid
TMS tetramethylsilane
TS transition state
UFF universal force field
ix
1. Introduction
1.1 Background of Computational Chemistry
Computational chemistry combines theoretical chemistry developments from as far back
as the early 20th century1,2 with computing resources to calculate theoretical parameters
for a variety of chemical systems. These chemical systems can be exactly described by
analytically solving the time-independent Schro¨dinger equation, Eq. (1.1). However, the
analytic solution to this equation is limited to only one-electron systems.
EΨ = HˆΨ (1.1)
Because solving the Schro¨dinger equation for a system of more than one electron is not
analytically possible, Hartree developed an approach shortly after Schro¨dinger’s publication
in 1926,2 known as self-consistent field (SCF) theory.3 The SCF approach to solving many-
electron systems formally places each electron into its own one-electron potential. The
eigenfunction of the Schro¨dinger equation, Ψ, is then described as a product of these one-
electron wave functions, known as the Hartree product, ΨHP (Equation 1.2a & 1.2b).
ΨHP =
n∏
i=1
ψi(ri) (1.2a)
Ψ(x1, x2, . . . , xn) = χ1(x1), χ2(x2), . . . , χn(xn) (1.2b)
The SCF approach constructs an initial guess of the one-electron wave functions, ψi, for
each occupied atomic orbital (AO). The solution of the one-electron Schro¨dinger equation,
Eq. (1.3), for each wave function generates a new set of wave functions. The process is
iteratively executed until a stop criterion is met, for example when the predicted change in
electronic energy is below a specified threshold value.
hiψi = εψi (1.3)
1
2The initial work by Hartree used a representation of the wave function that was not antisym-
metric, Eq. (1.2b). Soon after Hartree’s work, Fock expanded the theory to account for the
antisymmetric requirement of the wave functions through the use of a Slater determinant,4
giving rise to the Hartree-Fock (HF) method.5
The use of HF theory saw increased usage as computing technology began developing in
the 1950s. However, for most systems, the cost of evaluating the exchange energy was too
expensive given the computing resources available. In the early 1960s, work by Hohenberg
and Kohn6 as well as Kohn and Sham,7 addressed the issue of evaluating the many-body
wave function by instead describing the system as a collection of non-interacting electrons
in an effective potential described by the ground-state electron density of the system, now
referred to as density functional theory (DFT). By 1990, the number of papers citing DFT in
their title or abstract began to dramatically rise, and continues to do so (Fig. 1.1). Since the
initial development, DFT has been expanded to incorporate calculations for a wide variety
of chemical parameters, two of particular interest are computation of NMR chemical shift
values and computation of various thermodynamic quantities.
3Fig. 1.1 Number of Publications Listing DFT as a Topic
 
0
2000
4000
6000
8000
10000
12000
1975 1980 1985 1990 1995 2000 2005 2010
N
um
be
r o
f P
ub
lic
at
io
ns
 
Publication Year 
0
100
200
300
400
500
600
700
800
900
1975 1980 1985 1990 1995
Graph compiled from data provided from a search of “dft” or “density functional
theory” as a topic keyword on the Web of Knowledge database
1.2 Theory of Computing NMR Chemical Shifts
A chemical shift, as observed experimentally, is the result of a two-part calculation. First,
the magnetic shielding, σ, of a nucleus is proportional to the second derivative of energy
relative to the external magnetic field and the internal magnetic moment of the nucleus un-
der observation. The chemical shift is the observed difference in magnetic shielding values
for the observed nucleus in the molecule relative to the same nucleus in a reference com-
pound, commonly tetramethylsilane (TMS). Additionally, the chemical shift experienced
4by a nucleus is dependent upon the orientation of the nucleus with respect to the external
magnetic field, an effect termed chemical shift anisotropy (CSA). In a solution state NMR
experiment, this orientation effect is averaged by the rapid tumbling of the molecules.
In the computation of chemical shifts, the applied external magnetic field is represented
as a vector, which requires an origin. Selecting the position of the magnetic field is an
interesting problem, since we know the chemical shift is influenced by the position and
orientation of the nucleus relative to the external field (via the CSA effect). Three main
methods, continuous set of gauge transformations (CSGT),8–10 gauge-independent atomic
orbital (GIAO),10–14 and individual gauges for atoms in molecules (IGAIM)8,9 present var-
ious solutions to the problem of choosing the origin of the magnetic field. Regardless of the
method selected, a NMR calculation provides a magnetic shielding tensor for each nucleus
in the molecule. The tensor is a 3x3 matrix, describing the magnitude and direction of σ,
for each combination of the three axis directions (x, y and z):
σxx σxy σxz
σyx σyy σyz
σzx σzy σzz
 (1.4)
The tensor can be reduced to a coordinate frame where the off-diagonal components are
removed, resulting in a principal axis system, containing three diagonal elements (σxx, σyy
and σzz), and three eigenvectors (which describe the orientation of the principal axes).
The isotropic shielding, σiso, is the average of these three diagonal elements. This value is
translated to a chemical shift, δ, by subtracting the isotropic shielding of the same nucleus
in the reference molecule (computed in the same manner) from the isotropic shielding of
the nucleus under investigation.
51.3 Calculation of Thermodynamic Quantities by DFT
In evaluating the feasibility of unknown reactions, calculating accurate thermodynamic pa-
rameters is critical. Specifically, accurate calculation of the Gibb’s free energy change, ∆G,
and activation energy ∆G‡ provide insight into a reaction. The incorporation of electron
correlation effects in DFT allow for the computation of these thermodynamic quantities.15
However, because the functionals describing exchange interaction and electron correlation
is only known for a free-electron gas (through the Thomas-Fermi model16,17), DFT func-
tionals have been developed with a wide variety of solutions to describing the exchange and
correlation functionals. The choice of DFT functional is crucial to obtaining meaningful
data, and comparisons of DFT functional performances have been published for various
systems.18–20 The M06 suite of functionals21 has shown a broad applicability in calculation
of various reaction thermodynamics for a range of chemical systems, thus the M06-2X func-
tional was applied for all thermodynamic calculations in this work unless otherwise specified.
The 6-31+G(d,p) Pople-type basis set was applied for all optimization and thermodynamic
calculations unless indicated otherwise.
Energy calculations using an electronic structure approach such as DFT do not implicitly
include any temperature or pressure effects, that is, the quantities generated are only valid at
T = 0 K and p = 0 atm. One component of the thermodynamic calculation is the electronic
energy. The electronic energy is the calculated energy required to strip all electrons from
the atoms, and separate all atoms and electrons from each other infinitely far apart. To
include bulk effects based upon temperature, solvation and entropy, the theory of the Born-
Oppenheimer approximation22 is utilized. The Born-Oppenheimer approximation states
that the response of electrons to external perturbation is significantly more rapid than
that of a nucleus, such that the electron reorganization upon movement of a nucleus can
be viewed as nearly instantaneous. This approximation can be applied to incorporate
temperature effects by evaluating the total energy as a function of nuclear position on the
6Born-Oppenheimer potential energy surface (PES). The resulting Born-Oppenheimer PES
can be used to extract vibrational modes that can be used with the results of the DFT
calculation to describe thermodynamic quantities at finite temperatures and pressures. In
practice, a standard temperature of 298.150 K and pressure of 1.000 00 atm are used for
the calculation unless otherwise specified. From the incorporation of temperature and
pressure, thermal free energy (G) can be derived from the calculated enthalpy (H) and
entropy (S) terms. The combined value, sum of electronic and thermal free energies, in
solution represents the Gibb’s free energy of a system. This value is used for all free energy
calculations without further correction.
1.4 Methods for Locating a Transition State
A transition state (also referred to as a saddle point) is any point along a PES that has
a second derivative of energy with respect to the reaction coordinate that is negative,
but all second derivatives in another direction are positive. A transition state is uniquely
identifiable as having one and only one negative (imaginary) frequency. Transition states
are typically more difficult to locate than minima on the PES, but modern computational
software packages (e.q. Gaussian 0923) have provided algorithms to aid in their location.
The synchronous transit-guided quasi-Newton (STQN)24,25 and Berny26 are two algo-
rithms embedded into the Gaussian 0923 software package that are commonly utilized when
searching for a transition state. For the STQN algorithm, there are two further options,
originating from the quadratic synchronous transit (QST) approach, QST2 and QST3. For
QST2, a starting geometry and final geometry are provided, and the algorithm searches for
a saddle point along the path connecting those two points. The QST3 method is almost
identical except that an initial guess at the transition state is provided along with the
starting and final geometries. The Berny algorithm is the default optimization algorithm
Gaussian utilizes when performing standard geometry optimizations, and the method in
7which further optimization steps are chosen is altered in order to locate a transition state.
Once a saddle point has been located, there is no guarantee that it is actually a transition
state for the reaction under study. It is common to analyze the imaginary frequency to see
if the molecular vibration corresponds to the desired reaction. A more thorough method
to validating a given transition state is to carry out an intrinsic reaction coordinate (IRC)
analysis. Starting at the previously located transition state, this analysis tracks the molecule
down the PES in both the forward and backward direction. It continues until it reaches
the maximum number of steps set during the calculation, or when it reaches a minimum.
A successful IRC analysis provides a plot of the energy for each step along the PES back
to the reactant and toward the product. Using this method, a located transition state can
be confirmed for the pathway if the IRC leads to the expected minima along the reaction
coordinate (i.e., presumed reactant and product).
1.5 Solvation Modeling
An unmodified DFT calculation operates on the system without the presence of a solvent
(i.e., in the gas phase). In the condensed phase, solvents can play a significant role, influenc-
ing both conformational preference27 and reaction thermodynamics28 through interaction
with the solute molecules. Calculations in the condensed phase must then appropriately
model or account for these interactions either explicitly or implicitly.
Explicit modeling of these effects can be achieved by including individual solvent molecules
in the calculations. Calculations involving explicit modeling of solvent add substantial com-
plexity to the calculations by requiring additional interactions in the system.
Alternatively, models for defining the effect of the solvent on the solute implicitly, with-
out the need for defining individual solvent molecules, have also been developed. Implicit
8models benefit from greater simplicity in both computational complexity (or cost) and im-
plementation into a calculation for the user. Implicit models, also known as continuum
solvation models, define the solvent by a continuous medium and places the solute inside
this environment. The goal of implicit modeling is to accurately reflect electrostatic inter-
actions, dispersion effects, and cavitation changes that the solvent exerts on the solute. The
molecular cavity used is described by a series of interlocking van der Waals-spheres centered
on each atom of the solute. The radius of the spheres used is controlled by the protocol
selected for the computation.
2. Developing a Protocol for Facile
Computation of NMR Chemical Shifts
2.1 Introduction
The interrogation of organic reaction mixtures and structure elucidation by NMR spec-
troscopy is employed on a routine basis by experimental organic chemists. For even mod-
estly complex molecules, multiple types of NMR experiments are often required to fully
elucidate a molecules structure. The first commercial NMR instrument, the HR-30 by Var-
ian, was produced in 1952.29 Today, there is still continued interest in developing more
refined NMR experimental procedures aimed at structure elucidation.30,31 Computation of
these NMR chemical shift values can augment the current need for more advanced NMR
experimentation.
2.2 The Process of Calculating NMR Chemical Shifts
Calculating NMR chemical shifts at the most basic level involves a single calculation as
implemented in the Gaussian 0923 software utilizing the keyword NMR. The default method,
GIAO,10–14 calculates the magnetic shielding tensors of the individual atoms. Magnetic
shielding tensors of a shift reference (such as TMS) scale the values to the more under-
standable δ scale.
This analysis yields chemical shifts values for each atom in the geometry specified in
the program. However, since most molecular vibrations are of short duration on the NMR
timescale, the above method does not take into account the various conformations that
a molecule may sample during the course of an experimental NMR acquisition. Incorpo-
9
10
rating chemical shift values of multiple conformers can improve the matching between the
computed and experimental chemical shifts.
Incorporating multiple conformers into the chemical shift calculation is a twofold process.
The first step is to generate a set of conformers using a Monte-Carlo/multiple minimum
(MC/MM) search. This expands the conformational space sampled, providing a more accu-
rate representation of the conformers observed experimentally. After generating the set of
conformers, individual DFT geometry optimization calculations and frequency analysis of
each conformer is followed by calculation of each conformers NMR spectra. The thermody-
namic analysis provides relative energies of the conformers, which can be used to Boltzmann
weight the calculated NMR shifts, yielding a single set of averaged chemical shifts for the
structure.
2.2.1 Specific Implementation for Calculating NMR Chemical Shifts
To generate the initial set of conformers, a MC/MM conformational search was carried out
with Macromodel (v9.8)32 as implemented in Maestro (Schro¨dinger Software, v9.1.207).33
For each structure, the search utilized one of three force fields (AMBER94, OPLS 2005, or
MMFFs). A molecular mechanics (MM) current energy calculation was done utilizing each
of the three force fields. Whichever force field utilized the least number of medium- and
low-quality parameters for the energy calculation was picked for the conformational search.
The conformational search was conducted using MC/MM torsional sampling, keeping all
structures that fall within a 5.02 kcal/mol window.
After the conformational search, each conformer is exported to a Gaussian input for-
mat using a Python script developed by group member, Mr. Patrick Willoughby (write-
g09-inputs-default.py, A-1.1). Two files, one for running the geometry optimization/ther-
mochemistry calculation and one for the NMR calculation are generated from the script.
11
Geometry optimization is performed using the M06-2X21 functional with the 6-31+g(d,p)
Pople-type basis set. After optimization, frequency analysis is executed which includes a
calculation of thermochemical values for the system, including the Gibb’s Free Energy. Us-
ing the final geometry from the optimization, the NMR calculation is performed using the
B3LYP34–37 functional and the 6-311+g(2d,p) Pople-type basis set. Both the optimiza-
tion and NMR calculation are performed using the integral equation-formalism polarizable
continuum model (IEFPCM) solvation model,38–40 and typically in chloroform unless it is
otherwise noted. The radii of Bondi41 is used to calculate the moelcular cavity accessible
by the solvent (see section 1.5, page 8).
After calculating the NMR properties for each conformer, the script (nmr-data compilation.py,
A-2.1) performs a Boltzmann weighting of the conformers using the data from the thermo-
chemistry calculation. The chemical shifts for each conformer are scaled according to the
Boltzmann contribution calculated for that conformer. The combined sum of these scaled
shifts results in the average chemical shifts used to compare against experimental data.
2.3 Examining Optimization Protocols
Gaussian 09 calculates thermochemical information from the final optimized structure. The
standard optimization/thermochemical calculation protocol employed utilizes the opt key-
word without any modification, followed by a frequency analysis (using the freq keyword).
The geometry used for the frequency calculation must be a stationary point (in this case
a minimum) in order to obtain meaningful thermochemical data. As part of the frequency
calculation, an analytic Hessian matrix indicates if the input geometry is a stationary point
(by finding that the 2nd derivative of the PES is 0). Occasionally, the final geometry from
optimization is not a stationary point as determined by the analytic calculation of the Hes-
sian matrix. This occurs when the optimization utilizes an approximate Hessian matrix,
while the frequency calculation uses an analytically calculated Hessian. The thermochemical
12
information in this situation is not reliable.
We investigated a series of more rigorous optimization procedures, which more reliably
would ensure a minimum structure is obtained. The more rigorous the optimization options,
the longer the calculation takes. The large majority of structures we investigated were
tractable enough to allow for the most rigorous optimization to complete within a reasonable
time limit. Assessment of these protocols is based upon their computational speed and
reliability in finding a minimum structure.
Table 2.1 Optimization Procedures and Effect on Calculation Time
Entry # Optimization Protocol Relative Calculation Time
1 opt, freq 1.00
2 opt, opt=calcall 9.03
3 opt=calcfc, opt=calcfc, freq 8.20
4 opt=calcfc, opt=calcall 4.63
The default optimization (entry 1) is clearly the fastest method for optimization and
thermochemical calculation. However, as stated earlier, the optimization may not always
result in a geometry that is determined to be a stationary point during frequency analysis,
this results in inaccurate thermochemical results. Entry 2 utilizes an initial optimization
(with an approximate Hessian matrix) followed by an optimization with the calcall option.
The calcall option instructs Gaussian to calculate a new analytic Hessian matrix for each
optimization step, and then executes the frequency calculation after finding the stationary
point. Utilizing this option prevents the conflict where the final optimization geometry is
determined to not be a stationary point after the analytic Hessian matrix is calculated,
since the Hessian matrix is calculated at each optimization step. However, this benefit
13
comes at a significant computational cost. The cost can be especially high if numerous
optimization steps are required for the second optimization, when the Hessian matrix must
be calculated for each step. This occurs when the input geometry is greatly displaced from
the final geometry. The computational cost of this method could be decreased by reducing
the disparity between the final geometry of the first optimization and the finished optimized
geometry. In entry 2, this disparity is reduced by performing an initial optimization using
the computationally inexpensive opt protocol before the more expensive opt=calcall.
The protocol utilized for entries 3 and 4 uses the calcfc option. This option requests
that an analytic Hessian matrix be calculated for the starting geometry to guide the opti-
mization, but not every step as with the calcall option. Starting with the analytic Hessian
matrix will hopefully result in a final geometry that is closer to the geometry achieved from
the calcall optimization. The first attempt, entry 3, tried a two-step optimization with
one calcfc optimization followed by a second calcfc optimization. A subsequent frequency
calculation on the final geometry provides the thermodynamic information. While a slight
speed increase was obtained, the improvement was not satisfactory. Another protocol (entry
4) was tested, which combined the reliability of the calcall option and the decreased com-
putational cost of using the calcfc option to start the optimization. This combination gave
reliable thermochemical results (by ensuring a minimum stationary point was always ob-
tained) with a modest increase in computational cost. For future computational NMR work,
the protocol in entry 4 is used for all geometry optimizations unless a particular conformer
failed to optimize within the allowed time limits. In those cases, alternative multi-step
optimizations are employed to achieve full convergence prior to computing the NMR. The
default script (A-1.1) was updated to include a second output command in the Gaussian
input file for the calcall section of the protocol (write-g09-inputs-calcFCcalcall.py, A-1.2).
14
2.4 Methods of Analysis
The main way to evaluate the computed data is through statistical analysis compared to an
experimental spectrum. However, we have also developed a graphical comparison template
for the OriginPro software program for plotting the shift values of the spectra.
2.4.1 Statistical Analysis Methods
Statistical analysis methods are the primary resource used to evaluate the fit of computed
chemical shifts against an experimental spectrum. At least a partial assignment of the ex-
perimental spectrum is necessary in order to carry out this analysis. Correlation coefficients
(r), mean-absolute error (MAE), and CMAE are the three statistical parameters utilized
for comparison. Overall performance of the computational predication is assessed through
calculation of combined 1H and 13C values of these parameters, Eq. (2.1).42
MAEcomb =
√
MAEC ×MAEH (2.1a)
CMAEcomb =
√
CMAEC × CMAEH (2.1b)
rcomb = 1−
√
(1− rC)× (1− rH) (2.1c)
The CMAE is a MAE analysis after applying a linear correction to the computed values.
The CMAE analysis usually increase the difference between the CMAE value of the correct
computed/experimental pair and an incorrect computer/experimental pairing, improving
the possibility of identifying the structure corresponding to the experimental data. In all
cases, comparing the experimental spectrum with the correct structure’s computed spec-
trum is defined as a “matched” comparison, while any computed spectrum for an incorrect
structure is defined as a “mismatched” comparison.
The calculation of the MAE (or CMAE) involves pairing each computed shift with the
15
corresponding assigned experimental value. The definition for computing the MAE is:
MAE =
1
n
n∑
i=1
|δcomp,i − δexp,i| = 1
n
n∑
i=1
|ei| (2.2)
Where n is the number of chemical shift values, δcomp,i is the computed value of the ith
chemical shift, and δexp,i is the experimental value of the ith chemical shift. The value
δcomp,i − δexp,i can also be thought of as the error in the computed shift calculation of
the ith value, or ei. The CMAE, a derivation from this expression, is computed with the
following equations:
δcorr,i =
δcomp,i − a
b
(2.3a)
CMAE =
1
n
n∑
i=1
|δcorr,i − δexp,i| = 1
n
n∑
i=1
|ecorr,i| (2.3b)
For the CMAE analysis, a linear regression analysis of the computed and experimental shifts
gives the constants a and b which are used in Eq. (2.3a) to calculate the corrected shifts,
δcorr,i. The corrected shifts are then applied in a similar manner as the MAE to Eq. (2.3b),
where now the value ecorr,i represents the error in the corrected shift for the ith value. In
both cases, MAE and CMAE, a small value of ei or ecorr,i (typically ≤ 0.05 and ≤ 2 ppm
for 1H and 13C NMR respectively) for a computed structure corresponding to the correct
structure and larger values for computed shifts that have an incorrect structure compared
to the experimental structure. The correlation coefficient can have a value from -1 to 1,
with a value of 1 indicating an exact match between the computed and experimental shifts.
As an example to the analysis performed, the first step is to assemble a table (i.e.
Table 2.2). This example will utilize the analysis of cis-carvomenthone (201a, Fig. 2.1).
The table is set up so the corresponding shifts from the computed structure are matched
up with the assigned shifts of the experimental spectrum. After plotting the two data
sets, a linear regression analysis provides the values for the corrected shifts, Eq. (2.3a).
The original computed shifts, when compared against the experimental values provides
16
the “Error” column, and the MAE, while the new corrected shifts compared against the
experimental values provide the “Corrected Error” column, and the CMAE.
Fig. 2.1 Structure and Numbering of cis-carvomenthone (201a)
O
1
2
345
6
7
8
9
10
Hβ Hα
Table 2.2 Example MAE and CMAE Analysis of cis-Carvomenthone (201a)
Position Comp. 1H Exp. 1H Error
Corrected Corrected
Shifts Error
2 2.47 2.45 −0.02 2.39 0.06
3 α 1.87 1.87 0.00 1.83 0.04
3 β 1.70 1.68 −0.02 1.68 0.00
4 α 1.69 1.68 −0.01 1.67 0.01
4 β 1.88 1.68 −0.20 1.84 −0.16
5 1.61 1.68 0.07 1.59 0.09
6 α 2.36 2.33 −0.03 2.28 0.05
6 β 2.51 2.33 −0.18 2.42 −0.09
7 1.45 1.49 0.04 1.44 0.05
8 Me 0.90 0.91 0.01 0.94 −0.03
9 Me 0.88 0.89 0.01 0.92 −0.03
10 Me 1.06 1.10 0.04 1.08 0.02
(Corrected) Mean Absolute Errors: 0.05 0.05
17
In this example, we see that since the quality of the computed data is so high (an aver-
age absolute error across all 1H shifts of equal to or less than 0.05 ppm), there is little room
for the CMAE to improve the results. Shown in a separate table are the extra columns
for comparing the computed trans-carvomenthone (201b) with the cis-carvomenthone ex-
perimental data (a mismatched comparison, Table 2.3). In this case, the MAE starts at
Table 2.3 Example Mismatched MAE and CMAE Analysis of Carvomenthone (201)
Position
Comp. 201b Exp. 201a
Error
Corrected Corrected
1H 1H Shifts Error
2 2.48 2.45 −0.03 2.38 0.07
3 α 1.29 1.87 −0.44 1.39 0.48
3 β 2.12 1.68 0.58 2.08 −0.40
4 α 1.87 1.68 0.13 1.87 −0.19
4 β 1.55 1.68 −0.19 1.60 0.08
5 1.55 1.68 0.13 1.60 0.08
6 α 2.33 2.33 0.09 2.25 0.08
6 β 2.24 2.33 0.00 2.18 0.15
7 1.51 1.49 −0.02 1.57 −0.08
8 Me 0.91 0.91 0.00 1.06 −0.15
9 Me 0.89 0.89 0.00 1.05 −0.16
10 Me 0.92 1.10 0.18 1.07 0.03
(Corrected) Mean Absolute Errors: 0.15 0.16
0.15 ppm, and after the CMAE correction, increases to 0.16 ppm. The difference between
in the CMAE for match and mismatched increases by 320 %. This increase in disparity
between the two proposed structures demonstrates the utility of the CMAE analysis even
for small, relatively well-defined organic molecules. Additionally, this type of analysis is
useful even if only partial assignment of the experimental spectrum is possible. For this
example, the chemical shifts of position 3β, 4α, 4β, 5, 6α, 6β were unable to be unambigu-
ously assigned. If we repeat the analysis, including a new linear regression analysis with
only the remaining shifts, a larger separation between matched and mismatched errors is
observed for both MAE and CMAE (Table 2.4). An analogous process can be carried out
with 13C data.
18
Table 2.4 Summarized MAE and CMAE Results for cis-Carvomenthone Before and After
Removal of Uncertain Shifts
Matched Mismatched
Full Set of Shifts
MAE 0.05 0.15
CMAE 0.05 0.16
Partial Set of Shifts
MAE 0.02 0.14
CMAE 0.02 0.16
2.4.2 Qualitative Graphical Analysis
Statistical analysis is valuable for quantitative assessment of the fit for a computed data
set to an experimental spectrum. However, it is limited to meaningful application only
when some reasonable amount of assignment or correlation between the computed and
experimental shifts can be made. It can also be time consuming to correlate the shifts
to the experimental values, perform linear regression analysis, and recompute errors (for
CMAE) to arrive at a result. We needed a way to quickly dismiss stereoisomers, that due
to the distribution of chemical shifts on the spectrum, cannot be possible structures of the
experimental spectrum under analysis. These two factors prompted the design of a graphing
template that could quickly aid in comparison of possible structures and their NMR spectra.
Using the data analysis software OriginPro from OriginLab®, we have developed two
graph templates (one being Fig. 2.2) which provide a stacked comparison of two data sets
(any mixture of computed and experimental sets can be combined).
19
Fig. 2.2 Example of a Stacked Graphical Comparison
4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
33 4
5
5
6 67
8iPrCH
9iPrMe
10iPrMe
11Me
3 3 4 5
5
6 67
8iPrCH 9iPrMe
10iPrMe
11Me
O
O
5
2
3
4
6
7
8
1
12
11 9/10
proR/S
9/10
proR/S
H
H
C
i s
Chemical Shift (ppm)
Cis/Trans Normal Menthide
Computed 1H Values (CHCl3)
 
T r
a n
s
This template is useful in analyzing an experimental NMR spectrum when considering
one or more diastereomers. Regions of the computed NMR spectra where shifts are present
in only one of the diastereomers can be used as a guide for examining the experimental spec-
trum. In Fig. 2.2, only the trans diastereomer shows a shift in the ∼1.25 ppm region. Recall
that the average error in computed 1H chemical shifts for a “matched” comparison is often
less than 0.1 ppm, so even the fine differences in chemical shift in the 1.25 ppm region can
be used to guide the interpretation. Utilizing the template with an experimental spectrum
showing a shift at ∼1.25 ppm would quickly lead to a determination that the compound is
likely the trans diastereomer. The graphical comparison can aid in comparing the rest of
the peaks, or a formal statistical analysis could be performed with any peaks that have been
20
assigned. In this example, the relatively simple comparison is only between two possible
diastereomers. To address the complexity of quickly scanning multiple diastereomers, we
also developed a similar graphing template to allow plotting of up to four diastereomers.
2.5 Comparison of our Protocol with a Previously
Computed Natural Product
We begun testing our protocol on a natural product, nankakurine (202, Fig. 2.3), which was
previously calculated by Goodman and coworkers.43 Nankakurine was chosen for the com-
plex magnetic environment with through-space shielding, but was also simplified through a
rigid molecular structure reducing conformational flexibility. Two diastereomers, the revised
diastereomer (202a) and the originally proposed diastereomer (202b), were compared. The
epimeric center is indicated by a “*”.
Fig. 2.3 Nankakurine Natural Product Used to Test NMR Computation
N
H
N
CH3
CH3
Nankakurine
N
NH
CH3
CH3
202a 202b
For the 202 system, we found restricted conformational flexibility, observing only four
conformers for each epimer. However, within those four conformers, the 202 structures show
some significant conformational changes. There are four total conformers, in two distinct
sets (representing each chair flip of the molecule). Within each set of chair-flip conformers,
we observe a second conformer resulting from the nitrogen atom inversion at N1 (Fig. 2.4).
21
Fig. 2.4 Conformers of Nankakurine
0.00 kcal 0.160 kcal
0.624 kcal0.589 kcal
a)
c)
b)
d)
N1
N1
N1 N1
Conformer pairs a/c and b/d are related by nitrogen inversion
Conformer pairs a/b and c/d are related by chair-chair flips
Performing the statistical analysis on the system of 202 diastereomers, we found that the
CMAE values were very closely matched for both the correct and incorrect diastereomer.
From analysis of this system, we learned that due to the small structural change result-
ing from the diastereomeric pair, and the almost analogous conformational space sampled,
22
the majority of the shifts calculated were relatively well isolated from the change in di-
astereomer. In as, both diastereomers sampled the exact same four types of conformers
(chair-chair flip, and nitrogen inversion), as well as most of the protons are in roughly the
same environment, regardless of diastereomer analyzed. This results in CMAE values that
are both very low (0.054 and 0.072, respectively). However, we were encouraged by the
results in that, comparing the accuracy of our computed set (r, MAE and CMAE), to those
of Goodman,43 we observe a 37.9 % decrease in the CMAE (Table 2.5).
Table 2.5 Comparison of Our Protocol and Goodman’s on Computed Nankakurine Shifts
Matched Mismatched
Our Data Goodman Data Our Data Goodman Data
1H
r 0.9894 0.9508 0.9828 0.8570
MAE 0.104 0.108 0.130 0.177
CMAE 0.054 0.087 0.072 0.151
13C
r 0.9946 0.9865 0.9924 0.9804
MAE 4.108 1.505 4.026 1.622
CMAE 1.009 1.179 3.400 1.417
Combined
Parameters
rcomb 0.9924 0.9869 0.9885 0.9730
MAEcomb 0.653 0.403 0.724 0.536
CMAEcomb 0.233 0.322 0.494 0.461
Having verified the accuracy of our protocol to compute structures of moderate com-
plexity, and compare them to previous calculations, we attempted to extend our protocol
to calculations relevant to work within our group and collaborations. A central goal to
these investigations is to demonstrate the straightforward application of our protocol and
23
accompanying scripts to enhance analysis of the experimental NMR spectra.
2.6 Evaluating Stereoisomers of Bioderived Lactones
Lactones are a useful substrate in ring opening transesterification polymerization (ROTEP)
reactions,44 a growing field in the area of polymer synthesis. As polymers are used in
wide variety of daily products, there is a large incentive to use substrates that are derived
from renewable sources. In the Hoye group, Drs. Aman Kulshretha and Susanna Emond
investigated the synthesis of bio-derived lactones, Fig. 2.5.
24
Fig. 2.5 Set of Bio-derived Lactones Synthesized
O
O
O
O
O
O
O
OO
O
"Normal"
Lactones
"Abnormal"
Lactones
203
204 205
206 207
1“Normal” lactones are defined as containing the oxygen
on the more substituted side of the carbonyl
2“Abnormal” lactones contain the oxygen on the less
substituted side of the carbonyl.
The configuration of the stereocenters in the lactone influences the properties and type
of polymer synthesized.45 Previous work involving these lactones utilized low field-strength
NMR analysis, resulting in both overlapping resonances as well as an incomplete assignment
of all chemical shifts. We aimed to fully characterize the NMR spectra of these compounds
with the aid of computationally predicted NMR chemical shifts.
25
2.6.1 Lactones Derived from β-pinene: A Small Molecule Test Case
The lactones, 206 and 207 derived from the parent molecule β-pinene, were ideal candidates
to test our protocol on. There is limited conformational space to sample the molecule over
as the constrained [4.1.1]bicyclic skeleton limits the flexibility of the molecule. We could
also examine through-space shielding effects as one of the methyl groups will be placed
almost directly above the lactone ring. In order to compare the computationally predicted
chemical shifts against experimental data, Dr. Kulshretha prepared 206 and 207 through
Baeyer-Villiger oxidation of nopinone (208, Scheme 2.1). The oxidation generates both the
normal and abnormal lactones as a mixture.
Scheme 2.1 Synthesis of Normal and Abnormal β-pinene Lactones from Nopinone
O
OO
OO
m-CPBA
DCM, 80 °C
208 206 207
The comparison of computed shifts for a matched and mismatched structure is not
necessary here, as the chemical shift differences for each molecule are easily distinguished
by experimental NMR. Specifically, 207 contains two proton resonances next to the lactone
oxygen, while 206 only contains one proton resonance. However, we could still examine the
accuracy of the computed shifts for each structure (Table 2.6). Additionally, the computed
shifts (and the geometries from their calculation) would prove to be a valuable aid in
completing a full assignment of the experimental NMR spectra.
26
Table 2.6 Statistical Matching Parameters of Computed Shifts of β-Pinene Lactones
206 207
1H
r 0.9956 0.9980
MAE 0.088 0.080
CMAE 0.073 0.063
13C
r 0.9996 0.9997
MAE 4.064 4.474
CMAE 1.128 0.914
Combined
Parameters
rcomb 0.9986 0.9993
MAEcomb 0.598 0.598
CMAEcomb 0.287 0.239
We observed that the computed shifts match extremely well for both the normal and
abnormal lactones. For the 1H predicted shifts, the CMAE values of 0.088 and 0.080
indicate a high degree of agreement between the computationally predicted shifts and the
experimental values. Through the course of this project, we observed that the lowest 1H
CMAE values achieved are in the range of 0.05 to 0.1 ppm. Linear scaling of the shifts
can also have a significant impact on the computed error, as evidenced by the decrease in
error between the MAE and CMAE. The large decrease, especially for the 13C comparison
indicates the protocol contains a systematic error in the computation of the chemical shifts
(a similar effect was observed for nankakurine, 202, page 20).
Analysis of these lactones presented the opportunity to examine other NMR shift effects,
such as the through-space shielding effects experienced by the methyl group (and proton)
positioned directly over (and under) the lactone ring. The computed and experimental
27
values are summarized in Table 2.7. The maximum absolute error for any single proton
after linear correction was 0.15 and 0.11 ppm for the normal and abnormal lactones. While
the minimum absolute error was only 0.01 ppm for both lactones. We can see that especially
for the methyl groups, the predicted shifts are in excellent agreement with the experimental
values. In these bridged systems, we define the syn position of the bridge to be pointing
towards the ring system, while the anti position is defined as pointing away from the ring
system (see 3D model, Fig. 2.6, page 28). It appears that the syn protons were less well
predicted than the anti protons, while the methyl groups are predicted accurately to nearly
the same extent.
Table 2.7 Accuracy of 1H Computation for Bridging Methyl and Methylenes
Normal Lactone, 206 Abnormal Lactone, 207
Comp. Exp. Exp-Comp Comp. Exp. Exp-Comp
Methyl
Syn 0.88 0.89 0.01 1.08 1.04 −0.04
Anti 1.28 1.30 0.08 1.39 1.38 −0.01
Methylene
Syn 2.22 2.11 −0.11 2.39 2.30 −0.09
Anti 2.59 2.65 0.06 2.42 2.45 0.03
During assignment of the experimental NMR spectra, we found great utility in using
the optimized geometries determined for the NMR calculations. Guided by the Karplus
equation,46–48 we could use the computed geometries to inspect dihedral angles of specific
coupling interactions and verify the observed coupling constant was consistent with the
geometry.
The computed geometries also allowed us to interrogate interatomic distances. In order
to confirm the syn/anti orientation of the bridging methyl groups and the methylene (–
28
CH2–) hydrogens, a nuclear Overhauser effect (NOE) experiment can provide information
about the proximity of neighboring protons to the selected proton. The signal enhancement
observed can be correlated to interatomic distance with high accuracy for protons less than
4.0A apart.49 We used the computed geometries to guide our NOE experiment by select-
ing protons with interatomic distances well-suited for observation by an NOE experiment
(Fig. 2.6). The syn position is defined as facing towards the ring, while the anti position is
defined as facing away from the ring.
Fig. 2.6 Selected Interatomic Distances of Protons in β-Pinene Normal Lactone
2.703
2.260
3.772
2.291
3
6
9
8
5
4.038
Syn
Anti
Anti
Syn
1All distances reported are in A.
2Selected carbon numbering is given in cyan.
According to the computed interatomic distances, we planned that irradiating the “ax-
ial” proton on C3 should provide an NOE enhancement to the proton signal of the syn
methyl group, C9, but little to no signal for the anti methyl group, C8. We were then
guided by the large difference in interatomic distance between the anti methyl group, C8
and the two bridgehead methylene protons on C5. Irradiating the anti methyl group should
provide a large enhancement for the anti proton on C5, and minor if any enhancement for the
syn proton on C5. Through this two-step approach, we could confirm the syn/anti assign-
29
ment of both methyl groups on the bridgehead carbon, C7, and the methylene bridgehead
protons on C5.
2.6.2 Lactones From Menthone and Carvone: Pairs of Diastereomers
We continued our computational prediction of chemical shifts by extending the method to
analyzing pairs of diastereomers in a series of bio-derived lactones (Fig. 2.7). These lactones
have no thorough NMR characterization present in reported literature. The lactones are
derived from the corresponding parent compounds, menthone (209) and carvomenthone
(201), which are synthesized by Dr. Emond as separate diastereomers. Evaluation of
these compounds as diastereomers seems unnecessary at first. However, because there is no
thorough NMR characterization available in the literature, simple comparison to determine
the configuration was not possible. The accurate determination of the configurations in
these substrates is critical for understanding the resulting properties of polymers derived
from their use (see page 24).
30
Fig. 2.7 Lactones Derived from Menthone and Carvomenthone
O
O
O
O
O
O
O
O
O
O
O
O
O O
Menthone Carvomenthone
209 201
203a
203b
204a
204b
205a
205b
Statistical Comparison of the Normal cis/trans-Menthide
The menthide lactones are the first to be examined. This data set proved to be especially
troublesome, as all attempts to fully optimize the conformers of the normal cis-menthide
proved to be unsuccessful, failing to locate a minimum stationary point. The comparison for
this set will then be for only the experimental cis and trans compared against the computed
trans chemical shifts (Fig. 2.8).
31
Fig. 2.8 Diastereomers and Numbering Scheme of Normal Menthide
O
O
1
2
3 4
5
6 7 8
9
10
Hβ Hα
O
O
1
2
3 4
5
6 7 8
9
10
Hβ Hα
203a 203b
For this series, Dr. Emond was able to conclusively assign all the 13C resonances. In
the 1H data, there were some overlapping peaks that could not be resolved. Discussion
will relate only to the findings for the trans diastereomer since computed data for the cis
diastereomer is not available.
In the trans diastereomer, the H3β, H5, and H7 resonances were all overlapped in the
range of 1.85 ppm. This overlap did compare well with the computed results obtained, as
both H5 and H7 were computed to be at 1.75 and 1.78 ppm respectively. The computed
value of H3β was computed to be 1.91 ppm, however the overlapping region was broad so
distinction between these peaks was difficult. The largest error between the computed and
experimental value was for H6α, at 0.12 ppm. Throughout the course of this project, it
was observed that protons residing near heteroatoms, and pi systems are typically the least
reliable in terms of accurate computation. However, the overall CMAE for the computed
trans against the experimental trans values was only 0.05 ppm. This is contrasted with the
CMAE for the experimental cis against the computed trans which was at 0.20 ppm. Recall
that typically, values for a matched strongly matched comparison is below 0.1 ppm.
Due to the larger spectral width of the 13C NMR, Errors in the 13C NMR, when com-
paring computed and experimental data tend to be larger, due to the larger spectral width
in a 13C NMR experiment. Additionally, accurate computation of shifts near or part of a
32
pi systems is a common difficulty encountered throughout this project. In the case of com-
puting 13C shifts, the unscaled computed shift for C1 in the trans compound is 185.51 ppm,
while the experimental value is assigned at 174.80 ppm. For this protocol employed, these
pi system shifts are consistently over-predicted. In this menthide series, the other peaks
that were difficult to predict were those of the methine carbons, specifically, C3 and C7.
These both had corrected errors of over 2.0 ppm, while the majority of corrected errors
are well below 1.0 ppm. The C8 methyl group also shows a large error of 2.67 ppm, which
is likely due to the proximity to the lactone portion, influencing the chemical shift. The
observed chemical shift for the two methyl groups are 18.10 and 16.80 ppm with C8 being
more downfield.
Analysis of Carvomenthides from Carvomenthone
Dr. Emond used both the mixture and the pure substrates, separated by medium-pressure
liquid chromatography (MPLC), in the preparation of the carvomenthides (204a – 205b,
Scheme 2.2). Treatment of the lactone with meta-chloroperoxybenzoic acid (m-CPBA) and
trifluoroacetic acid (TFA) provides the Baeyer-Villager oxidation products (204a – 205b).
33
Scheme 2.2 Synthesis of Carvomenthides from Carvone
O
MPLC
sepn.
O
O
O
O
O
O
O
O
O
O
mCPBA (2 equiv)
CF3CO2H (1.1 equiv)
DCM, rt
mCPBA (2 equiv)
CF3CO2H (1.1 equiv)
DCM, rt
Carvone
201a
201b
204a
204b
205a
205b
Computation of the chemical shift for the complete set of lactones was also completed
during this time. Before statistical analysis of the lactones could take place, spectral assign-
ment of at least some key resonances were needed. In this instance, the use of the graphical
output (Fig. 2.2) for the computed shifts proved a useful tool for Dr. Emond to quickly
distinguish relevant peaks in the complex NMR spectra.
Additional data computed during the calculation of the chemical shifts also proved
quite valuable. In particular, the thermodynamic computation and Boltzmann weighting
of the conformers had an occasion to provide useful insight into the dominant conformer
in a population. In particular, during the analysis of the normal carvomenthides, the cis
diastereomer (204a) showed a conformational preference for a chair-like conformation where
the isopropyl group occupied an axial position (Fig. 2.9).
34
Fig. 2.9 Lowest Energy Conformer of Normal cis-Carvomenthide (204a)
This conformer of 204a was the predominant conformer predicted. The relative energy
of the next lowest energy conformer was 1.49 kcal higher than this conformer, and was the
chair-chair flip conformer. Visualizing this “non-intuitive” conformer, guided evaluation of
coupling constants. In particular, Dr. Emond was guided to assess a long-range W-coupling
interaction only present due to the axial orientation of the isopropyl group.
A similar effect was also observed for the lowest energy conformer of the abnormal cis-
carvomenthide (205a) diastereomer. In this diastereomer, the isopropyl group was also
found to occupy an axial position as the dominant conformer. In this case, the difference in
relative energy for the next lowest energy conformer was even greater, at 2.08 kcal higher
than the conformer with the isopropyl group axial. Again, Dr. Emond was able to utilize
the conformational data generated even before thorough analysis of the computed shifts
was complete. The conformational predication confirmed the experimental NMR findings
(Fig. 2.10).
35
Fig. 2.10 Conformational Preference and Supported NMR Assignments of Abnormal cis-
Carvomenthide (205a)
1
2
3 4
5
6
7
8
9
10
β
α
ddd 12.9, 4.2, 1.7 Hz
dd, 12.8, 1.4 Hz
ddq, 9.0, 4.4, 6.7 Hz
The experimental spectrum revealed only a single large coupling for H2, and also a single
large coupling for both H6β and H6α. The lowest energy conformer by 2.08 kcal (Fig. 2.10),
with the isopropyl group axial, is the only way to satisfy the requirements of the observed
coupling constants. If a conformer of a chair-chair flip were the dominant conformer, then
H6β would have a large two large coupling constants. One geminal, and one vicinal to the
now axial proton on C5.
Once Dr. Emond had completed her NMR assignments, the data was passed to me to
perform the statistical comparison of the computed and experimentally measured chemical
shifts for the three sets of lactones (203, 204, 205).
Statistical Comparison of Normal cis/trans-Carvomenthide
Both sets of computed chemical shifts were obtained for the normal carvomenthides (204).
Additionally, the experimental spectra for these compounds were more resolved and sep-
arated than those of the normal menthide series. The analysis will include comparison of
36
both diastereomers (Fig. 2.11) compared against both sets of computed chemical shift data.
Fig. 2.11 Diastereomers and Numbering Scheme for Normal Carvomenthide
O
O
1
2
3 4
5
6
7
8
9
10
Hβ Hα
O
O
1
2
3 4
5
6
7
8
9
10
Hβ Hα
204a 204b
For this pair of diastereomers, Dr. Emond was able to assign with great certainty
the trans diastereomer. The cis diastereomer proved more difficult as mentioned earlier, it
adopts an unusual conformational orientation with the isopropyl group in the axial position.
This locked conformation did facilitate observation of some long range-coupling within the
molecule to aid in the assignment.
In a similar situation as before, we observe that the computed shifts for the atoms next
to the carbonyl group (H3α/β) typically suffer the greatest in accuracy. Surprisingly, the
cis diastereomer has fairly accurate computation of those values. After scaling the shifts,
the errors drop to =0.05 and 0.00 ppm. However, the scaling for the cis diastereomer was
assisted slightly as some peaks were not assignable, so could not be included. This reduces
the number of data points to fit the linear regression line to, which reduces complexity
and the chance of outliers skewing the fitting results. In the trans diastereomer, which is
fully assigned, the H3α/β errors are more in line with the typical expectation of 0.11 and
=0.12 ppm.
The effect of switching from cis to trans has a large effect on the 4β proton shift. In
the trans diastereomer, the shift is predicted to be 1.53 ppm, while in the cis diastereomer,
it is 2.04 ppm. The CMAE values are summarized, highlighting how distinct the two sets
37
of computed shifts are (Table 2.8).
Table 2.8 Calculated CMAE Values for Normal Carvomenthide (204)
Experimental
204a 204b
Matched Mismatched Matched Mismatched
Computed
1H 0.04 0.13 0.05 0.19
13C 1.16 2.79 1.26 1.21
Solely relying on the computed 13C shifts for the assignment of the trans diastereomer
may have lead to the wrong answer. However, on the scale of 13C errors, a difference of only
0.05 ppm would be considered inconclusive. Looking to the provided 1H comparison would
then give a clear indicator that the correct assignment is in fact to the trans diastereomer,
based on a CMAE of 0.05 ppm for the matched trans configuration, compared to 0.19 ppm
for the cis configuration.
Statistical Analysis of Abnormal cis/trans-Carvomenthide
Analysis of the abnormal cis/trans-carvomenthide is the last pair of diastereomers analyzed
using our NMR computation protocol. It is also the only set that has a fully assigned
experimental spectrum, so a complete analysis of the shifts is possible. The abnormal
carvomenthide diastereomers (Fig. 2.12) were found to be one of the more straight-forward
pairs to analyze. With only minor guidance from the computed shifts, Dr. Emond was able
to assign the trans diastereomers shifts fully.
38
Fig. 2.12 Diastereomers and Numbering Scheme for Abnormal Carvomenthide
O
O
1
2
3
4
5
6
7
8
9
10
Hβ
Hα
O
O
1
2
3
4
5
6
7
8
9
10
Hβ
Hα
205a 205b
The optimization process showed that, unsurprisingly, the trans diastereomer prefers
a conformer where both the isopropyl and methyl group are equatorial. However, initial
evaluation of the experimental NMR was not as clear cut as the DFT calculated geometries.
Through collaborative work, H2 was found to have a unique shift and a large (i.e., 10.9 Hz)
coupling constant which indicated an axial orientation. This led to the conclusion that the
experimental NMR and computed geometry were in agreement.
The experimental NMR data for the cis diastereomer was more problematic. With the
guidance of 3D models from the NMR computation, we could probe the various coupling
constants and orientations of the molecule. We were fortunate that there was only one
conformer present in any significant quantity. This allowed for use of the computed geometry
to aid in the coupling constant analysis.
The simple coupling constant analysis may have damaged the quality of the computed
NMR data, by facilitating full assignment of the experimental spectrum. In looking at
the CMAE value for the cis diastereomer, the matched and mismatched values are 0.11
and 0.10 ppm respectively. When a full set of computed and experimental shifts can be
matched up, the impact of outliers can negatively impact the assignment. In this case, the
computed shift for both H3β and H4β in the cis diastereomer show corrected errors of 0.40
and =0.51 ppm. Removing these two outliers from the analysis results in a CMAE decrease
39
to 0.04 ppm. We are confident in our assignment of the experimental spectra, so in this case,
these values are not erroneous and should be included in the analysis. However, utilizing
shifts with uncertain assignment can be troublesome for this very reason. The matching for
the trans isomer is very good, with a CMAE value of only 0.05 ppm, compared to the other
1H CMAE values (Table 2.9).
Table 2.9 Calculated CMAE Values for Abnormal Carvomenthide (205)
Experimental
205a 205b
Matched Mismatched Matched Mismatched
Computed
1H 0.11 0.10 0.14 0.05
13C 1.70 2.51 1.72 1.33
2.7 Concluding Remarks
The computation of NMR chemical shifts is not only manageable and straight-forward, but
the utility of such data is invaluable for the assessment of complex NMR spectra. In this
chapter, the ability of a rapid and reliable NMR computation protocol was compared first
against another method for distinguishing between diastereomers. The protocol was then
tested against a previously unknown set of compounds, which prior to their assignment had
little to no experimental data available in the literature. We also gained further under-
standing of the conformational and stereochemical properties of these lactones for use in
the development new biorenewable polymers.
Further, the utility of non-chemical shift related data generated in the process was shown
to be crucial answering various questions that arose. The thermodynamic preferences, and
visualization of the conformational space sampled both provide clues and information that
are helpful in completing an NMR chemical assignment of a complex product.
3. Examining Thermodynamics of Benzyne
Formation and Reaction
3.1 Introduction to Benzyne: Structure, Formation and
Reactivity
3.1.1 The Structure of Benzyne
The aryne class of compounds are a set of neutral, reactive organic intermediates, formally
derived from a parent arene by abstraction of two hydrogens. These reactive intermediates
were first described in 1902 by Stoermer and Kahlert, when they described the existence of
the aryne derived from β-elimination of 3-bromobenzofuran.50 The simplest aryne however
is benzyne (301), derived from the parent arene, benzene (302), and while the first aryne
was described in 1902, it wasn’t until 1927 that the presence of benzyne was used to ratio-
nalize a reaction outcome.51 There are three possible isomers of benzyne, named according
to the relative position of the two unpaired electrons to each other (Fig. 3.1). Henceforth
“benzyne” will refer to the ortho- isomer (301).
Fig. 3.1 Isomers of Benzyne
ortho-benzyne meta-benzyne para-benzyne
301 302 303
The ortho- isomer of benzyne (301), also referred to as 1,2-didehydrobenzene is fre-
quently utilized in organic synthesis as a reactive intermediate. The para- isomer (304) is
ubiquitous in biological pathways, and is a key intermediate in the Bergman cyclization.52
40
41
The meta-benzyne (303) isomer’s existence and structure is still under active investigation,
utilizing work in mass spectrometry,53 scanning tunneling microscopy54 and computational
chemistry.55
There are multiple ways of representing the structure of benzyne (Fig. 3.2). Some
representations include the “allene” form (301a), the “alkyne” form (301b), and the kekule´
form (301c). These forms are especially pertinent to research conducted in our lab towards
the synthesis of 301 (discussed in 3.1.3), where 301a best represents the initial structure
after initial formation, and 301b & 301c best represent the reactivity observed for 301.
Fig. 3.2 Various Representations of Benzyne
"Allene" "Alkyne" "Kekulé"
301a 301b 301c
3.1.2 Reactivity of Benzyne
Looking at representations 301b and 301c we see that benzyne can be considered as a
benzene ring containing a triple bond. The reactivity of benzyne arises from the strain
placed on the six-membered ring by the inclusion of a triple bond. Considering that the
optimum orientation for the p orbitals forming a triple bond is achieved when the two
orbitals are aligned parallel to each other with a dihedral angle of 0°, a large distortion is
observed for the triple bond of benzyne. In benzyne, the p orbitals involved in the triple
bond are pointed away from each other, resulting in diminished electron density between
the two carbon atoms (Fig. 3.3).
42
Fig. 3.3 Overlap of the p Orbitals in Benzyne’s Triple Bond
Orbitals generated from NBO56 analysis and
visualized with an isovalue of 0.08
3.1.3 Synthesis of Benzyne
Formally, the generation of 301 is a 1,2-elimination from 302, and in the most basic version,
this elimination is simply an abstraction of two hydrogens (Scheme 3.1). However, this
pathway is not synthetically feasible. Various methodologies have been developed for the
generation of benzyne, most often pairing the elimination of one substituent with a second
stable leaving group to facilitate the elimination, or through extrusion of highly-stable gases.
These methods have been reviewed previously.57
43
Scheme 3.1 1,2-Elimination of an Arene to form an Aryne
H
H
1,2-Elimination
302 301
In addition to the previous methodology for generation of benzyne, Dr. Beeraiah Baire
observed cyclization of a linear tetrayne precursor 305 to a tricyclic benzenoid product 306
(Scheme 3.2).
Scheme 3.2 Cyclization of a Linear Tetrayne to Benzenoid 306
O
TBS
MnO2, CH2Cl2
room temperature
5h, 53 %
HO OTBS
OTBS
O
TBSO
305 306
We proposed that this product arises by a [4 + 2] cycloaddition, or hexadehydro-Diels-
Alder (HDDA) reaction, of 305 to give a benzyne intermediate 307. This reactive benzyne
intermediate then undergoes intramolecular trapping by the silyl ether through a net 1,3-
migration (proceeding through zwitterion 308) of the silyl group from the ether oxygen to
the distal benzyne carbon, yielding the final benzenoid 306 (Scheme 3.3).
44
Scheme 3.3 Mechanism of Benzenoid Formation from Linear Tetrayne
MnO2, CH2Cl2
room temperature
5h, 53 %
O
Si tBu
O
Si tBu
O
TBS
O
Si tBu
HO OTBS
OTBS
O
O
TBSO
TBSOTBSOTBSO
O O
305
309
307308306
In this mechanism, we see that from the initial [4 + 2] cycloaddition of 305, we arrive at
a resonance form of benzyne, 309, analogous to that of 301a described earlier. The available
scope of this reaction has been extensively tested and further work on this reaction is pursued
by members in the group. While pursuing synthetic work to broaden our understanding of
the scope for this transformation, we turned our attention towards gaining insight into the
thermodynamics of this transformation and the subsequent reactions. These calculations
utilized the conductor-like polarizable continuum model (CPCM) solvation model58,59 with
universal force field (UFF)60 radii in chloroform solvation unless otherwise specified.
45
3.2 Ring-Size Restrictions on Fused Benzynocycloalkane
Formation
During the initial investigation of this reaction, it was observed that a combination of elec-
tronic and steric effects in the starting triyne influenced the temperature required, rate and
efficiency of the transformation in Scheme 3.2. An additional variable was the atom-length
of the tether that connected the alkyne and diyne pieces together. The transformation of a
pure hydrocarbon triyne into benzyne (310 to 311, Scheme 3.4) has only been achieved un-
der very high temperature and low pressure (600 ◦C and 10=2 torr) by Johnson and cowork-
ers.61,62 Still, this most basic model system was an ideal choice for modeling this reaction
of 310, and used to study the effect tether length had on the thermodynamics of forming
the benzyne intermediate.
Scheme 3.4 Model to Examine Thermodynamics of Benzynocycloalkane Formation
7-n7-n
n
n
n
1
2
3
a  
b  
c
310 311
We predicted that with decreasing ring size, the increased strain would eventually result
in an unfavorable (∆G > 0) reaction. The added hydrocarbon “tail” was added to allow
for direct comparison of thermodynamic results (Table 3.1) between different ring sizes, by
either removing or adding carbons to the “tail” as the ring size changed. The addition
of the “tail” was shown to have no effect on the overall trend or calculated ∆G values by
calculation of the analogous reaction (Scheme 3.5) for triynes containing no “tail” (∆G w/o
tail).
46
Scheme 3.5 Analogous Model Benzynocycloalkane Formation without Extra “Tail”
n
n
n
1
2
3
a  
b  
c
312 313
The difference in measured ∆G values is likely due to the large flexibility in the “tail”
portion. The large flexible portion causes the PES to have a wide and shallow minimum,
which adds variable amount of error to the calculation. However, the two model reactions
show agreement in the overall trend and approximate magnitude in differences between the
various ring sizes.
Table 3.1 Calculated ∆G Values for Benzynocycloalkane Formation from 310 and 312
Entry #
∆G Rel. ∆G ∆G w/o “Tail”
kcal/mol kcal/mol kcal/mol
a 20.85 0.00 19.23
b −9.37 −35.29 −12.61
c −35.14 −62.24 −38.14
In the three tether lengths examined, only the tether corresponding to formation of the
benzynocyclopropane 311a showed a free energy corresponding to an unfavorable reaction.
Surprisingly, even the formation of the four-membered benzynocyclobutane 311b showed an
overall free energy change corresponding to =9.37 kcal/mol, and was over 35 kcal/mol lower
in energy than that of 311a. Having previously observed formation of a five-membered ring
(306), it was expected that this would show a favorable free energy.
47
A second isomer of the fused cyclobutane 313b exists, namely the ring-opened diene
(314). The thermodynamic impact of maintaining the fused bicyclic system was investi-
gated by computing the change in free energy from 313b to 314 (Scheme 3.6).
Scheme 3.6 Ring-Opening of Benzynocyclobutane to a Diene
313b 314
By undergoing the ring-opening, the strain from the four-membered ring is relieved.
However, a computed change in free energy of 9.95 kcal/mol indicates that the resulting
ring-opened diene is less stable than the fused bicycle. As a comparison, the calculated ∆G
for the analogous reaction with the extra “tail” extension calculated to be 9.22 kcal/mol.
Opening the cyclobutane ring results in loss of strong aromatic character to one of at least
non-aromatic properties. The measurement of the bond length alternation (∆R), defined
as the difference between the longest and shortest bond in the ring, provides an indication
of aromatic character.63 Molecules that are aromatic in nature will have a small ∆R, while
anti-aromatic molecules will have a high ∆R. The calculated ∆R for 314 is almost twice
that of 313b (the full list of bond lengths is given in Table 3.2). Additionally, when the
cyclobutane undergoes ring-opening, the two methylenes are allowed to twist to avoid steric
buttressing between the vinyl hydrogens. This results in a dihedral angle between the two
exocyclic carbons of 22.190°, while the cyclobutane ring in 313b is locked at a dihedral of
0.000°.
48
Table 3.2 Bond Lengths for 311b and 314
313b 314
(A) (A)
1.38514 1.44533
1.25211 1.22375
1.38619 1.44174
1.41704 1.35777
1.39630 1.48308
1.40226 1.52673
∆R 0.16493 0.30298
St. Dev. 0.06046 0.10824
To confirm the alkyne in benzyne was not exerting an unknown effect, the analysis was
carried out on the analogous benzene system, going from benzocyclobutane (315) to the
ring-opened diene (316, Scheme 3.7). For this transformation, a free energy difference of
14.68 kcal/mol was calculated, demonstrating an even greater thermodynamic preference to
the cyclobutane isomer instead of the ring-opened isomer.
Scheme 3.7 Ring-Opening of Benzocyclobutane to the Diene 316
315 316
Evaluating the bond length alternation demonstrates an even more dramatic shift away
from aromatic character, with the difference coming to almost a ten-fold increase in ∆R
49
values (Table 3.3). The similarity between the calculated ∆R values for the unopened
benzyne 313b and the ring-opened benzene 316 serve to provide gague, indicating the
strain placed on the aromatic character of the system by the inclusion of the triple bond
in the benzyne ring. The similar distortion effect from steric buttressing is also observed,
with the dihedral angle of the exocyclic methylenes in 316 measuring at 22.173°.
Table 3.3 Bond Lengths for 315 and 316
315 316
(A) (A)
1.38675 1.46638
1.39284 1.49209
1.38675 1.46638
1.40323 1.34759
1.40106 1.45872
1.40323 1.34759
∆R 0.01648 0.14450
St. Dev. 0.00788 0.06467
3.3 Thermodynamics and Transition States of Small
Molecule Intermolecular Trapping
Part of the aryne class of compounds, benzyne is classified as being highly reactive, a fact
further evidenced by the available literature on reactions of benzyne.64,65 These methods
are usually aim at achieving further synthetic goals. An area under represented is reactions
of benzyne with small molecule traps to generate further, possibly moderately reactive
compounds. To evaluate this area, the thermodynamic reactivity of benzyne was evaluated
50
with a selection of seven small molecule traps, which give rise to a total of twelve distinct
products (Fig. 3.4)
Fig. 3.4 Small Molecule Traps and Corresponding Products with Benzyne
N C O
MeOCO
N C S
MeSCS
N N
H
Me
N N C O
NN Me
O
O
O
O
N
N
N
O
Me
N
O
Me
O
N
S
Me
N
S
Me
S
N Me
S
S
S
S
317 318 319 320 321 322 323
317a 318a 319a 319b
320a 320b 321a 321b
322a 322b 322c 323a
Demonstrating the highly reactive nature of benzyne, all of the small molecule trapping
products, except for that from N2 (318a) were calculated to be lower in free energy than
that of the starting materials. There is some precedent for highly stable molecules like CO2
to undergo addition reactions with benzyne when part of a multi-component reaction.66
Free energies in solution were calculated for all products, and the overall free energy change
was calculated as the difference between the product and the two independent starting
materials (Fig. 3.5).
51
Fig. 3.5 Calculated Free Energy Difference of Trapping Products
31
7a
31
8a
31
9a
31
9b
32
0a
32
0b
32
1a
32
1b
32
2a
32
2b
32
2c
32
3a
−100
−80
−60
−40
−20
0
20
40
−48.93
31.78
−26.9
−13.62
−49.71
−42.27
−49.25−46.85
−44.14
−55.74
−51.07
−97.69
F
re
e
E
n
er
gy
D
iff
er
en
ce
(k
ca
l/
m
o
l)
These results indicate that for every small molecule trap, generation of a carbene from
benzyne is a favorable reaction pathway, including CO2. Unexpectedly, the trapping of
carbon monoxide to give benzocyclopropanone (323a) has the largest difference in free
energy. This could be understood by considering the combination of two relatively high
energy species into an stable aromatic compound. A limited number of these systems were
tracked further in attempts to locate transition states.
52
3.3.1 Transition State and Analysis of Benzodioxole Carbene Formation
The formation of the benzodioxole carbene 319b is computed to have a favorable free energy
difference of =13.62 kcal/mol in chloroform. The computed geometry of the transition state
(TS) leading to 319b shows it is completely planar and C2v symmetric. While the reaction
may be energetically favorable in terms of absolute product and reactant free energies, the
reaction could have a prohibitively high barrier to activation, which required locating a
transition state for this transformation.
Initial attempts to locate the transition state by either QST2 or QST3 proved to be
unsuccessful. The subsequent TS transition state search utilized the approximate geometry
from the failed QST2 calculation as a starting point. Utilizing this method, a transition
state was located (Fig. 3.6), containing a single imaginary frequency of =552.72 cm=1
Fig. 3.6 Transition State Leading to Formation of 319b
The imaginary frequency corresponds to a molecular vibration that indicated the pos-
sibility of an asynchronous ring closing to 319b. In order to verify that this process is
concerted and asynchronous, an IRC analysis was performed starting from the obtained
transition state geometry. The IRC analysis proceeded very smoothly, to show in the re-
verse direction the CO2 slowly moving away from the benzyne ring to separate starting
substrates, and in the forward direction to closing first one C–O bond, and then the next.
53
The absence of any second local minimum prior to formation of the carbene found in the
IRC analysis provides further support for the postulated concerted and asynchronous tran-
sition state. A fine grained step-by-step snapshot of the reaction PES and the molecular
rearrangement leading to the transition state, and on to product was achieved by obtaining
up to 100 points along the reaction coordinate in each direction. The resulting energy dia-
gram provides thorough detail and molecular geometries for each point along the coordinate
(Fig. 3.7).
Fig. 3.7 Intrinsic Reaction Coordinate Plot for the Formation of 319b
a)
b)
c)
a) Starting geometry
b) Transition state geometry
c) Final geometry
54
With confirmation that the transition state connects the reactants to the products as-
signment of the transition state to this transformation can be made with much greater
certainty. From the IRC, the activation energy for the reaction is also easily assessed, which
is calculated to be at 34.03 kcal/mol.
3.3.2 Generation of N-heterocyclic Carbenes by Benzyne Trapping
N-heterocylic carbene (NHC) are a class of persistent carbene that are exceptionally stable,
some even thermodynamically stable when kept dry and free of oxygen. Their robust nature
has found them used as ligands in transition metal catalysis.67,68 The initial screening of
small molecule traps found that the generation of an NHC by trapping with benzyne is a
favorable process with a difference in free energy of =48.93 kcal/mol (Scheme 3.8). Moreover
the tethered NHC 317a, could also be accessed by generating the benzyne through the triyne
cyclization (Scheme 3.2, page 43) providing rapid access to functionalized benzenoid NHCs.
Scheme 3.8 Generation of NHC Through Hydrogen Abstraction By Benzyne
N
H
NMeNNMe
H
∆G = -48.93 kcal/mol
317 301 317a
It was unknown at the time whether the mechanism for this reaction would be step-
wise or concerted. Early attempts at finding a transition state were successful utilizing the
QST2 and QST3 algorithms. The transition state located had one imaginary frequency at
=1542.04 cm=1. This molecular vibration of the transition state (Fig. 3.8) appeared to be
isolated to only a proton transfer between the imidazole carbon and the benzyne carbon.
The transition state for the proton transfer is completely planar with respect to the four
non-hydrogen atoms comprising the 5-membered ring in the transition state. However, after
55
proton transfer, there is a relaxation of the geometry and 317a twists to a dihedral angle
of 34.3°.
Fig. 3.8 Transition State For Proton Transfer From Zwitterionic Intermediate to Benzyne
In order to then reoptimize the structure back to the starting material, the transition
state was perturbed slightly to bias it towards dissociation. An unexpected result produced
a new minimum that was not the separated products, but instead an intermediate structure
324. The resulting minimum appeared to be a geometry just before the proton transfer
step, providing indication of a step-wise mechanism (Scheme 3.9).
Scheme 3.9 NHC Generation By Benzyne Through Zwitterionic Intermediate
N
H
NMeNNMe
H
NNMe
H
+
[H+]
Transfer
δ
δ
317 301 324 317a
Examining the Mulliken charges revealed a zwitterionic species with a highly negative
(-2.324) charge on one benzyne carbon, and a very positive (1.671) charge on the other
carbon, considering that almost all other atoms had Mulliken charges between -0.3 and 0.3
(Fig. 3.9).
56
Fig. 3.9 Zwitterionic Intermediate on to NHC Formation, Prior to Proton Transfer
1Red indicates negative charge, while green indicates positive charge
2The benzyne carbons have Mulliken charges of -2.324 and 1.671
The nitrogen tethered to the benzyne ring also has a partial negative charge. This could
indicate the mechanism proceeds through initial nucleophilic attack by nitrogen on benzyne,
followed by a large amount of the triple bond electron density being placed onto the distal
benzyne carbon. This benzyne carbon is now electron rich enough to undergo hydrogen-
atom abstraction of the C–H bond of the imidazole portion, generating the NHC. Like
NHC 317a, this intermediate also shows a torqued central four-atom unit with a dihedral
measuring 25.0°.
Finding that the mechanism for the NHC generation proceeds step-wise meant that there
should be a first transition state for the initial nucleophilic attack on benzyne. However,
all attempts to locate a transition state for this process were unsuccessful. In some cases,
the interaction of two approaching species towards each other can suffer from basis set
superposition error (BSSE). At some intermediate distance, the overlap of the individual
species basis sets will lead to an artificial lowering of the overall energy. This may lead
to incorrect or failed optimizations as the predicted energies do not lead to the correct
optimization choices by the algorithm. To correct for this energy discrepancy, a calculation
known as the counterpoise calculation69,70 can separate these interactions to determine the
57
error introduced by BSSE. Still, in the case of the first transition state, and even attempting
to find an imidazole/benzyne pre-complex, the counterpoise calculation indicated no lower
energy pre-complex or possible lead to a first transition state.
Turning back to the zwitterionic intermediate 324 and the proton transfer transition
state, the goal became to verify the connection between the intermediate 324 and NHC
317a. Similar to the previously checked transition state, an IRC calculation was the best
way to verify the relationship between the three species. Of particular interest was the
dihedral distortion observed for both 324 and 317a, but not in the transition state. The
IRC calculation proved to be very helpful and also opened some further questions (Fig. 3.10).
In the IRC analysis, both the forward and reverse searches led to geometries that remained
planar. In examining the energy plot, it appears that the energies are approaching a plateau,
not showing any indication of further distortion as seen in 324 and 317a. We were not able
to establish if there is a further barrier to distorting to the final geometries.
58
Fig. 3.10 Intrinsic Reaction Coordinate Plot for Proton Transfer Step of NHC Formation
a)
b)
c)
a) Starting geometry
b) Transition state geometry
c) Final geometry
While the first transition state remained elusive, the role solvent played was also briefly
investigated. The role of solvent would likely be most critical for the zwitterionic interme-
diate as well as the subsequent proton transfer step. The optimized solvent geometries were
reoptimized without using a continuum solvent model (gas phase) to observe what effect
lack of solvent would have on the stability of these species. When looking at the gas phase
energies, it follows the expectation that invoking charged species in the gas phase results in
a destabilizing effect. It is clear that the first step, ending at the zwitterionic intermediate
is much less favorable in the gas phase. However, the overall reaction to the neutral carbene
59
is found to be more favorable (Fig. 3.11).
Fig. 3.11 Free Energy Diagram of NHC Formation By Benzyne Trapping of N-Methyl
Imidazole
∆G1
∆G2
∆G2
C
D
A + B
CHCl3
None
R
el
at
iv
e 
En
er
gy
N
H
NMeNNMe
H
NNMe
H
+
[H+]
Transfer
A B C D
Reaction Coordinate
δ
δ
3.4 Concluding Remarks
The highly reactive nature of benzyne results in diverse patterns of reactivity. This same
diverse reactivity results in a difficulty storing, handling and preparing benzyne in a simple
way. The new methodology (the HDDA reaction), and further reactions of benzyne were in-
vestigated computationally to better understand the basics of this reactive intermediate. In
this chapter, the effect of ring-size in a fused bicyclic ring system was explored with respect
to the free energy of the cyclization reaction to make benzyne. Further understanding was
60
gained by the study of the effect substituents had on the relative aromatic/anti-aromatic
character of the resulting benzyne, through analysis of ring-opening free energy calculations.
Further computational studies were conducted on the reactivity of benzyne itself. The
highly reactive nature of benzyne led to unexpected reactions with highly stable molecules
such as CO2 that were predicted to lead to energetically favorable products that included
carbenes and 4-membered fused ring systems. Two of these systems, the benzodioxole car-
bene and the NHC produced by a reaction with benzyne were further explored. Transition
states were identified for each system and verified as valid transition states utilizing intrinsic
reaction coordinate (IRC) analysis, which connected the computed transition states with
the reactants and products. Utilizing the compiled data for the generation of the NHC,
a free energy diagram describing the reaction in both chloroform and the gas phase was
presented. The computation of favorable reaction thermodynamics for these systems has
led to further investigation, and we are now looking to test the feasibility of these reactions
experimentally.
References
[1] Heisenberg, W. Z. Phys. 1925, 33, 879.
[2] Schro¨dinger, E. Ann. Phys. 1926, 79, 361.
[3] Hartree, D. R. Proc. Cambridge Phil. Soc. 1928, 24, 89–110.
[4] Slater, J. C. Phys. Rev. 1929, 34, 1293–1322.
[5] Fock, V. Z. Phys. 1930, 61, 126–148.
[6] Hohenberg, P.; Kohn, W. Phys. Rev. 1964, 136, B864–B871.
[7] Kohn, W.; Sham, L. J. Phys. Rev. 1965, 140, A1133–A1138.
[8] Keith, T. A.; Bader, R. F. W. Chem. Phys. Lett. 1992, 194, 1–8.
[9] Keith, T. A.; Bader, R. F. W. Chem. Phys. Lett. 1993, 210, 223–231.
[10] Cheeseman, J. R.; Trucks, G. W.; Keith, T. A.; Frisch, M. J. J. Chem. Phys 1996,
104, 5497–5509.
[11] London, F. J. Phys. Radium 1937, 8, 397–409.
[12] McWeeny, R. Phys. Rev. 1962, 126, 1028.
[13] Ditchfield, R. Mol. Phys. 1974, 27, 789–807.
[14] Wolinksi, K.; Hilton, J. F.; Pulay, P. J. Am. Chem. Soc. 1990, 112, 8251–8260.
[15] Willis, B. G.; Jensen, K. F. J. Phys. Chem. A 1998, 102, 2613–2623.
[16] Thomas, L. H. Proc. Cambridge Philos. Soc. 1927, 23, 542–548.
[17] Fermi, E. Rend. Accad. Naz. Lincei 1927, 6, 602–607.
[18] Valdes, H.; Pluha´c˘kova´, K.; Pitona´k, M.; R˘eza´c˘, J.; Hobza, P. Phys. Chem. Chem.
Phys. 2008, 10, 2747–2757.
[19] Wheeler, S. E.; Moran, A.; Pieniazek, S. N.; Houk, K. N. J. Phys. Chem. A. 2009,
113, 10376–10384.
[20] Dang, L.; Yang, X.; Zhou, J.; Brothers, E. N.; Hall, M. B. J. Phys. Chem. A. 2012,
116, 476–482.
[21] Zhao, Y.; Truhlar, D. G. Theor. Chem. Account 2008, 120, 215–241.
61
62
[22] Born, M.; Oppenheimer, J. R. Ann. Phys. 1927, 84, 457–484.
[23] Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheese-
man, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakat-
suji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.;
Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Nor-
mand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.;
Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Mo-
rokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dap-
prich, S.; Daniels, A. D.; o¨. Farkas,; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.;
Fox, D. J. Gaussian 09 Revision A.1. Gaussian Inc. Wallingford CT 2009.
[24] Peng, C.; Schlegel, H. B. Israel J. Chem 1993, 33, 449–454.
[25] Peng, C.; Ayala, P. Y.; Schlegel, H. B.; Frisch, M. J. J. Comp. Chem. 1996, 17, 49–56.
[26] Schlegel, H. B. J. Comp. Chem. 1982, 3, 214–218.
[27] Barnett, C. B.; Naidoo, K. J. J. Phys. Chem. B 2008, 112, 15450–15459.
[28] Vlasov, V. M. Russ. Chem. Rev. 2006, 75, 765–796.
[29] Shoolery, J. N. Anal. Chem. 1993, 65, 731A–741A.
[30] Claridge, T. D. W.; Perez-Victoria, I. Org. Biomol. Chem. 2003, 1, 3632–3634.
[31] Furrer, J. Chem. Commun. 2010, 46, 3396–3398.
[32] MacroModel, version 9.9, Schrdinger, LLC, New York, NY, 2011.
[33] Maestro, version 9.2, Schrdinger, LLC, New York, NY, 2011.
[34] Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
[35] Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789.
[36] Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, 1200–1211.
[37] Stehens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994,
98, 11623–11627.
[38] Miertusˇ, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55, 117–129.
[39] Miertusˇ, S.; Tomasi, J. Chem. Phys. 1982, 65, 239–245.
63
[40] Pascual-ahuir, J. L.; Silla, E.; Tun˜on, I. Journal of Computational Chemistry 1994,
15, 1127–1138.
[41] Bondi, A. J. Phys. Chem. 1964, 68, 441–451.
[42] Smith, S. G.; Goodman, J. M. J. Org. Chem. 2009, 74, 4597–4607.
[43] Smith, S.; Goodman, J. J. Am. Chem. Soc. 2010, 132, 12946–12959.
[44] Martello, M. T.; Burns, A.; Hillmyer, M. ACS Macro Lett. 2012, 1, 131–135.
[45] Ovitt, T. M.; Coates, G. W. J. Am. Chem. Soc. 2002, 124, 1316–1326.
[46] Karplus, M. J. Chem. Phys. 1959, 30, 11–15.
[47] Karplus, M. J. Am. Chem. Soc. 1963, 85, 2870–2871.
[48] Minch, M. J. Concepts Magn. Reson. 6, 41–56.
[49] Butts, C. P.; Jones, C. R.; Towers, E. C.; Flynn, J. L.; Appleby, L.; Barron, N. J. Org.
Biomol. Chem. 2011, 9, 177–184.
[50] Stoermer, R.; Kahlert, B. Ber. Dtsch. Chem. Ges. 1902, 35, 1633–1640.
[51] Bachmann, W. E.; Clarke, H. T. J. Am. Chem. Soc. 1927, 49, 2089–2098.
[52] Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660–661.
[53] Attygalle, A. B.; Nishshanka, U.; Weisbecker, C. S. J. Am. Chem. Mass Spectrom.
2011, 22, 1515–1525.
[54] Simic-Milosevic, V.; Bocquet, M.-L.; Morgenstern, K. Surf. Sci. 2009, 603, 2479–2483.
[55] Evangelista, F. A.; Simmonett, A. C.; Schaefer III, H. F.; Mukherjee, D.; Allen, W. D.
Phys. Chem. Chem. Phys. 2009, 11, 4728–4741.
[56] Glendening, E. D.; Reed, A. E.; Carpenter, J. E.; Weinhold, F. NBO Version 3.1.
[57] Kitamura, T. Aust. J. Chem 2010, 63, 981–1001.
[58] Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995–2001.
[59] Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. J. Comput. Chem. 2003, 24, 669–681.
[60] Rappe, A. K.; Casewit, C. J.; Colwell, K. S.; Goddard, W. A.; Skiff, W. M. J. Am.
Chem. Soc 1992, 114, 10024–10035.
[61] Bradley, A. Z.; Johnson, R. P. J. Am. Chem. Soc. 1997, 119, 9917–9918.
[62] Kociolek, M. G.; Johnson, R. P. Tetrahedron Lett. 1999, 40, 4141–4144.
64
[63] Najafian, K.; Schleyer, P. v. R.; Tidwell, T. T. Org. Biomol. Chem. 2003, 1, 3410–3417.
[64] Bryce, M. Advances in Heterocyclic Chemistry 1981, 28, 183.
[65] Campbell, C. D.; Rees, C. W. J. Chem. Soc. C 1969, 5, 748–751.
[66] Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. J. Am. Chem. Soc. 2006, 128,
11040–11041.
[67] Crudden, C. M.; Allen, D. P. Coord. Chem. Rev. 2004, 248, 2247–2273.
[68] Herrmann, W. A. Angew. Chem. Int. Ed. 2002, 41, 1290–1309.
[69] Boys, S. F.; Bernardi, F. Mol. Phys. 1970, 19, 553–566.
[70] Simon, S.; Duran, M.; Dannenberg, J. J. J. Chem. Phys. 1996, 105, 11024–11031.
Scripts and Utilities
A-1 Maestro Scripts
A-1.1 write-g09-inputs-default.py
write-g09-inputs-default.py
#####################################################################
#####################################################################
# #
# By Patrick H. Willoughby , August 2011 #
# #
# This python script is intended to be run from the Maestro #
# Command Input Area. #
# #
# While in the command input area enter: #
# pythonimport "title of this script" #
# #
# If you can't see the command input area then open Maestro , #
# select Maestro and check the box to the left of #
# "Command Input Area" #
# #
#####################################################################
#####################################################################
from schrodinger import maestro
from schrodinger import structure
from schrodinger import project
import os
from math import exp as exp
######################################################################
##################### BEGIN main program loop ######################
def main ():
# Dictionary holding column names for project table properties depending on the
force field being used
columns = {'mm2' : ['r_mmod_Potential_Energy -MM2*', '
r_mmod_Relative_Potential_Energy -MM2*'], 'mm3': ['r_mmod_Potential_Energy -MM3
*', 'r_mmod_Relative_Potential_Energy -MM3*'],
'amber ': ['r_mmod_Potential_Energy -AMBER*', 'r_mmod_Relative_Potential_Energy -
AMBER*'], 'opls': ['r_mmod_Potential_Energy -OPLSA*', '
r_mmod_Relative_Potential_Energy -OPLSA*'],
'amber94 ': ['r_mmod_Potential_Energy -AMBER94 ', 'r_mmod_Relative_Potential_Energy -
AMBER94 '], 'mmff': ['r_mmod_Potential_Energy -MMFF94 ', '
r_mmod_Relative_Potential_Energy -MMFF94 '],
'mmffs ': ['r_mmod_Potential_Energy -MMFF94s ', 'r_mmod_Relative_Potential_Energy -
MMFF94s '], 'opls2001 ': ['r_mmod_Potential_Energy -OPLS -AA', '
r_mmod_Relative_Potential_Energy -OPLS -AA'],
'opls2005 ': ['r_mmod_Potential_Energy -OPLS -2005', '
r_mmod_Relative_Potential_Energy -OPLS -2005 ']}
# Start by selecting all entries in the project table , and making sure the first
entry is in the workspace
maestro.command("entryselectall")
65
maestro.command("eplayergotofirst")
# Grab the entire project table
pt = maestro.project_table_get ()
currentforcefield = ''
for forcefield in columns.keys():
if not pt[1][ columns[forcefield ][0]] == None :
currentforcefield = forcefield
break
# Create a directory to store the input files.
os.popen( "mkdir " + str( pt[1]['s_m_title ']+'-gaussian_files ' ) )
# Create a dictionary with keys being each conformer name and a list of the
# absolute and relative MM energies for the conformer.
energies = {}
# Make a loop to operate on every conformation in the project table.
# This loop operates on one conformation.
conf_num = 1
for row in pt.selected_rows:
structure = maestro.workspace_get ()
# Open the output file for writing
outputfile = open( row['s_m_title '] + "-opt_freq -conf -" + str(conf_num) + ".
com", 'w' )
nmr_outputfile = open( row['s_m_title '] + "-nmr -conf -" + str(conf_num) + '.
com', 'w' )
# Add the conformer energy to the dictionary of energies
energies[ str( row['s_m_title '] + row['s_m_entry_id '] ) ] =[ row[columns[
currentforcefield ][0]], row[columns[currentforcefield ][1]] ]
# Write the Gaussian stuff that goes into every input deck.
print >> outputfile , gaussian_input( "link", str( pt[1]['s_m_title ']), str(
conf_num ))
print >> nmr_outputfile , gaussian_nmr_input( "link", str( pt[1]['s_m_title '])
, str( conf_num ) )
print >> outputfile , gaussian_input( "route" )
print >> nmr_outputfile , gaussian_nmr_input( "route" )
print >> outputfile , gaussian_input( "title", str( pt[1]['s_m_title ']), str(
conf_num ))
print >> nmr_outputfile , gaussian_nmr_input( "title", str( pt[1]['s_m_title '
]), str( conf_num ))
print >> outputfile , gaussian_input( "molecule" )
print >> nmr_outputfile , gaussian_nmr_input( "molecule" )
print >> nmr_outputfile , gaussian_nmr_input( "readline" )
print >> nmr_outputfile , gaussian_nmr_input( "end" )
# This loop operates on one atom.
for atom in structure.atom:
outputstring = "%2s %10.6f %10.6f %10.6f" % (atom.element , atom.x, atom.y
, atom.z)
print >> outputfile , outputstring
print >> outputfile , gaussian_input( "readline" )
print >> outputfile , gaussian_input("end")
66
# Close the opened output file.
outputfile.flush ()
outputfile.close ()
nmr_outputfile.flush()
nmr_outputfile.close()
maestro.command("eplayerstepahead")
conf_num += 1
# Write the collected energy data for each conformer to a CSV file
# Sum the exponential relative energies to create the denominator term
denominator = 0
for key in energies:
denominator = denominator + exp( -( energies[key ][1] * 1000 ) / ( 8.314472 *
298.15 ) )
energiesfile = open( str( pt[1]['s_m_title '] ) + '_MM_energies.csv', 'w' )
energiesfile.write( 'Conformer ,MM Energy ,Relative MM Energy ,Boltzman Weight\n\n'
)
for key in energies:
temp = exp( -( energies[key ][1] * 1000 ) / ( 8.314472 * 298.15 ) ) /
denominator
energiesfile.write( str( key ) + ',' + str( energies[key ][0] ) + ',' + str(
energies[key ][1] ) + ',' + str( temp ) + '\n' )
energiesfile.flush ()
energiesfile.close ()
# Archive and compress the input files in the folder for easy transfer over sftp
os.popen( "sleep 2; tar cjf " + str( pt[1]['s_m_title '] ) + ".tar.bz2 " + str( pt
[1]['s_m_title '] + '*conf*.com') )
# Move the created input files "-gaussian_files" directory.
os.popen( "mv " + str( pt[1]['s_m_title '] + '*conf* ' ) + str( pt[1]['s_m_title '
]+'-gaussian_files ') )
####################### END main program loop ######################
######################################################################
# define extra functions
def convert_mmat_symbol(mmat):
# mmat2Number = {1:'C ',2:'C ',3:'C ',15:'O ',16:'O ',24:'N ',25:'N ',26:'N ',41:'H ',42:'H
',43:'H ',49:'S ',56:'F ',57:'Cl ',58:'Br ',59:'I '}
# symbol = mmat2Number[mmat]
# return symbol
return {1:'C' ,2:'C' ,3:'C' ,15:'O' ,16:'O' ,24:'N' ,25:'N' ,26:'N' ,41:'H' ,42:'H' ,43:'H'
,49:'S' ,56:'F' ,57:'Cl' ,58:'Br' ,59:'I'}[mmat]
def gaussian_input(which_section ,candidate_filename="X", conformer_number="Y"):
# Current acceptable values for which_section are
# link , route , title , molecule , and end
ENDLINE = "\n"
LINK1 = "%mem =16gb\n"
LINK2 = "%nproc =8\n"
LINK3 = "%%chk=%s \n" % (candidate_filename +'-conf -' + conformer_number + ".
chk")
67
LINK4 = "\nradii=bondi"
ROUTE1 = "# m062x /6 -31+G(d,p) opt=(verytight ,calcfc) integral(ultrafinegrid)
scrf=(iefpcm ,read ,solvent=chloroform)"
TITLE1 = "Candidate Structure: %s, Conformer: %s geometry optimization and
frequency calculation with chloroform solvation" % (candidate_filename ,
conformer_number)
MOL1 = "0 1"
CARTHEAD = " X Y Z\n"
LINKZERO = LINK1 + LINK2 + LINK3
ROUTE = ROUTE1 + ENDLINE
TITLE = TITLE1 + ENDLINE
MOLECULE = MOL1
READLINE = LINK4 +ENDLINE
END = ENDLINE
if (which_section == "link"): return LINKZERO
if (which_section == "route"): return ROUTE
if (which_section == "title"): return TITLE
if (which_section == "molecule"): return MOLECULE
if (which_section == "readline"): return READLINE
if (which_section == "end"): return END
return "There is a problem generating the gaussian file."
def gaussian_nmr_input(which_section ,candidate_filename="X",conformer_number="Y"):
ENDLINE = "\n"
LINK1 = "%mem =16gb\n"
LINK2 = "%nproc =8\n"
LINK3 = "%%chk=%s \n" % (candidate_filename + '-conf -' + conformer_number + '
.chk')
LINK4 = "radii=bondi\n"
ROUTE1 = "# b3lyp /6 -311+G(2d,p) nmr guess=read geom=check integral(
ultrafinegrid) scrf=(iefpcm ,read ,solvent=chloroform)"
TITLE1 = "Candidate Structure: %s, Conformer: %s, NMR calculation with
chloroform solvation" % (candidate_filename ,conformer_number)
MOL1 = "0 1"
CARTHEAD = " X Y Z\n"
LINKZERO = LINK1 + LINK2 + LINK3
ROUTE = ROUTE1 + ENDLINE
TITLE = TITLE1 + ENDLINE
MOLECULE = MOL1 + ENDLINE
READLINE = LINK4 + ENDLINE
END = ENDLINE
if (which_section == "link"): return LINKZERO
if (which_section == "route"): return ROUTE
if (which_section == "title"): return TITLE
if (which_section == "molecule"): return MOLECULE
if (which_section == "readline"): return READLINE
if (which_section == "end"): return END
return "There is a problem generating the gaussian file."
######################################################################
######################################################################
# Run the program
main()
68
A-1.2 write-g09-inputs-calcFCcalcall.py
write-g09-inputs-calcFCcalcall.py
#####################################################################
#####################################################################
# #
# By Daniel J. Marell , January 2012 #
# #
# This is a revised program of the parent #
# write -g09 -inputs -default.py #
# Written by Patrick H. Willoughby , August 2011 #
# #
# This modified version produces a Gaussian 09 input file #
# to run a 2-part optimization , a calcFC opt then a calcall opt #
# #
# This python script is intended to be run from the Maestro #
# Command Input Area. #
# #
# While in the command input area enter: #
# pythonimport "title of this script" #
# #
# If you can't see the command input area then open Maestro , #
# select Maestro and check the box to the left of #
# "Command Input Area" #
# #
#####################################################################
#####################################################################
from schrodinger import maestro
from schrodinger import structure
from schrodinger import project
import os
from math import exp as exp
######################################################################
##################### BEGIN main program loop ######################
def main ():
# Dictionary holding column names for project table properties depending on the
force field being used
columns = {'mm2' : ['r_mmod_Potential_Energy -MM2*', '
r_mmod_Relative_Potential_Energy -MM2*'], 'mm3': ['r_mmod_Potential_Energy -MM3
*', 'r_mmod_Relative_Potential_Energy -MM3*'],
'amber ': ['r_mmod_Potential_Energy -AMBER*', 'r_mmod_Relative_Potential_Energy -
AMBER*'], 'opls': ['r_mmod_Potential_Energy -OPLSA*', '
r_mmod_Relative_Potential_Energy -OPLSA*'],
'amber94 ': ['r_mmod_Potential_Energy -AMBER94 ', 'r_mmod_Relative_Potential_Energy -
AMBER94 '], 'mmff': ['r_mmod_Potential_Energy -MMFF94 ', '
r_mmod_Relative_Potential_Energy -MMFF94 '],
'mmffs ': ['r_mmod_Potential_Energy -MMFF94s ', 'r_mmod_Relative_Potential_Energy -
MMFF94s '], 'opls2001 ': ['r_mmod_Potential_Energy -OPLS -AA', '
r_mmod_Relative_Potential_Energy -OPLS -AA'],
'opls2005 ': ['r_mmod_Potential_Energy -OPLS -2005', '
r_mmod_Relative_Potential_Energy -OPLS -2005 ']}
# Start by selecting all entries in the project table , and making sure the first
entry is in the workspace
maestro.command("entryselectall")
maestro.command("eplayergotofirst")
69
# Grab the entire project table
pt = maestro.project_table_get ()
currentforcefield = ''
for forcefield in columns.keys():
if not pt[1][ columns[forcefield ][0]] == None :
currentforcefield = forcefield
break
# Create a directory to store the input files.
os.popen( "mkdir " + str( pt[1]['s_m_title ']+'-gaussian_files ' ) )
# Create a dictionary with keys being each conformer name and a list of the
# absolute and relative MM energies for the conformer.
energies = {}
# Make a loop to operate on every conformation in the project table.
# This loop operates on one conformation.
conf_num = 1
for row in pt.selected_rows:
structure = maestro.workspace_get ()
# Open the output file for writing
outputfile = open( row['s_m_title '] + "-opt_freq -conf -" + str(conf_num) + ".
com", 'w' )
nmr_outputfile = open( row['s_m_title '] + "-nmr -conf -" + str(conf_num) + '.
com', 'w' )
# Add the conformer energy to the dictionary of energies
energies[ str( row['s_m_title '] + row['s_m_entry_id '] ) ] =[ row[columns[
currentforcefield ][0]], row[columns[currentforcefield ][1]] ]
# Write the Gaussian stuff that goes into every input deck.
print >> outputfile , gaussian_input( "link", str( pt[1]['s_m_title ']), str(
conf_num ))
print >> nmr_outputfile , gaussian_nmr_input( "link", str( pt[1]['s_m_title '])
, str( conf_num ) )
print >> outputfile , gaussian_input( "route" )
print >> nmr_outputfile , gaussian_nmr_input( "route" )
print >> outputfile , gaussian_input( "title", str( pt[1]['s_m_title ']), str(
conf_num ))
print >> nmr_outputfile , gaussian_nmr_input( "title", str( pt[1]['s_m_title '
]), str( conf_num ))
print >> outputfile , gaussian_input( "molecule" )
print >> nmr_outputfile , gaussian_nmr_input( "molecule" )
print >> nmr_outputfile , gaussian_nmr_input( "readline" )
print >> nmr_outputfile , gaussian_nmr_input( "end" )
# This loop operates on one atom.
for atom in structure.atom:
outputstring = "%2s %10.6f %10.6f %10.6f" % (atom.element , atom.x, atom.y
, atom.z)
print >> outputfile , outputstring
print >> outputfile , gaussian_input( "readline" )
print >> outputfile , gaussian_input("end")
70
print >> outputfile , gaussian_input( "link2", str( pt[1]['s_m_title ']), str(
conf_num ))
print >> outputfile , gaussian_input( "route2" )
print >> outputfile , gaussian_input( "title2", str( pt[1]['s_m_title ']), str
( conf_num ))
print >> outputfile , gaussian_input( "molecule2" )
print >> outputfile , gaussian_input( "end")
# Close the opened output file.
outputfile.flush ()
outputfile.close ()
nmr_outputfile.flush()
nmr_outputfile.close()
maestro.command("eplayerstepahead")
conf_num += 1
# Write the collected energy data for each conformer to a CSV file
# Sum the exponential relative energies to create the denominator term
denominator = 0
for key in energies:
denominator = denominator + exp( -( energies[key ][1] * 1000 ) / ( 8.314472 *
298.15 ) )
energiesfile = open( str( pt[1]['s_m_title '] ) + '_MM_energies.csv', 'w' )
energiesfile.write( 'Conformer ,MM Energy ,Relative MM Energy ,Boltzman Weight\n\n'
)
for key in energies:
temp = exp( -( energies[key ][1] * 1000 ) / ( 8.314472 * 298.15 ) ) /
denominator
energiesfile.write( str( key ) + ',' + str( energies[key ][0] ) + ',' + str(
energies[key ][1] ) + ',' + str( temp ) + '\n' )
energiesfile.flush ()
energiesfile.close ()
# Archive and compress the input files in the folder for easy transfer over sftp
os.popen( "sleep 2; tar cjf " + str( pt[1]['s_m_title '] ) + ".tar.bz2 " + str( pt
[1]['s_m_title '] + '*conf*.com') )
# Move the created input files "-gaussian_files" directory.
os.popen( "mv " + str( pt[1]['s_m_title '] + '*conf* ' ) + str( pt[1]['s_m_title '
]+'-gaussian_files ') )
####################### END main program loop ######################
######################################################################
# define extra functions
def convert_mmat_symbol(mmat):
# mmat2Number = {1:'C ',2:'C ',3:'C ',15:'O ',16:'O ',24:'N ',25:'N ',26:'N ',41:'H ',42:'H
',43:'H ',49:'S ',56:'F ',57:'Cl ',58:'Br ',59:'I '}
# symbol = mmat2Number[mmat]
# return symbol
return {1:'C' ,2:'C' ,3:'C' ,15:'O' ,16:'O' ,24:'N' ,25:'N' ,26:'N' ,41:'H' ,42:'H' ,43:'H'
,49:'S' ,56:'F' ,57:'Cl' ,58:'Br' ,59:'I'}[mmat]
def gaussian_input(which_section ,candidate_filename="X", conformer_number="Y"):
# Current acceptable values for which_section are
71
# link , route , title , molecule , and end
ENDLINE = "\n"
LINK1 = "%mem =16gb\n"
LINK2 = "%nproc =8\n"
LINK3 = "%%chk=%s \n" % (candidate_filename +'-conf -' + conformer_number + ".
chk")
LINK4 = "\nradii=bondi"
ROUTE1 = "# m062x /6 -31+G(d,p) opt=(verytight ,calcfc) integral(ultrafinegrid)
scrf=(iefpcm ,read ,solvent=chloroform)"
TITLE1 = "Candidate Structure: %s, Conformer: %s geometry optimization and
frequency calculation with chloroform solvation" % (candidate_filename ,
conformer_number)
MOL1 = "0 1"
CARTHEAD = " X Y Z\n"
LINK2_1 = "--Link1 --\n"
LINK2_2 = "%%chk=%s" % (candidate_filename + '-conf -' + conformer_number + ".
chk")
ROUTE2 = "# m062x /6 -31+G(d,p) opt=(verytight ,calcall) integral(ultrafinegrid)
scrf=check geom=checkpoint"
TITLE2 = "Candidate Structure: %s, Conformer: %s geometry optimization and
frequency calculation with chloroform solvation" % (candidate_filename ,
conformer_number)
MOL2 = "0 1"
LINKZERO = LINK1 + LINK2 + LINK3
ROUTE = ROUTE1 + ENDLINE
TITLE = TITLE1 + ENDLINE
MOLECULE = MOL1
READLINE = LINK4 +ENDLINE
END = ENDLINE
LINK2 = LINK2_1 + LINK2_2
ROUTE2 = ROUTE2 + ENDLINE
TITLE2 = TITLE2 + ENDLINE
MOLECULE2 = MOL2
if (which_section == "link"): return LINKZERO
if (which_section == "route"): return ROUTE
if (which_section == "title"): return TITLE
if (which_section == "molecule"): return MOLECULE
if (which_section == "readline"): return READLINE
if (which_section == "end"): return END
if (which_section == "link2"): return LINK2
if (which_section == "route2"): return ROUTE2
if (which_section == "title2"): return TITLE2
if (which_section == "molecule2"): return MOLECULE2
return "There is a problem generating the gaussian file."
def gaussian_nmr_input(which_section ,candidate_filename="X",conformer_number="Y"):
ENDLINE = "\n"
LINK1 = "%mem =16gb\n"
LINK2 = "%nproc =8\n"
LINK3 = "%%chk=%s \n" % (candidate_filename + '-conf -' + conformer_number + '
.chk')
72
LINK4 = "radii=bondi\n"
ROUTE1 = "# b3lyp /6 -311+G(2d,p) nmr guess=read geom=check integral(
ultrafinegrid) scrf=(iefpcm ,read ,solvent=chloroform)"
TITLE1 = "Candidate Structure: %s, Conformer: %s, NMR calculation with
chloroform solvation" % (candidate_filename ,conformer_number)
MOL1 = "0 1"
CARTHEAD = " X Y Z\n"
LINKZERO = LINK1 + LINK2 + LINK3
ROUTE = ROUTE1 + ENDLINE
TITLE = TITLE1 + ENDLINE
MOLECULE = MOL1 + ENDLINE
READLINE = LINK4 + ENDLINE
END = ENDLINE
if (which_section == "link"): return LINKZERO
if (which_section == "route"): return ROUTE
if (which_section == "title"): return TITLE
if (which_section == "molecule"): return MOLECULE
if (which_section == "readline"): return READLINE
if (which_section == "end"): return END
return "There is a problem generating the gaussian file."
######################################################################
######################################################################
# Run the program
main()
73
A-2 NMR Scripts
A-2.1 nmr-data compilation.py
nmr-data compilation.py
#################################################################
# #
# nmr -data_compilation.py #
# #
# Copyright Patrick H. Willoughby September 2011 #
# #
# Does Bolzmann -analysis and searches for imaginary #
# frequencies , and compiles the NMR shielding tensors #
# then prints the data into several .csv files for #
# viewing in a spreadsheet application #
# #
#################################################################
import sys
import re
import math
HARTREE_TO_KCAL = 627.509391
TEMPERATURE = 298.0
GAS_CONSTANT = 0.001986
PROTON_SHIFT_TMS = input(""" Enter the computed NMR shield tensor for the protons in
TMS:
""")
CARBON_SHIFT_TMS = input(""" Enter the computed NMR shield tensor for the protons in
TMS:
""")
OUTPUT_PREFIX = raw_input(""" Enter the name of the candidate structure:
""") + "-nmr_data_compilation"
#Below are the index values for the master data structure.
NAME = 0; CONF_NUM = 1; ENERGY = 2; KCAL_E = 3; REL_E = 4; BOLTZMANN_FACTOR = 5;
MOL_X = 6; CARBON_CS = 7; PROTON_CS = 8; IMAG_FREQUENCIES = 9
#Below are the index values for the proton and carbon chemical shift data
substructures.
ATOM_NUMBER = 0 ; ISOTROPIC_VALUE = 1; REF_SHIFT = 2; WEIGHTED_SHIFT = 3;
def main():
lofc_freq = read_gaussian_freq_outfiles ()
lofc_nmr = read_gaussian_nmr_outfiles ()
locs = prepare_list_of_chemical_shifts(lofc_nmr)
lofe = get_list_of_free_energies(lofc_freq)
lofe = boltzmann_analysis(lofe)
lofe = report_chemical_shifts(lofc_nmr , lofe)
summed_proton_shifts = final_proton_chemical_shifts(lofe)
summed_carbon_shifts = final_carbon_chemical_shifts(lofe)
lofe = count_imaginary_freq(lofc_freq , lofe)
write_final_shift_csv(summed_proton_shifts ,summed_carbon_shifts)
write_master_csv(lofe)
def boltzmann_analysis(lofe):
lofe = kcal_convert(lofe)
minE = find_minimum_E(lofe)
74
lofe = calc_rel_E(lofe , minE)
lofe = calc_boltzmann_weights(lofe)
denom = calc_boltzmann_denomenator(lofe)
lofe = calc_mol_fraction(lofe ,denom)
return lofe
def report_chemical_shifts(lofc_nmr ,lofe):
get_chemical_shifts(lofc_nmr , lofe)
ref_chemical_shift(lofe)
boltzmann_chemical_shifts(lofe)
return lofe
def write_master_csv(lofe):
masterpwriter = open(OUTPUT_PREFIX+"-master_proton.csv",'w')
mastercwriter = open(OUTPUT_PREFIX+"-master_carbon.csv",'w')
print >> masterpwriter , "filename , energy (a.u.), energy (kcal), rel energy (kcal)
, boltzmann factor , eq mole fraction , imaginary freqs"
for conformation in lofe:
print >> masterpwriter , conformation[NAME],",", conformation[ENERGY],",",
conformation[KCAL_E],",", conformation[REL_E],",",conformation[
BOLTZMANN_FACTOR],",", conformation[MOL_X],",", conformation[
IMAG_FREQUENCIES]
print >>masterpwriter , " "
for conformation in lofe:
print >> masterpwriter , "conformation",",", conformation[NAME],",", "mole
fraction",",", conformation[MOL_X]
print >> masterpwriter , "Atom Number , Isotropic Value , Shift of Ref , Ref
Chemical Shift , Avg Chemical Shift"
for proton in conformation[PROTON_CS ]:
print >> masterpwriter , proton[ATOM_NUMBER],",", proton[ISOTROPIC_VALUE],
",", PROTON_SHIFT_TMS ,",",proton[REF_SHIFT],",",proton[
WEIGHTED_SHIFT]
print >> masterpwriter , " "
print >> mastercwriter , "filename , energy (a.u.), energy (kcal), rel energy (kcal)
, boltzmann factor , eq mole fraction"
for conformation in lofe:
print >> mastercwriter , conformation[NAME],",", conformation[ENERGY],",",
conformation[KCAL_E],",", conformation[REL_E],",",conformation[
BOLTZMANN_FACTOR],",", conformation[MOL_X]
print >>mastercwriter , " "
for conformation in lofe:
print >> mastercwriter , "conformation",",", conformation[NAME],",", "mole
fraction",",", conformation[MOL_X]
print >> mastercwriter , "Atom Number , Isotropic Value , Shift of Ref , Ref
Chemical Shift , Avg Chemical Shift"
for carbon in conformation[CARBON_CS ]:
print >> mastercwriter , carbon[ATOM_NUMBER],",", carbon[ISOTROPIC_VALUE],
",", CARBON_SHIFT_TMS ,",",carbon[REF_SHIFT],",",carbon[
WEIGHTED_SHIFT]
print >> mastercwriter , " "
def write_final_shift_csv(summed_proton_shifts ,summed_carbon_shifts):
ATOM_NUMBER = 0; SHIFT = 1
pwriter = open(OUTPUT_PREFIX+"-avg_proton.csv",'w')
cwriter = open(OUTPUT_PREFIX+"-avg_carbon.csv",'w')
75
print >> pwriter , "ATOM NUMBER , CHEMICAL SHIFT"
for item in summed_proton_shifts:
print >> pwriter , item[ATOM_NUMBER],",",item[SHIFT]
print >> cwriter , "ATOM NUMBER , CHEMICAL SHIFT"
for item in summed_carbon_shifts:
print >> cwriter , item[ATOM_NUMBER],",",item[SHIFT]
return 0
def final_proton_chemical_shifts(lofe):
ATOM_NUMBER = 0; SHIFT = 1
final_proton_cshift = []
for proton in lofe [0][ PROTON_CS ]:
final_proton_cshift.append ([ proton[ATOM_NUMBER],proton[WEIGHTED_SHIFT ]])
for conformation in lofe [1:]:
counter = 0
for proton in conformation[PROTON_CS ]:
final_proton_cshift[counter ][SHIFT] += proton[WEIGHTED_SHIFT]
counter += 1
return final_proton_cshift
def final_carbon_chemical_shifts(lofe):
ATOM_NUMBER = 0; SHIFT = 1
final_carbon_cshift = []
for carbon in lofe [0][ CARBON_CS ]:
final_carbon_cshift.append ([ carbon[ATOM_NUMBER],carbon[WEIGHTED_SHIFT ]])
for conformation in lofe [1:]:
counter = 0
for carbon in conformation[CARBON_CS ]:
final_carbon_cshift[counter ][SHIFT] += carbon[WEIGHTED_SHIFT]
counter += 1
return final_carbon_cshift
def kcal_convert(lofe):
NAME = 0; CONF_NUM = 1; ENERGY = 2
for entry in lofe:
entry.append(entry[ENERGY] * HARTREE_TO_KCAL)
return lofe
def find_minimum_E(lofe):
minE = 0
for entry in lofe: #This finds the minimum energy
if entry[KCAL_E] < minE:
minE = entry[KCAL_E]
return minE
def calc_rel_E(lofe , minE):
for entry in lofe:
entry.append(entry[KCAL_E] - minE)
return lofe
76
def calc_boltzmann_weights(lofe):
for entry in lofe:
entry.append(math.exp( (-1 * entry[REL_E ]) / (TEMPERATURE * GAS_CONSTANT)))
return lofe
def calc_boltzmann_denomenator(lofe):
Boltzmann_denomenator = 0
for entry in lofe:
Boltzmann_denomenator = Boltzmann_denomenator + entry[BOLTZMANN_FACTOR]
return Boltzmann_denomenator
def calc_mol_fraction(lofe ,Boltzmann_denomenator):
for entry in lofe:
entry.append(entry[BOLTZMANN_FACTOR ]/ Boltzmann_denomenator)
return lofe
def ref_chemical_shift(lofe):
for conformation in lofe:
for proton in conformation[PROTON_CS ]:
proton.append(abs(PROTON_SHIFT_TMS - float(proton[ISOTROPIC_VALUE ])))
for carbon in conformation[CARBON_CS ]:
carbon.append(abs(CARBON_SHIFT_TMS - float(carbon[ISOTROPIC_VALUE ])))
return lofe
def boltzmann_chemical_shifts(lofe):
for conformation in lofe:
for proton in conformation[PROTON_CS ]:
proton.append(proton[REF_SHIFT] * conformation[MOL_X])
for carbon in conformation[CARBON_CS ]:
carbon.append(carbon[REF_SHIFT] * conformation[MOL_X])
return lofe
def get_chemical_shifts(lofc_nmr , lofe):
ATOM_NUMBER = 0; ATOM_SYMBOL = 1; ISOTROPIC_VALUE = 4
counter = 0
for file in lofc_nmr:
proton_chemicalshift_table = []
carbon_chemicalshift_table = []
for line in file [2]:
if "Isotropic" in line:
linesplit = line.split ()
if linesplit[ATOM_SYMBOL] == "C":
carbon_chemicalshift_table.append ([ linesplit[ATOM_NUMBER],
linesplit[ISOTROPIC_VALUE ]])
if linesplit[ATOM_SYMBOL] == "H":
proton_chemicalshift_table.append ([ linesplit[ATOM_NUMBER],
linesplit[ISOTROPIC_VALUE ]])
lofe[counter ]. append(carbon_chemicalshift_table)
lofe[counter ]. append(proton_chemicalshift_table)
counter += 1
return lofe
def prepare_list_of_chemical_shifts(lofc_nmr):
list_of_chemical_shifts = []
for file in lofc_nmr:
list_of_chemical_shifts.append ([file[0],file [1]])
77
return list_of_chemical_shifts
def count_imaginary_freq(lofc_freq , lofe):
LINE_POS_OF_FREQUENCY_A = 2; LINE_POS_OF_FREQUENCY_B = 3; LINE_POS_OF_FREQUENCY_C
= 4;
counter = 0
for file in lofc_freq:
IMAG_FREQUENCIES = 0
for line in file [2]:
if "Frequencies -- " in line:
freq_linesplit = line.split()
if float(freq_linesplit[LINE_POS_OF_FREQUENCY_A ]) < 0:
IMAG_FREQUENCIES = IMAG_FREQUENCIES + 1
if float(freq_linesplit[LINE_POS_OF_FREQUENCY_B ]) < 0:
IMAG_FREQUENCIES = IMAG_FREQUENCIES + 1
if float(freq_linesplit[LINE_POS_OF_FREQUENCY_C ]) < 0:
IMAG_FREQUENCIES = IMAG_FREQUENCIES + 1
lofe[counter ]. append(IMAG_FREQUENCIES)
counter += 1
return lofe
def get_list_of_free_energies(lofc_freq):
LINE_POS_OF_FREE_ENERGY = 7
list_of_free_energies = []
for file in lofc_freq:
for line in file [2]:
if "Free Energies=" in line:
free_linesplit = line.split()
free_energy = float(free_linesplit[LINE_POS_OF_FREE_ENERGY ])
list_of_free_energies.append ([file[0],file[1], free_energy ])
return list_of_free_energies
def get_conf_number(filename):
split_filename = re.findall(r'\w+', filename)
rev_filename = split_filename [::-1]
conf_number = rev_filename [1]
split_conf_number = re.findall('[0-9]*',conf_number)
return split_conf_number [0]
def read_gaussian_nmr_outfiles ():
list_of_nmr_outfiles = []
list_of_files= sys.argv [1:]
for file in list_of_files:
if file.find('nmr -') !=-1:
list_of_nmr_outfiles.append ([file ,int(get_conf_number(file)),open(file ,"r
").readlines ()])
return list_of_nmr_outfiles
def read_gaussian_freq_outfiles ():
list_of_freq_outfiles = []
list_of_files= sys.argv [1:]
for file in list_of_files:
if file.find('freq -') !=-1:
list_of_freq_outfiles.append ([file ,int(get_conf_number(file)),open(file ,"
r").readlines ()])
return list_of_freq_outfiles
78
if __name__ == "__main__":
main()
print """
The script successfully performed the Boltzmann weighting ,
compiled the results of the NMR computation , and assembled
these data in the following . c s v files:
%s-master_proton.csv
%s-avg_proton.csv
%s-master_carbon.csv
%s-avg_carbon.csv
""" % (OUTPUT_PREFIX ,OUTPUT_PREFIX ,OUTPUT_PREFIX ,OUTPUT_PREFIX)
79
Supporting Information
S-I Calculated Geometries, Energies and NMR Shielding
Tensors for Compounds with Computed NMR Shifts
S-I.1 cis-Carvomenthone (201a) . . . . . . . . . . . . . . . . . . . . . . . 81
S-I.2 trans-Carvomenthone (201b) . . . . . . . . . . . . . . . . . . . . . . 97
S-I.3 Nankakurine – Revised Diastereomer(202a) . . . . . . . . . . . . . . 111
S-I.4 Nankakurine – Originally Proposed Diastereomer (202b) . . . . . . 120
S-I.5 Normal trans-Menthide (203b) . . . . . . . . . . . . . . . . . . . . . 129
S-I.6 Normal cis-Carvomenthide (204a) . . . . . . . . . . . . . . . . . . . 135
S-I.7 Normal trans-Carvomenthide (204b) . . . . . . . . . . . . . . . . . . 147
S-I.8 Abnormal cis-Carvomenthide (205a) . . . . . . . . . . . . . . . . . . 153
S-I.9 Abnormal trans-Carvomenthide (205b) . . . . . . . . . . . . . . . . 167
S-I.10 Normal Lactone of β-Pinene (206) . . . . . . . . . . . . . . . . . . . 175
S-I.11 Abnormal Lactone of β-Pinene (207) . . . . . . . . . . . . . . . . . . 177
All geometries extracted are in the standard (x,y,z) coordinate system. Energies reported
(in hartrees) indicate the level of theory they are obtained at. Energies reported include: 1)
energies from optimizations (SCF Energy), 2) energies from NMR calculations (SCF Energy
from NMR), 3) Gibb’s free energy (Sum of Electronic and Thermal Free Energies)
80
S-I.1 cis-Carvomenthone (201a)
Fig. S1 201a – Conformer 1
SCF Energy - E(RM062X) =466.957 997 808
SCF Energy from NMR - E(RB3LYP) =467.291 748 885
Sum of Electronic and Thermal Free Energies =466.729 834 000
Table S1 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201a – Conformer 1
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =0.947 279 =1.520 474 =0.078 644 146.8990 36.7086
2 C =1.929 336 =0.349 551 0.140 883 131.7715 51.8361
3 C =0.009 795 0.951 482 1.240 809 133.3244 50.2832
4 C 0.981 364 =0.180 309 0.887 180 131.1437 52.4639
5 C 0.206 542 =1.507 481 0.925 378 150.8655 32.7421
6 H =0.558 595 =1.467 469 =1.104 474 30.3115 1.5534
7 H =1.506 878 =2.459 165 =0.004 839 29.9441 1.9208
8 H =2.386 502 =0.496 909 1.132 360 29.3401 2.5248
Continued on next page
81
Table S1 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
9 H 0.455 963 1.938 412 1.250 219 29.2453 2.6196
10 H =0.421 000 0.756 911 2.239 580 29.2676 2.5973
11 H 1.756 700 =0.206 501 1.666 171 30.2016 1.6633
12 H =0.198 261 =1.643 411 1.937 060 30.0152 1.8497
13 H 0.875 732 =2.353 144 0.742 262 29.7904 2.0745
14 C =1.158 504 0.955 909 0.256 239 =46.6537 230.2613
15 O =1.436 235 1.940 260 =0.408 895 — —
16 C =3.016 347 =0.296 113 =0.923 351 167.1928 16.4148
17 H =3.726 141 0.511 314 =0.728 917 30.5584 1.3065
18 H =2.576 264 =0.124 870 =1.910 794 31.0415 0.8234
19 H =3.562 432 =1.243 466 =0.948 868 31.2574 0.6075
20 C 1.696 244 0.083 370 =0.457 179 150.5958 33.0118
21 H 0.935 249 0.243 733 =1.235 681 30.5290 1.3359
22 C 2.560 603 1.346 770 =0.389 124 160.9833 22.6243
23 H 1.968 764 2.247 522 =0.208 676 30.3877 1.4772
24 H 3.303 203 1.257 385 0.413 548 31.4642 0.4007
25 H 3.099 708 1.490 272 =1.330 442 31.0125 0.8524
26 C 2.560 127 =1.108 166 =0.880 626 161.7347 21.8729
27 H 3.264 694 =1.373 171 =0.082 076 31.3929 0.4720
28 H 1.961 874 =1.993 797 =1.111 927 30.5926 1.2723
29 H 3.142 353 =0.858 344 =1.772 744 31.0731 0.7918
82
Fig. S2 201a – Conformer 2
SCF Energy - E(RM062X) =466.956 332 496
SCF Energy from NMR - E(RB3LYP) =467.292 225 553
Sum of Electronic and Thermal Free Energies =466.729 305 000
Table S2 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201a – Conformer 2
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 1.424 114 =1.143 683 =1.120 536 146.4062 37.2014
2 C 2.195 203 =0.176 827 =0.202 202 131.1068 52.5008
3 C =0.073 020 0.877 348 0.435 844 141.7922 41.8154
4 C =0.789 636 =0.070 617 =0.546 520 131.3300 52.2776
5 C =0.011 499 =1.386 942 =0.648 099 153.2530 30.3546
6 H 1.976 538 =2.088 242 =1.180 966 30.0260 1.8389
7 H 1.396 110 =0.724 037 =2.134 023 29.9765 1.8884
8 H 3.116 761 0.146 486 =0.696 650 29.4200 2.4449
Continued on next page
83
Table S2 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
9 H =0.086 538 0.432 163 1.440 704 29.4323 2.4326
10 H =0.549 288 1.859 116 0.492 529 29.7829 2.0820
11 H =0.756 334 0.402 956 =1.540 534 30.1614 1.7035
12 H =0.519 913 =2.059 022 =1.349 380 30.5611 1.3038
13 H =0.004 452 =1.892 692 0.325 649 29.8378 2.0271
14 C 1.375 868 1.076 467 0.049 014 =50.3354 233.9430
15 O 1.867 534 2.189 700 =0.045 680 — —
16 C 2.568 401 =0.822 919 1.142 887 163.4942 20.1134
17 H 3.109 829 =0.116 017 1.777 945 30.8288 1.0361
18 H 1.687 232 =1.168 500 1.690 878 30.3607 1.5042
19 H 3.214 300 =1.687 326 0.963 115 30.8579 1.0070
20 C =2.280 997 =0.275 531 =0.211 384 144.9660 38.6416
21 H =2.654 392 =0.999 607 =0.949 876 30.1496 1.7153
22 C =2.522 330 =0.864 209 1.181 564 167.2746 16.3330
23 H =1.975 811 =1.799 060 1.337 487 30.6863 1.1786
24 H =2.224 859 =0.158 417 1.965 298 31.2912 0.5737
25 H =3.587 474 =1.074 633 1.320 137 31.0366 0.8283
26 C =3.085 333 1.015 784 =0.384 231 160.6166 22.9910
27 H =2.819 419 1.754 639 0.379 635 30.9689 0.8960
28 H =2.910 146 1.465 692 =1.367 139 31.0495 0.8154
29 H =4.157 045 0.815 684 =0.287 405 30.8726 0.9923
84
Fig. S3 201a – Conformer 3
SCF Energy - E(RM062X) =466.956 327 984
SCF Energy from NMR - E(RB3LYP) =467.292 250 850
Sum of Electronic and Thermal Free Energies =466.728 725 000
Table S3 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201a – Conformer 3
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 1.069 944 =1.380 230 =0.930 407 146.3687 37.2389
2 C 2.125 406 =0.490 498 =0.246 712 131.0681 52.5395
3 C 0.220 363 1.140 003 0.352 450 134.2092 49.3984
4 C =0.783 981 0.247 741 =0.403 220 131.3784 52.2292
5 C =0.327 588 =1.213 486 =0.326 712 160.9567 22.6509
6 H 1.395 792 =2.424 589 =0.865 453 30.0197 1.8452
7 H 1.026 282 =1.124 240 =1.996 525 30.0774 1.7875
8 H 3.038 053 =0.468 779 =0.850 797 29.4176 2.4473
9 H 0.214 840 0.872 421 1.418 417 29.0464 2.8185
10 H =0.036 369 2.199 709 0.267 211 29.9743 1.8906
11 H =0.748 035 0.548 670 =1.462 202 30.1926 1.6723
Continued on next page
85
Table S3 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
12 H =1.030 843 =1.860 373 =0.862 238 30.3425 1.5224
13 H =0.326 212 =1.544 730 0.719 734 30.2536 1.6113
14 C 1.630 234 0.941 682 =0.156 379 =49.9573 233.5649
15 O 2.339 985 1.884 480 =0.468 537 — —
16 C 2.487 328 =0.994 010 1.160 979 163.4995 20.1081
17 H 3.231 466 =0.343 186 1.628 721 30.8287 1.0362
18 H 1.613 116 =1.040 207 1.816 542 30.3684 1.4965
19 H 2.908 495 =2.000 986 1.088 700 30.8721 0.9928
20 C =2.229 594 0.492 866 0.075 604 144.8184 38.7892
21 H =2.369 091 1.583 363 0.087 169 30.3860 1.4789
22 C =3.250 557 =0.090 559 =0.905 106 160.2374 23.3702
23 H =3.082 747 0.281 337 =1.921 187 30.9751 0.8898
24 H =3.196 289 =1.184 464 =0.929 533 30.8364 1.0285
25 H =4.268 169 0.181 460 =0.607 387 30.8193 1.0456
26 C =2.499 704 =0.029 417 1.489 735 166.9560 16.6516
27 H =2.470 474 =1.124 255 1.515 284 31.2187 0.6462
28 H =1.775 475 0.347 408 2.218 895 30.7412 1.1237
29 H =3.495 328 0.281 051 1.821 547 31.0377 0.8272
Fig. S4 201a – Conformer 4
86
SCF Energy - E(RM062X) =466.956 274 003
SCF Energy from NMR - E(RB3LYP) =467.292 236 672
Sum of Electronic and Thermal Free Energies =466.728 989 000
Table S4 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201a – Conformer 4
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 1.257 157 =1.439 734 =0.777 704 146.8870 36.7206
2 C 2.209 321 =0.378 327 =0.201 676 131.7479 51.8597
3 C 0.120 221 1.057 961 0.291 344 135.6344 47.9732
4 C =0.805 184 =0.039 694 =0.274 288 129.5862 54.0214
5 C =0.131 557 =1.411 259 =0.135 308 154.9697 28.6379
6 H 1.713 282 =2.428 749 =0.655 619 30.0183 1.8466
7 H 1.148 405 =1.270 140 =1.856 584 30.0554 1.8095
8 H 3.103 464 =0.301 973 =0.828 549 29.4490 2.4159
9 H 0.169 582 0.942 022 1.385 379 29.6147 2.2502
10 H =0.251 988 2.061 785 0.078 847 29.3970 2.4679
11 H =0.948 082 0.160 971 =1.349 209 30.6499 1.2150
12 H =0.747 276 =2.179 817 =0.610 782 29.9870 1.8779
13 H =0.068 506 =1.673 550 0.930 511 30.3729 1.4920
14 C 1.536 195 0.978 577 =0.236 443 =49.6073 233.2149
15 O 2.114 866 1.968 633 =0.655 364 — —
16 C 2.649 535 =0.702 209 1.235 671 163.7384 19.8692
17 H 3.323 556 0.068 892 1.619 239 30.8280 1.0369
18 H 1.798 463 =0.781 985 1.917 790 30.3665 1.4984
19 H 3.180 424 =1.658 678 1.245 600 30.8746 0.9903
20 C =2.194 285 0.007 543 0.393 422 142.4909 41.1167
21 H =2.045 641 =0.189 701 1.466 683 30.5450 1.3199
22 C =2.855 160 1.382 292 0.245 401 161.0610 22.5466
23 H =2.304 365 2.170 485 0.764 483 30.5420 1.3229
24 H =2.927 302 1.658 532 =0.814 035 31.4003 0.4646
25 H =3.869 272 1.363 248 0.656 050 31.0358 0.8291
26 C =3.129 835 =1.068 547 =0.167 565 160.5330 23.0746
27 H =3.214 795 =0.969 715 =1.257 059 31.3359 0.5290
28 H =2.784 799 =2.080 814 0.056 125 30.3947 1.4702
29 H =4.132 526 =0.959 482 0.256 922 30.9868 0.8781
87
Fig. S5 201a – Conformer 5
SCF Energy - E(RM062X) =466.953 841 772
SCF Energy from NMR - E(RB3LYP) =467.288 664 184
Sum of Electronic and Thermal Free Energies =466.725 996 000
Table S5 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201a – Conformer 5
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =0.723 626 1.481 195 0.312 356 143.6563 39.9513
2 C =1.853 099 0.555 267 =0.177 218 132.7238 50.8838
3 C =0.068 415 =0.894 230 =1.311 024 129.8990 53.7086
4 C 1.066 540 0.085 768 =0.934 668 133.1814 50.4262
5 C 0.487 175 1.479 217 =0.626 049 155.6621 27.9455
6 H =0.441 136 1.177 411 1.325 561 30.2359 1.6290
7 H =1.122 863 2.498 598 0.392 162 29.9357 1.9292
8 H =2.162 861 0.915 704 =1.170 989 29.2985 2.5664
9 H 0.290 138 =1.927 290 =1.345 508 29.6379 2.2270
10 H =0.431 646 =0.631 045 =2.314 564 29.0318 2.8331
11 H 1.683 558 0.194 494 =1.836 311 29.6307 2.2342
12 H 0.175 243 1.931 584 =1.577 090 30.0050 1.8599
13 H 1.270 993 2.128 627 =0.221 362 29.7931 2.0718
14 C =1.283 307 =0.830 677 =0.412 327 =48.1059 231.7135
Continued on next page
88
Table S5 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
15 O =1.784 797 =1.834 815 0.066 813 — —
16 C =3.048 455 0.547 241 0.765 011 167.0990 16.5086
17 H =3.850 558 =0.091 825 0.388 249 30.5350 1.3299
18 H =2.755 449 0.171 612 1.750 532 31.0387 0.8262
19 H =3.437 599 1.562 354 0.884 983 31.2517 0.6132
20 C 2.024 800 =0.506 818 0.124 036 141.5152 42.0924
21 H 2.310 503 =1.492 337 =0.271 166 30.0877 1.7772
22 C 3.306 644 0.322 102 0.242 734 159.2106 24.3970
23 H 3.769 661 0.485 502 =0.736 194 31.0290 0.8359
24 H 3.106 267 1.301 048 0.692 038 30.8343 1.0306
25 H 4.034 200 =0.188 302 0.881 828 30.8093 1.0556
26 C 1.423 304 =0.734 409 1.514 618 162.3639 21.2437
27 H 1.274 317 0.214 378 2.040 351 31.3093 0.5556
28 H 0.466 322 =1.264 430 1.478 720 30.8850 0.9799
29 H 2.109 931 =1.335 490 2.119 438 31.0346 0.8303
Fig. S6 201a – Conformer 6
SCF Energy - E(RM062X) =466.954 233 138
SCF Energy from NMR - E(RB3LYP) =467.287 425 809
Sum of Electronic and Thermal Free Energies =466.725 564 000
89
Table S6 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201a – Conformer 6
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =1.067 873 1.457 736 0.511 627 146.2731 37.3345
2 C =1.891 108 0.340 785 =0.156 833 132.2590 51.3486
3 C 0.265 807 =0.433 855 =1.348 492 137.4884 46.1192
4 C 1.075 398 0.687 927 =0.667 613 135.0751 48.5325
5 C 0.143 409 1.861 077 =0.327 740 145.3729 38.2347
6 H =0.753 718 1.132 192 1.510 298 30.0260 1.8389
7 H =1.723 165 2.322 689 0.663 303 29.8992 1.9657
8 H =2.285 593 0.759 210 =1.097 985 29.4018 2.4631
9 H 0.857 699 =1.340 018 =1.507 943 29.3388 2.5261
10 H =0.059 201 =0.073 909 =2.335 040 29.4490 2.4159
11 H 1.785 924 1.062 091 =1.415 662 29.7914 2.0735
12 H =0.216 171 2.300 123 =1.268 615 29.7328 2.1321
13 H 0.714 327 2.641 922 0.187 347 30.0611 1.8038
14 C =1.002 871 =0.808 677 =0.608 696 =47.6969 231.3045
15 O =1.323 086 =1.973 671 =0.441 114 — —
16 C =3.048 757 =0.130 780 0.713 098 166.8276 16.7800
17 H =3.662 022 =0.872 808 0.197 442 30.3557 1.5092
18 H =2.671 211 =0.588 551 1.633 552 31.0766 0.7883
19 H =3.681 525 0.718 535 0.986 118 31.2293 0.6356
20 C 1.933 665 0.188 338 0.524 814 143.0595 40.5481
21 H 2.125 348 1.061 544 1.164 765 30.1494 1.7155
22 C 1.285 503 =0.899 753 1.390 880 159.0823 24.5253
23 H 0.297 993 =0.623 384 1.770 601 31.1669 0.6980
24 H 1.176 069 =1.833 818 0.829 042 31.1894 0.6755
25 H 1.922 748 =1.108 988 2.255 882 31.0184 0.8465
26 C 3.285 571 =0.325 835 0.017 964 157.5125 26.0951
27 H 3.141 625 =1.163 610 =0.675 406 30.8893 0.9756
28 H 3.837 860 0.458 438 =0.509 075 30.9713 0.8936
29 H 3.905 242 =0.684 065 0.846 238 31.0509 0.8140
90
Fig. S7 201a – Conformer 7
SCF Energy - E(RM062X) =466.953 710 188
SCF Energy from NMR - E(RB3LYP) =467.289 314 281
Sum of Electronic and Thermal Free Energies =466.727 282 000
Table S7 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201a – Conformer 7
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 1.231 528 =1.460 191 0.482 700 152.1221 31.4855
2 C 1.945 435 =0.422 925 =0.395 703 136.2583 47.3493
3 C 0.000 966 1.035 835 0.455 611 136.6020 47.0056
4 C =0.864 015 =0.083 460 =0.135 294 140.2733 43.3343
5 C =0.293 029 =1.462 853 0.268 207 152.1140 31.4936
6 H 1.468 885 =1.237 905 1.531 263 30.4238 1.4411
7 H 1.643 741 =2.453 257 0.278 058 30.0601 1.8048
8 H 1.605 707 =0.562 609 =1.435 029 29.4187 2.4462
9 H =0.000 145 0.964 298 1.554 808 29.8059 2.0590
10 H =0.360 889 2.034 540 0.201 201 29.2667 2.5982
11 H =0.811 900 0.006 980 =1.231 930 30.4572 1.4077
12 H =0.551 669 =2.194 403 =0.504 176 29.6975 2.1674
13 H =0.783 950 =1.797 004 1.191 237 30.5104 1.3545
14 C 1.449 598 0.952 364 0.014 336 =48.5747 232.1823
15 O 2.170 062 1.936 077 0.017 219 — —
16 C 3.464 204 =0.529 627 =0.344 579 167.6816 15.9260
17 H 3.937 226 0.231 549 =0.968 269 30.2190 1.6459
18 H 3.821 485 =0.394 560 0.681 770 31.3312 0.5337
Continued on next page
91
Table S7 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
19 H 3.783 313 =1.515 870 =0.692 517 31.1850 0.6799
20 C =2.349 512 0.049 374 0.248 985 142.0973 41.5103
21 H =2.411 492 =0.031 855 1.345 481 30.6751 1.1898
22 C =2.943 002 1.397 516 =0.170 554 160.7544 22.8532
23 H =2.489 049 2.238 963 0.358 648 30.5190 1.3459
24 H =2.804 210 1.556 987 =1.247 201 31.4079 0.4570
25 H =4.017 851 1.420 290 0.034 290 31.0065 0.8584
26 C =3.176 994 =1.084 498 =0.365 112 161.1760 22.4316
27 H =3.092 711 =1.064 026 =1.459 062 31.3815 0.4834
28 H =2.853 370 =2.069 683 =0.019 143 30.4460 1.4189
29 H =4.234 704 =0.970 259 =0.108 763 30.9909 0.8740
Fig. S8 201a – Conformer 8
SCF Energy - E(RM062X) =466.953 455 609
SCF Energy from NMR - E(RB3LYP) =467.288 701 398
Sum of Electronic and Thermal Free Energies =466.726 233 000
92
Table S8 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201a – Conformer 8
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 1.026 231 =1.371 230 0.653 581 152.2754 31.3322
2 C 1.931 206 =0.540 525 =0.267 892 136.4702 47.1374
3 C 0.054 994 1.170 622 0.130 361 134.7346 48.8730
4 C =0.833 922 0.045 376 =0.410 587 143.3979 40.2097
5 C =0.458 634 =1.300 292 0.248 415 160.8053 22.8023
6 H 1.157 574 =1.003 469 1.679 549 30.4432 1.4217
7 H 1.368 450 =2.410 895 0.653 931 30.0427 1.8222
8 H 1.719 255 =0.831 207 =1.310 043 29.4053 2.4596
9 H =0.031 396 1.229 844 1.225 656 29.4193 2.4456
10 H =0.223 296 2.151 300 =0.268 622 29.8239 2.0410
11 H =0.615 693 =0.041 399 =1.485 086 29.7943 2.0706
12 H =0.688 055 =2.111 551 =0.450 754 30.1663 1.6986
13 H =1.077 809 =1.471 524 1.136 411 30.2896 1.5753
14 C 1.518 404 0.920 257 =0.166 373 =49.3697 232.9773
15 O 2.313 179 1.835 611 =0.297 058 — —
16 C 3.416 960 =0.736 481 0.010 471 167.6090 15.9986
17 H 4.028 174 =0.120 987 =0.652 377 30.1524 1.7125
18 H 3.651 392 =0.457 024 1.043 166 31.3491 0.5158
19 H 3.691 615 =1.785 175 =0.131 895 31.1662 0.6987
20 C =2.334 098 0.388 794 =0.313 981 146.7238 36.8838
21 H =2.486 715 1.279 009 =0.940 821 30.1533 1.7116
22 C =3.192 510 =0.740 259 =0.890 005 161.1179 22.4897
23 H =2.855 379 =1.024 139 =1.893 011 30.9803 0.8846
24 H =3.147 864 =1.630 947 =0.253 178 30.9616 0.9033
25 H =4.240 591 =0.432 706 =0.957 184 30.8745 0.9904
26 C =2.793 215 0.743 132 1.103 157 168.4562 15.1514
27 H =2.625 792 =0.086 223 1.799 520 31.1438 0.7211
28 H =2.275 879 1.624 682 1.493 130 30.9977 0.8672
29 H =3.865 916 0.961 156 1.105 185 31.2097 0.6552
93
Fig. S9 201a – Conformer 9
SCF Energy - E(RM062X) =466.953 313 023
SCF Energy from NMR - E(RB3LYP) =467.288 955 672
Sum of Electronic and Thermal Free Energies =466.726 162 000
Table S9 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201a – Conformer 9
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 1.296 870 =1.510 475 0.187 298 151.9584 31.6492
2 C 1.991 984 =0.271 688 =0.395 861 136.2841 47.3235
3 C =0.168 981 0.832 015 0.463 525 141.5454 42.0622
4 C =0.839 728 =0.216 678 =0.432 209 142.6075 41.0001
5 C =0.185 688 =1.599 011 =0.218 790 153.9736 29.6340
6 H 1.389 239 =1.468 696 1.280 514 30.3781 1.4868
7 H 1.832 733 =2.409 735 =0.132 427 30.0514 1.8135
8 H 1.808 301 =0.255 989 =1.482 787 29.4050 2.4599
9 H =0.229 302 0.521 082 1.517 471 29.7422 2.1227
10 H =0.633 628 1.819 505 0.392 016 29.6622 2.2027
11 H =0.649 057 0.084 075 =1.472 429 29.9127 1.9522
12 H =0.285 494 =2.173 632 =1.146 571 30.0357 1.8292
13 H =0.734 624 =2.154 040 0.550 476 30.1956 1.6693
14 C 1.305 179 0.973 667 0.145 185 =49.3624 232.9700
15 O 1.902 761 2.020 157 0.330 240 — —
16 C 3.495 456 =0.250 773 =0.145 160 167.4931 16.1145
17 H 3.955 018 0.645 972 =0.565 367 30.1527 1.7122
Continued on next page
94
Table S9 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
18 H 3.702 797 =0.265 259 0.930 119 31.3445 0.5204
19 H 3.964 204 =1.129 368 =0.596 765 31.1711 0.6938
20 C =2.372 610 =0.273 128 =0.270 023 147.0947 36.5129
21 H =2.701 149 =1.183 705 =0.792 342 30.2888 1.5761
22 C =2.816 579 =0.380 738 1.191 744 166.8357 16.7719
23 H =2.303 388 =1.187 693 1.724 664 30.7613 1.1036
24 H =2.621 456 0.555 433 1.727 021 31.4373 0.4276
25 H =3.892 106 =0.574 407 1.248 266 31.0640 0.8009
26 C =3.058 171 0.919 574 =0.941 384 160.4789 23.1287
27 H =2.773 345 1.861 354 =0.458 677 30.9336 0.9313
28 H =2.790 336 0.986 918 =2.000 722 31.0167 0.8482
29 H =4.146 886 0.830 339 =0.870 327 30.8848 0.9801
Fig. S10 201a – Conformer 10
SCF Energy - E(RM062X) =466.954 233 138
SCF Energy from NMR - E(RB3LYP) =467.287 425 809
Sum of Electronic and Thermal Free Energies =466.725 564 000
95
Table S10 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201a – Conformer 10
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =1.067 873 1.457 736 0.511 627 146.2731 37.3345
2 C =1.891 108 0.340 785 =0.156 833 132.2590 51.3486
3 C 0.265 807 =0.433 855 =1.348 492 137.4884 46.1192
4 C 1.075 398 0.687 927 =0.667 613 135.0751 48.5325
5 C 0.143 409 1.861 077 =0.327 741 145.3729 38.2347
6 H =0.753 717 1.132 192 1.510 298 30.0260 1.8389
7 H =1.723 164 2.322 689 0.663 303 29.8992 1.9657
8 H =2.285 593 0.759 210 =1.097 984 29.4018 2.4631
9 H 0.857 699 =1.340 018 =1.507 943 29.3388 2.5261
10 H =0.059 201 =0.073 909 =2.335 040 29.4490 2.4159
11 H 1.785 924 1.062 090 =1.415 662 29.7914 2.0735
12 H =0.216 171 2.300 123 =1.268 615 29.7328 2.1321
13 H 0.714 327 2.641 922 0.187 347 30.0611 1.8038
14 C =1.002 871 =0.808 677 =0.608 696 =47.6969 231.3045
15 O =1.323 086 =1.973 671 =0.441 114 — —
16 C =3.048 757 =0.130 780 0.713 098 166.8276 16.7800
17 H =3.662 022 =0.872 807 0.197 442 30.3557 1.5092
18 H =2.671 211 =0.588 550 1.633 553 31.0766 0.7883
19 H =3.681 525 0.718 535 0.986 118 31.2293 0.6356
20 C 1.933 665 0.188 338 0.524 814 143.0595 40.5481
21 H 2.125 347 1.061 544 1.164 765 30.1494 1.7155
22 C 1.285 503 =0.899 753 1.390 880 159.0823 24.5253
23 H 0.297 993 =0.623 385 1.770 601 31.1669 0.6980
24 H 1.176 069 =1.833 818 0.829 042 31.1894 0.6755
25 H 1.922 748 =1.108 988 2.255 882 31.0184 0.8465
26 C 3.285 571 =0.325 835 0.017 964 157.5125 26.0951
27 H 3.141 625 =1.163 610 =0.675 406 30.8893 0.9756
28 H 3.837 861 0.458 438 =0.509 074 30.9713 0.8936
29 H 3.905 242 =0.684 065 0.846 238 31.0509 0.8140
96
S-I.2 trans-Carvomenthone (201b)
Fig. S11 201b – Conformer 1
SCF Energy - E(RM062X) =466.958 742 037
SCF Energy from NMR - E(RB3LYP) =467.294 925 758
Sum of Electronic and Thermal Free Energies =466.731 688 000
Table S11 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201b – Conformer 1
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 1.349 734 =1.413 211 =0.543 057 142.5474 41.0602
2 C 2.040 902 =0.366 200 0.353 530 132.3439 51.2637
3 C =0.202 526 0.872 719 0.484 908 137.6391 45.9685
4 C =0.852 544 =0.176 471 =0.440 836 130.1289 53.4787
5 C =0.147 725 =1.524 219 =0.254 736 147.0047 36.6029
6 H 1.844 495 =2.379 401 =0.397 047 29.7406 2.1243
7 H 1.503 029 =1.130 495 =1.593 787 30.5210 1.3439
8 H 1.907 593 =0.692 481 1.396 784 29.3767 2.4882
9 H =0.350 857 0.571 287 1.531 060 29.6724 2.1925
10 H =0.627 216 1.869 712 0.344 799 29.6302 2.2347
11 H =0.667 394 0.145 127 =1.477 897 30.1341 1.7308
12 H =0.601 710 =2.270 210 =0.917 536 30.2779 1.5870
13 H =0.289 232 =1.879 104 0.775 149 30.0001 1.8648
14 C 1.287 467 0.947 001 0.237 120 =47.3047 230.9123
15 O 1.840 402 1.992 941 =0.059 911 — —
Continued on next page
97
Table S11 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
16 C =2.383 485 =0.265 760 =0.277 992 145.0583 38.5493
17 H =2.705 632 =1.083 645 =0.938 594 30.1447 1.7202
18 C =3.080 296 1.011 890 =0.753 540 160.4320 23.1756
19 H =2.861 100 1.854 724 =0.088 947 30.9653 0.8996
20 H =2.762 585 1.285 739 =1.765 042 31.0323 0.8326
21 H =4.166 293 0.875 662 =0.762 902 30.8652 0.9997
22 C =2.830 505 =0.611 796 1.145 078 167.1825 16.4251
23 H =2.593 110 0.200 542 1.841 176 31.3204 0.5445
24 H =3.914 911 =0.757 832 1.172 168 31.0485 0.8164
25 H =2.361 957 =1.528 073 1.516 258 30.6946 1.1703
26 C 3.523 708 =0.219 352 0.043 327 167.1575 16.4501
27 H 3.996 633 0.516 084 0.698 454 30.5762 1.2887
28 H 4.030 661 =1.179 838 0.172 283 31.2203 0.6446
29 H 3.667 986 0.111 077 =0.989 921 31.0515 0.8134
Fig. S12 201b – Conformer 2
SCF Energy - E(RM062X) =466.958 696 298
SCF Energy from NMR - E(RB3LYP) =467.294 939 888
Sum of Electronic and Thermal Free Energies =466.731 445 000
98
Table S12 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201b – Conformer 2
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 1.070 206 =1.510 199 =0.134 644 142.5389 41.0687
2 C 1.997 068 =0.418 154 0.436 980 132.1375 51.4701
3 C 0.036 630 1.221 656 0.230 094 130.0821 53.5255
4 C =0.852 496 0.110 557 =0.364 412 130.2084 53.3992
5 C =0.402 716 =1.248 204 0.183 326 154.8504 28.7572
6 H 1.384 564 =2.479 379 0.267 310 29.7329 2.1320
7 H 1.210 687 =1.554 635 =1.223 583 30.6179 1.2470
8 H 1.865 119 =0.420 859 1.530 250 29.4019 2.4630
9 H =0.105 113 1.258 617 1.318 840 29.2819 2.5830
10 H =0.214 049 2.201 045 =0.186 892 29.8123 2.0526
11 H =0.672 771 0.103 336 =1.451 068 30.1546 1.7103
12 H =1.017 424 =2.051 149 =0.237 542 30.0668 1.7981
13 H =0.543 798 =1.270 183 1.272 717 30.4201 1.4448
14 C 1.498 036 0.937 477 =0.031 359 =46.7583 230.3659
15 O 2.218 612 1.737 916 =0.604 289 — —
16 C =2.351 547 0.417 422 =0.170 198 144.9460 38.6616
17 H =2.498 593 1.453 127 =0.508 295 30.3529 1.5120
18 C =2.809 641 0.331 468 1.288 628 167.0181 16.5895
19 H =2.767 913 =0.700 864 1.653 008 31.2315 0.6334
20 H =2.201 353 0.952 110 1.953 900 30.7517 1.1132
21 H =3.846 770 0.669 691 1.376 963 31.0545 0.8104
22 C =3.224 698 =0.481 773 =1.049 769 160.1269 23.4807
23 H =3.165 888 =1.527 580 =0.728 767 30.8518 1.0131
24 H =4.274 235 =0.177 359 =0.987 272 30.8107 1.0542
25 H =2.917 659 =0.430 032 =2.099 544 30.9745 0.8904
26 C 3.460 388 =0.655 633 0.091 781 167.2123 16.3953
27 H 4.102 648 0.115 324 0.524 326 30.5790 1.2859
28 H 3.781 431 =1.630 218 0.470 336 31.2195 0.6454
29 H 3.604 838 =0.642 021 =0.992 936 31.0394 0.8255
99
Fig. S13 201b – Conformer 3
SCF Energy - E(RM062X) =466.958 737 191
SCF Energy from NMR - E(RB3LYP) =467.294 947 024
Sum of Electronic and Thermal Free Energies =466.731 747 000
Table S13 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201b – Conformer 3
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 1.232 523 =1.494 193 =0.246 662 142.8533 40.7543
2 C 2.083 401 =0.377 359 0.386 546 132.7970 50.8106
3 C =0.036 886 1.069 566 0.412 465 131.3684 52.2392
4 C =0.883 714 =0.082 298 =0.170 358 128.3371 55.2705
5 C =0.233 654 =1.427 035 0.180 032 148.1897 35.4179
6 H 1.665 067 =2.463 206 0.024 951 29.7647 2.1002
7 H 1.302 037 =1.409 600 =1.340 280 30.5873 1.2776
8 H 2.006 435 =0.487 268 1.479 421 29.3753 2.4896
9 H =0.116 741 1.037 331 1.509 789 29.8346 2.0303
10 H =0.383 385 2.046 494 0.070 811 29.2541 2.6108
11 H =0.882 767 0.021 983 =1.267 995 30.6002 1.2647
12 H =0.779 078 =2.244 486 =0.299 773 29.6883 2.1766
13 H =0.307 915 =1.584 812 1.266 777 30.5451 1.3198
14 C 1.427 517 0.947 662 0.054 081 =46.5522 230.1598
15 O 2.030 720 1.858 353 =0.489 192 — —
16 C =2.348 666 0.007 270 0.302 207 142.3173 41.2903
17 H =2.344 577 =0.109 192 1.397 228 30.5551 1.3098
18 C =3.204 916 =1.113 275 =0.297 112 160.4951 23.1125
19 H =3.151 036 =1.089 296 =1.392 772 31.3425 0.5224
Continued on next page
100
Table S13 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
20 H =2.889 960 =2.104 745 0.036 981 30.4074 1.4575
21 H =4.253 411 =0.985 147 =0.011 252 30.9865 0.8784
22 C =2.978 352 1.363 219 =0.033 757 160.8729 22.7347
23 H =2.901 430 1.563 552 =1.109 771 31.3836 0.4813
24 H =4.039 755 1.366 047 0.232 364 31.0355 0.8294
25 H =2.502 304 2.189 558 0.499 734 30.5662 1.2987
26 C 3.542 766 =0.435 851 =0.041 170 167.3265 16.2811
27 H 4.124 549 0.366 729 0.418 494 30.5794 1.2855
28 H 3.980 265 =1.395 461 0.248 448 31.2165 0.6484
29 H 3.628 134 =0.331 549 =1.127 257 31.0653 0.7996
Fig. S14 201b – Conformer 4
SCF Energy - E(RM062X) =466.955 461 680
SCF Energy from NMR - E(RB3LYP) =467.289 083 772
Sum of Electronic and Thermal Free Energies =466.727 051 000
101
Table S14 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201b – Conformer 4
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =0.893 936 =1.436 626 =0.634 939 150.9879 32.6197
2 C =1.844 048 =0.221 613 =0.612 828 130.9046 52.7030
3 C =0.222 521 0.916 524 1.041 548 137.2696 46.3380
4 C 0.782 858 =0.239 846 0.850 592 131.9194 51.6882
5 C =0.023 445 =1.528 884 0.622 084 156.7503 26.8573
6 H =0.249 535 =1.372 788 =1.519 681 29.7687 2.0962
7 H =1.493 482 =2.346 859 =0.749 928 30.3031 1.5618
8 H =2.222 428 =0.026 281 =1.621 403 29.4258 2.4391
9 H 0.258 047 1.879 261 1.223 737 29.4282 2.4367
10 H =0.858 010 0.690 165 1.907 887 29.0433 2.8216
11 H 1.354 894 =0.348 459 1.783 123 30.2662 1.5987
12 H =0.655 841 =1.702 335 1.501 912 29.8465 2.0184
13 H 0.642 106 =2.393 980 0.549 722 30.0462 1.8187
14 C =1.120 840 1.039 450 =0.169 574 =49.7469 233.3545
15 O =1.277 319 2.101 026 =0.751 786 — —
16 C 1.799 238 0.066 858 =0.272 269 150.4728 33.1348
17 H 1.245 258 0.316 575 =1.189 957 30.4278 1.4371
18 C 2.691 747 =1.140 869 =0.571 881 161.5309 22.0767
19 H 3.183 015 =1.489 893 0.345 256 31.3818 0.4831
20 H 2.130 079 =1.978 646 =0.994 454 30.5764 1.2885
21 H 3.472 809 =0.869 076 =1.288 354 31.0464 0.8185
22 C 2.672 577 1.274 964 0.082 679 161.0573 22.5503
23 H 3.205 725 1.095 561 1.024 580 31.4690 0.3959
24 H 3.419 577 1.446 905 =0.698 171 31.0027 0.8622
25 H 2.091 144 2.194 147 0.189 179 30.4076 1.4573
26 C =3.048 210 =0.454 066 0.317 492 162.6137 20.9939
27 H =3.694 107 0.427 927 0.351 633 30.8504 1.0145
28 H =3.637 069 =1.296 307 =0.056 773 30.8007 1.0642
29 H =2.734 152 =0.689 472 1.338 556 30.2932 1.5717
102
Fig. S15 201b – Conformer 5
SCF Energy - E(RM062X) =466.952 104 799
SCF Energy from NMR - E(RB3LYP) =467.286 751 340
Sum of Electronic and Thermal Free Energies =466.724 302 000
Table S15 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201b – Conformer 5
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 1.001 648 =1.096 008 1.243 359 154.2702 29.3374
2 C 2.083 027 =0.413 510 0.399 669 134.7689 48.8387
3 C 0.146 973 1.259 034 0.105 407 134.0390 49.5686
4 C =0.671 436 0.040 361 =0.353 862 144.2059 39.4017
5 C =0.348 908 =1.202 406 0.511 370 164.0290 19.5786
6 H 0.869 394 =0.524 229 2.169 387 29.9579 1.9070
7 H 1.345 983 =2.091 958 1.541 747 30.1704 1.6945
8 H 2.986 509 =0.264 267 1.002 937 29.5251 2.3398
9 H =0.052 047 1.472 110 1.165 343 29.1997 2.6652
10 H =0.097 212 2.157 601 =0.468 831 29.9413 1.9236
11 H =0.352 227 =0.176 055 =1.383 479 29.8132 2.0517
12 H =0.360 577 =2.093 123 =0.126 034 30.1972 1.6677
Continued on next page
103
Table S15 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
13 H =1.133 316 =1.355 143 1.260 899 30.3219 1.5430
14 C 1.624 187 0.974 553 =0.025 983 =51.0793 234.6869
15 O 2.412 173 1.794 228 =0.468 338 — —
16 C =2.177 979 0.358 464 =0.445 608 146.0257 37.5819
17 H =2.277 280 1.169 985 =1.180 437 30.1780 1.6869
18 C =2.779 958 0.855 013 0.871 284 168.7446 14.8630
19 H =2.672 212 0.110 808 1.668 441 31.1118 0.7531
20 H =2.313 879 1.785 303 1.209 206 30.9726 0.8923
21 H =3.850 051 1.047 661 0.745 269 31.1952 0.6697
22 C =2.957 744 =0.847 601 =0.975 688 161.1378 22.4698
23 H =2.954 666 =1.668 394 =0.249 732 30.9353 0.9296
24 H =4.001 016 =0.578 742 =1.167 890 30.8847 0.9802
25 H =2.524 054 =1.220 658 =1.909 938 31.0009 0.8640
26 C 2.474 229 =1.229 574 =0.843 139 163.4837 20.1239
27 H 3.246 481 =0.710 779 =1.416 244 30.5298 1.3351
28 H 2.863 452 =2.204 431 =0.535 265 30.8673 0.9976
29 H 1.615 096 =1.399 482 =1.499 520 30.6629 1.2020
Fig. S16 201b – Conformer 6
SCF Energy - E(RM062X) =466.952 169 912
SCF Energy from NMR - E(RB3LYP) =467.287 082 314
Sum of Electronic and Thermal Free Energies =466.724 397 000
104
Table S16 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201b – Conformer 6
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =1.281 844 =1.347 021 =0.966 600 154.4547 29.1529
2 C =2.166 654 =0.389 752 =0.165 233 134.9143 48.6933
3 C =0.089 338 1.102 828 =0.526 719 136.1630 47.4446
4 C 0.717 031 =0.064 906 0.067 223 141.1892 42.4184
5 C 0.154 447 =1.425 126 =0.420 991 155.4493 28.1583
6 H =1.258 777 =1.008 776 =2.009 148 29.8891 1.9758
7 H =1.733 181 =2.344 875 =0.974 780 30.1995 1.6654
8 H =3.149 157 =0.297 224 =0.642 706 29.5214 2.3435
9 H =0.011 737 1.083 719 =1.624 844 29.6049 2.2600
10 H 0.268 290 2.076 249 =0.186 453 29.4009 2.4640
11 H 0.601 366 =0.008 040 1.160 884 30.4916 1.3733
12 H 0.202 728 =2.150 572 0.397 968 29.7417 2.1232
13 H 0.801 037 =1.817 189 =1.215 591 30.4955 1.3694
14 C =1.556 198 1.001 789 =0.169 212 =50.4127 234.0203
15 O =2.217 947 1.984 915 0.121 133 — —
16 C 2.226 988 0.052 763 =0.216 918 141.0417 42.5659
17 H 2.362 915 =0.047 610 =1.305 060 30.6114 1.2535
18 C 2.992 924 =1.080 307 0.473 679 160.9051 22.7025
19 H 2.862 740 =1.013 585 1.561 131 31.4021 0.4628
20 H 2.652 626 =2.068 556 0.152 851 30.4258 1.4391
21 H 4.063 706 =1.008 050 0.259 920 30.9624 0.9025
22 C 2.807 171 1.400 362 0.221 331 160.9586 22.6490
23 H 2.575 492 1.591 273 1.276 712 31.4209 0.4440
24 H 3.896 324 1.397 912 0.113 600 31.0140 0.8509
25 H 2.419 041 2.234 890 =0.367 908 30.5501 1.3148
26 C =2.384 597 =0.849 217 1.285 775 163.9955 19.6121
27 H =3.031 426 =0.147 461 1.817 874 30.6152 1.2497
28 H =2.859 321 =1.834 819 1.291 653 30.8804 0.9845
29 H =1.438 678 =0.925 087 1.830 813 30.6634 1.2015
105
Fig. S17 201b – Conformer 7
SCF Energy - E(RM062X) =466.953 089 581
SCF Energy from NMR - E(RB3LYP) =467.287 211 393
Sum of Electronic and Thermal Free Energies =466.725 333 000
Table S17 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201b – Conformer 7
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =1.129 636 =1.619 720 =0.174 225 149.3055 34.3021
2 C =1.877 989 =0.322 140 =0.499 184 131.5022 52.1054
3 C =0.167 395 0.573 630 1.194 317 135.8610 47.7466
4 C 0.923 180 =0.430 129 0.735 022 138.7858 44.8218
5 C 0.376 707 =1.406 641 =0.328 933 158.3843 25.2233
6 H =1.484 353 =2.415 219 =0.837 657 30.0669 1.7980
7 H =1.361 541 =1.938 230 0.851 893 30.2923 1.5726
8 H =1.849 365 =0.154 469 =1.584 306 29.8052 2.0597
9 H 0.265 789 1.505 446 1.567 833 29.9035 1.9614
10 H =0.741 728 0.121 207 2.014 888 28.9461 2.9188
11 H 1.190 827 =1.026 021 1.617 147 29.4852 2.3797
12 H 0.914 005 =2.357 659 =0.265 170 30.2028 1.6621
Continued on next page
106
Table S17 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
13 H 0.561 346 =1.010 554 =1.336 935 30.7291 1.1358
14 C =1.185 827 0.881 500 0.125 254 =52.5217 236.1293
15 O =1.483 861 2.019 762 =0.197 923 — —
16 C 2.209 138 0.297 666 0.291 049 143.1862 40.4214
17 H 2.571 006 0.845 810 1.172 702 30.1527 1.7122
18 C 1.972 417 1.324 836 =0.819 942 167.6185 15.9891
19 H 1.596 420 0.850 588 =1.733 577 31.3888 0.4761
20 H 1.254 972 2.094 704 =0.520 315 30.8847 0.9802
21 H 2.911 932 1.825 427 =1.074 838 31.2995 0.5654
22 C 3.295 211 =0.700 273 =0.116 871 161.2287 22.3789
23 H 3.023 975 =1.218 744 =1.043 383 31.0341 0.8308
24 H 4.245 477 =0.186 094 =0.290 981 30.9639 0.9010
25 H 3.453 846 =1.456 310 0.660 115 30.9799 0.8850
26 C =3.342 451 =0.354 006 =0.044 323 162.6955 20.9121
27 H =3.862 593 0.562 514 =0.332 076 30.4972 1.3677
28 H =3.855 338 =1.206 400 =0.499 164 30.7767 1.0882
29 H =3.403 920 =0.462 428 1.044 237 31.1107 0.7542
Fig. S18 201b – Conformer 8
107
SCF Energy - E(RM062X) =466.951 917 684
SCF Energy from NMR - E(RB3LYP) =467.286 782 118
Sum of Electronic and Thermal Free Energies =466.724 125 000
Table S18 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201b – Conformer 8
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =1.291 417 =1.510 044 =0.613 975 153.8449 29.7627
2 C =2.149 708 =0.298 511 =0.236 785 134.8801 48.7275
3 C 0.125 379 0.851 543 =0.619 722 141.1419 42.4657
4 C 0.678 394 =0.174 537 0.386 027 143.5242 40.0834
5 C 0.029 829 =1.564 391 0.171 892 157.3139 26.2937
6 H =1.074 726 =1.464 346 =1.687 762 29.8641 2.0008
7 H =1.864 780 =2.429 050 =0.452 220 30.2009 1.6640
8 H =3.023 848 =0.240 849 =0.896 429 29.5304 2.3345
9 H 0.307 781 0.505 174 =1.647 144 29.5079 2.3570
10 H 0.583 502 1.837 990 =0.512 343 29.7804 2.0845
11 H 0.391 774 0.181 857 1.385 458 29.9327 1.9322
12 H =0.132 448 =2.028 770 1.150 895 29.9425 1.9224
13 H 0.726 213 =2.219 363 =0.363 751 30.3404 1.5245
14 C =1.369 494 0.990 937 =0.452 892 =51.2074 234.8150
15 O =1.930 105 2.074 510 =0.467 289 — —
16 C 2.219 551 =0.254 708 0.381 074 146.1775 37.4301
17 H 2.477 902 =1.137 847 0.983 533 30.2554 1.6095
18 C 2.858 231 0.964 733 1.049 804 160.7440 22.8636
19 H 2.641 671 1.881 754 0.490 515 30.9447 0.9202
20 H 2.488 420 1.095 808 2.071 805 31.0246 0.8403
21 H 3.946 596 0.855 479 1.092 866 30.8944 0.9705
22 C 2.797 817 =0.453 552 =1.022 558 167.0340 16.5736
23 H 2.681 697 0.455 899 =1.622 846 31.4110 0.4539
24 H 3.867 573 =0.676 658 =0.965 901 31.0225 0.8424
25 H 2.311 797 =1.275 848 =1.558 383 30.7336 1.1313
26 C =2.654 397 =0.354 425 1.214 215 163.6904 19.9172
27 H =3.270 686 0.518 860 1.440 776 30.5317 1.3332
28 H =3.257 982 =1.255 141 1.359 385 30.8787 0.9862
29 H =1.824 712 =0.383 300 1.927 377 30.6481 1.2168
108
Fig. S19 201b – Conformer 9
SCF Energy - E(RM062X) =466.952 950 502
SCF Energy from NMR - E(RB3LYP) =467.287 345 108
Sum of Electronic and Thermal Free Energies =466.725 286 000
Table S19 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
201b – Conformer 9
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =1.450 621 1.543 053 0.114 296 149.1717 34.4359
2 C =1.963 109 0.122 886 0.376 269 131.5161 52.0915
3 C 0.107 375 =0.414 220 =1.053 371 142.2883 41.3193
4 C 0.910 903 0.769 779 =0.453 568 138.4010 45.2066
5 C 0.031 416 1.634 243 0.475 991 151.6810 31.9266
6 H =2.043 167 2.253 562 0.699 907 30.0912 1.7737
7 H =1.598 998 1.804 539 =0.942 842 30.2391 1.6258
8 H =2.025 973 =0.038 549 1.461 280 29.7778 2.0871
9 H 0.747 077 =1.248 584 =1.350 658 29.7025 2.1624
10 H =0.413 908 =0.063 293 =1.955 085 29.3186 2.5463
11 H 1.215 128 1.399 894 =1.298 737 29.6260 2.2389
Continued on next page
109
Table S19 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
12 H 0.384 074 2.669 942 0.442 743 30.0154 1.8495
13 H 0.148 737 1.298 657 1.515 542 30.6355 1.2294
14 C =0.981 774 =0.920 918 =0.140 656 =52.8652 236.4728
15 O =1.112 918 =2.101 546 0.138 016 — —
16 C 2.203 822 0.314 344 0.256 096 144.5982 39.0094
17 H 2.575 265 1.191 479 0.806 260 30.3175 1.5474
18 C 3.285 520 =0.096 329 =0.745 381 160.5258 23.0818
19 H 2.971 629 =0.967 947 =1.331 146 30.8959 0.9690
20 H 3.509 535 0.717 676 =1.442 464 31.0671 0.7978
21 H 4.211 167 =0.366 068 =0.227 051 30.9428 0.9221
22 C 1.961 883 =0.812 202 1.265 292 166.0253 17.5823
23 H 1.677 139 =1.739 273 0.755 121 31.3412 0.5237
24 H 2.873 788 =1.014 094 1.835 558 31.2173 0.6476
25 H 1.169 330 =0.568 978 1.980 962 31.0916 0.7733
26 C =3.343 962 =0.132 138 =0.239 599 162.8704 20.7372
27 H =3.700 865 =1.135 863 0.001 854 30.4652 1.3997
28 H =4.063 388 0.598 078 0.142 007 30.7982 1.0667
29 H =3.301 946 =0.029 791 =1.329 591 31.1301 0.7348
110
S-I.3 Nankakurine – Revised Diastereomer(202a)
Fig. S20 202a – Conformer 1
SCF Energy - E(RM062X) =775.099 413 763
SCF Energy from NMR - E(RB3LYP) =775.608 465 248
Sum of Electronic and Thermal Free Energies =774.683 062 000
Table S20 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
202a – Conformer 1
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 2.645 924 =0.284 964 1.121 739 145.6803 38.1985
2 C 3.061 887 =0.314 747 =1.738 533 138.1991 45.6797
3 C 4.192 868 =0.744 373 =0.813 030 152.3163 31.5625
4 C 3.609 622 =1.293 585 0.487 818 158.2814 25.5974
5 H 2.179 934 =0.733 573 2.004 648 29.7536 2.1014
6 H 3.222 428 0.584 598 1.466 674 30.9379 0.9171
7 H 2.482 083 =1.204 262 =2.037 409 28.7647 3.0903
8 H 3.460 033 0.135 058 =2.653 243 29.1953 2.6597
Continued on next page
111
Table S20 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
9 H 4.817 200 =1.495 056 =1.309 066 30.3061 1.5489
10 H 4.826 006 0.126 259 =0.596 497 30.5419 1.3131
11 H 4.407 002 =1.530 092 1.200 573 30.3571 1.4979
12 H 3.088 045 =2.236 207 0.278 539 30.2190 1.6360
13 C =0.540 580 =1.145 592 0.929 915 143.9137 39.9651
14 C 0.528 585 =0.902 319 =0.152 946 143.2553 40.6235
15 C 1.550 392 0.221 805 0.156 845 124.5810 59.2978
16 C 0.851 532 1.450 518 0.800 680 133.6760 50.2028
17 C 0.027 293 1.042 491 2.023 216 147.7008 36.1780
18 C =1.109 706 0.152 585 1.532 850 140.8497 43.0291
19 H =0.057 217 =1.683 382 1.759 072 30.1175 1.7375
20 H 0.034 879 =0.650 236 =1.095 222 30.0622 1.7928
21 H 1.056 471 =1.849 267 =0.318 437 29.5661 2.2889
22 H 1.648 183 2.146 325 1.095 154 30.7693 1.0857
23 H 0.631 687 0.517 402 2.770 335 29.9253 1.9297
24 H =0.375 923 1.941 621 2.506 378 30.4385 1.4165
25 H =1.749 305 =0.127 780 2.381 335 30.3971 1.4579
26 C =0.086 446 2.231 626 =0.127 235 121.2219 62.6569
27 C =2.015 491 0.916 314 0.549 213 113.5813 70.2975
28 H =0.424 133 3.132 366 0.426 930 29.8436 2.0114
29 H 0.446 378 2.597 638 =1.011 354 28.8531 3.0019
30 C =1.676 245 =2.030 980 0.395 150 138.2550 45.6238
31 H =2.274 539 =2.393 781 1.244 793 30.6875 1.1675
32 H =1.256 990 =2.917 557 =0.100 028 30.3609 1.4941
33 C =2.623 346 =1.297 773 =0.565 200 156.7968 27.0820
34 H =2.066 223 =1.014 811 =1.468 623 29.9263 1.9287
35 C =3.143 840 =0.016 140 0.093 255 140.5753 43.3035
36 H =2.466 640 1.767 252 1.104 586 29.9266 1.9284
37 H =3.843 967 0.497 571 =0.574 314 29.7727 2.0823
38 H =3.719 835 =0.292 135 0.988 647 31.0288 0.8262
39 C =3.780 339 =2.203 913 =0.982 867 159.2459 24.6329
40 H =4.373 272 =2.494 855 =0.106 965 31.3512 0.5038
41 H =4.447 095 =1.695 357 =1.687 373 30.8820 0.9730
42 H =3.413 599 =3.118 855 =1.460 210 30.8992 0.9558
43 N =1.242 229 1.456 093 =0.582 487 — —
44 C =2.064 595 2.286 645 =1.451 361 138.6569 45.2219
45 H =1.433 234 2.735 618 =2.223 064 29.7894 2.0656
46 H =2.833 329 1.693 382 =1.950 341 29.0105 2.8445
Continued on next page
112
Table S20 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
47 H =2.559 918 3.103 363 =0.892 348 30.5140 1.3410
48 N 2.230 050 0.694 822 =1.070 475 — —
49 H 1.515 066 0.996 756 =1.729 488 30.5467 1.3083
Fig. S21 202a – Conformer 2
SCF Energy - E(RM062X) =775.100 103 338
SCF Energy from NMR - E(RB3LYP) =775.608 650 973
Sum of Electronic and Thermal Free Energies =774.683 317 000
Table S21 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
202a – Conformer 2
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 2.436 785 =1.463 642 0.335 760 143.8831 39.9957
2 C 3.347 842 0.815 163 =1.194 158 138.6495 45.2293
3 C 4.362 162 =0.199 298 =0.671 990 152.0445 31.8343
4 C 3.834 867 =0.889 967 0.588 171 158.7253 25.1535
Continued on next page
113
Table S21 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
5 H 2.517 451 =2.253 240 =0.423 130 30.8939 0.9611
6 H 2.044 026 =1.934 560 1.242 063 29.5917 2.2633
7 H 3.683 857 1.233 490 =2.147 971 29.2891 2.5659
8 H 3.271 957 1.653 911 =0.481 210 28.8450 3.0100
9 H 4.537 151 =0.952 804 =1.451 113 30.4388 1.4162
10 H 5.316 786 0.299 237 =0.473 118 30.2837 1.5713
11 H 3.811 408 =0.173 291 1.418 671 30.2860 1.5690
12 H 4.512 905 =1.695 019 0.891 609 30.4443 1.4107
13 C =0.864 170 =1.474 087 0.429 833 144.3132 39.5656
14 C 0.145 710 =1.118 514 =0.675 380 132.8788 51.0000
15 C 1.437 946 =0.418 854 =0.207 682 124.0051 59.8737
16 C 1.127 296 0.657 679 0.879 662 148.9117 34.9671
17 C 0.309 197 0.064 695 2.029 323 147.3410 36.5378
18 C =1.044 757 =0.348 908 1.466 351 140.9032 42.9756
19 H =0.470 152 =2.341 556 0.979 800 29.9665 1.8885
20 H =0.342 920 =0.462 403 =1.400 072 29.8296 2.0254
21 H 0.426 551 =2.036 459 =1.209 457 30.8017 1.0533
22 H 2.074 429 1.040 107 1.275 229 29.4513 2.4037
23 H 0.811 355 =0.791 728 2.491 734 30.0990 1.7560
24 H 0.178 137 0.823 974 2.811 333 30.3396 1.5154
25 H =1.676 775 =0.739 991 2.275 884 30.3868 1.4682
26 C 0.359 565 1.878 373 0.362 737 121.6389 62.2399
27 C =1.790 029 0.870 640 0.893 145 113.6116 70.2672
28 H 0.300 690 2.613 168 1.192 882 29.7802 2.0748
29 H 0.906 819 2.370 584 =0.449 834 28.8777 2.9773
30 C =2.221 500 =1.870 588 =0.170 288 138.2905 45.5883
31 H =2.830 663 =2.346 919 0.612 902 30.7196 1.1354
32 H =2.076 641 =2.619 907 =0.960 513 30.4272 1.4278
33 C =3.016 025 =0.679 061 =0.723 592 156.6151 27.2637
34 H =2.469 807 =0.251 985 =1.575 498 29.9699 1.8851
35 C =3.146 721 0.406 198 0.349 938 140.3431 43.5357
36 H =1.972 091 1.574 576 1.734 304 29.9450 1.9100
37 H =3.736 733 1.247 452 =0.029 365 29.7731 2.0819
38 H =3.712 071 =0.007 465 1.197 858 31.0292 0.8258
39 C =4.391 312 =1.126 565 =1.215 975 159.1578 24.7210
40 H =4.976 257 =1.545 227 =0.387 746 31.3432 0.5118
41 H =4.954 493 =0.286 009 =1.635 239 30.8937 0.9613
42 H =4.302 700 =1.897 286 =1.989 063 30.9209 0.9341
Continued on next page
114
Table S21 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
43 N =0.983 787 1.562 025 =0.127 741 — —
44 C =1.626 866 2.785 172 =0.587 218 138.5632 45.3156
45 H =0.954 743 3.308 664 =1.272 801 29.7621 2.0929
46 H =2.550 916 2.565 779 =1.125 750 29.0003 2.8547
47 H =1.863 629 3.466 958 0.251 882 30.4825 1.3725
48 N 2.059 430 0.152 112 =1.422 053 — —
49 H 1.407 621 0.808 380 =1.847 538 30.3482 1.5068
Fig. S22 202a – Conformer 3
SCF Energy - E(RM062X) =775.098 714 564
SCF Energy from NMR - E(RB3LYP) =775.607 445 851
Sum of Electronic and Thermal Free Energies =774.682 378 000
115
Table S22 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
202a – Conformer 3
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 2.427 184 =1.439 529 0.369 460 142.0715 41.8073
2 C 3.370 652 0.790 557 =1.204 556 137.7926 46.0862
3 C 4.371 559 =0.221 778 =0.641 539 150.1807 33.6981
4 C 3.824 501 =0.870 158 0.631 618 158.7501 25.1287
5 H 2.516 824 =2.238 460 =0.380 719 30.9575 0.8975
6 H 2.023 430 =1.906 295 1.273 903 29.4687 2.3863
7 H 3.720 345 1.178 797 =2.166 587 29.2229 2.6321
8 H 3.293 613 1.649 953 =0.526 064 29.0328 2.8222
9 H 4.544 823 =1.002 011 =1.396 021 30.5804 1.2746
10 H 5.333 295 0.268 517 =0.452 127 30.3446 1.5104
11 H 3.792 695 =0.129 119 1.440 557 30.1670 1.6880
12 H 4.491 690 =1.670 628 0.969 605 30.3860 1.4690
13 C =0.851 891 =1.458 922 0.444 775 144.6802 39.1986
14 C 0.151 260 =1.106 597 =0.668 113 133.6128 50.2660
15 C 1.437 561 =0.395 052 =0.203 977 124.4472 59.4316
16 C 1.119 814 0.697 552 0.856 042 147.7643 36.1145
17 C 0.311 741 0.116 320 2.018 544 147.8452 36.0336
18 C =1.039 753 =0.321 532 1.467 543 140.7315 43.1473
19 H =0.448 311 =2.315 334 1.005 031 29.9749 1.8801
20 H =0.334 944 =0.459 733 =1.400 461 29.6419 2.2131
21 H 0.436 094 =2.032 649 =1.188 767 30.8838 0.9712
22 H 2.064 019 1.096 587 1.243 054 29.6003 2.2547
23 H 0.823 948 =0.724 154 2.498 494 30.1023 1.7527
24 H 0.174 037 0.890 853 2.783 988 30.4089 1.4461
25 H =1.663 301 =0.709 113 2.285 325 30.3693 1.4857
26 C 0.338 942 1.899 501 0.318 253 121.4644 62.4144
27 C =1.800 683 0.882 239 0.881 445 113.8601 70.0187
28 H 0.279 383 2.651 226 1.133 653 29.9027 1.9523
29 H 0.878 847 2.363 745 =0.512 419 28.6473 3.2077
30 C =2.207 538 =1.876 363 =0.144 305 138.2342 45.6446
31 H =2.808 355 =2.348 473 0.647 929 30.7155 1.1395
32 H =2.058 564 =2.634 801 =0.925 063 30.4309 1.4241
33 C =3.016 763 =0.700 584 =0.709 382 156.5783 27.3005
34 H =2.477 570 =0.277 835 =1.567 842 29.9480 1.9070
35 C =3.155 148 0.396 139 0.351 480 140.2151 43.6637
36 H =1.986 223 1.596 004 1.713 958 29.9365 1.9185
Continued on next page
116
Table S22 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
37 H =3.756 062 1.226 105 =0.035 622 29.7704 2.0846
38 H =3.712 135 =0.013 190 1.207 044 31.0306 0.8244
39 C =4.388 742 =1.169 456 =1.190 947 159.1629 24.7159
40 H =4.966 565 =1.582 741 =0.355 006 31.3432 0.5118
41 H =4.962 285 =0.340 970 =1.620 054 30.8928 0.9622
42 H =4.294 481 =1.950 028 =1.953 457 30.9258 0.9292
43 N =1.006 415 1.563 446 =0.153 307 — —
44 C =1.661 752 2.770 464 =0.635 090 138.7943 45.0845
45 H =0.997 600 3.283 907 =1.335 819 29.7841 2.0709
46 H =2.587 035 2.532 496 =1.163 851 29.0189 2.8361
47 H =1.899 934 3.469 423 0.189 801 30.5144 1.3406
48 N 2.022 770 0.242 895 =1.407 698 — —
49 H 2.080 179 =0.473 257 =2.132 935 31.3822 0.4728
Fig. S23 202a – Conformer 4
SCF Energy - E(RM062X) =775.098 524 888
SCF Energy from NMR - E(RB3LYP) =775.607 656 183
Sum of Electronic and Thermal Free Energies =774.682 323 000
117
Table S23 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
202a – Conformer 4
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 2.619 772 =0.312 170 1.125 398 144.1494 39.7294
2 C 3.094 781 =0.288 116 =1.730 957 137.4027 46.4761
3 C 4.199 376 =0.763 551 =0.787 745 150.4350 33.4438
4 C 3.580 236 =1.324 774 0.491 240 158.1751 25.7037
5 H 2.142 258 =0.767 199 1.999 422 29.6409 2.2141
6 H 3.202 961 0.546 794 1.489 599 31.0189 0.8361
7 H 2.502 112 =1.147 967 =2.067 897 29.0270 2.8280
8 H 3.521 587 0.174 974 =2.626 402 29.1156 2.7394
9 H 4.824 211 =1.515 067 =1.283 792 30.3854 1.4696
10 H 4.846 027 0.090 086 =0.539 916 30.6898 1.1652
11 H 4.359 030 =1.588 966 1.214 945 30.2962 1.5588
12 H 3.046 524 =2.254 525 0.255 529 30.0791 1.7759
13 C =0.528 484 =1.145 721 0.896 736 144.5278 39.3510
14 C 0.523 258 =0.882 027 =0.198 207 144.7889 39.0899
15 C 1.548 052 0.222 355 0.140 632 124.2952 59.5836
16 C 0.845 532 1.449 996 0.779 978 133.7418 50.1370
17 C 0.033 002 1.039 822 2.009 478 147.9836 35.8952
18 C =1.099 546 0.140 739 1.524 822 140.7997 43.0791
19 H =0.030 909 =1.691 997 1.711 849 30.1130 1.7420
20 H 0.022 967 =0.592 862 =1.124 423 29.9063 1.9487
21 H 1.042 112 =1.828 140 =0.394 768 29.8387 2.0163
22 H 1.638 267 2.153 407 1.074 025 30.7665 1.0885
23 H 0.645 317 0.523 851 2.755 949 29.9376 1.9174
24 H =0.377 012 1.936 983 2.490 615 30.4735 1.3815
25 H =1.724 531 =0.155 812 2.378 677 30.3872 1.4678
26 C =0.099 648 2.224 425 =0.146 676 121.6807 62.1981
27 C =2.024 366 0.908 504 0.562 669 113.8320 70.0468
28 H =0.421 530 3.135 691 0.400 595 29.9942 1.8608
29 H 0.427 602 2.557 730 =1.044 953 28.4934 3.3616
30 C =1.665 799 =2.032 102 0.367 156 138.0600 45.8188
31 H =2.248 223 =2.410 287 1.221 129 30.6902 1.1648
32 H =1.247 419 =2.909 094 =0.145 505 30.3441 1.5109
33 C =2.633 216 =1.294 721 =0.569 227 156.6910 27.1878
34 H =2.091 475 =0.995 439 =1.476 690 29.8979 1.9571
35 C =3.153 963 =0.026 158 0.113 978 140.3689 43.5099
36 H =2.471 654 1.751 769 1.133 253 29.9293 1.9257
Continued on next page
118
Table S23 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
37 H =3.868 227 0.490 493 =0.536 161 29.7739 2.0811
38 H =3.713 750 =0.317 988 1.014 678 31.0399 0.8151
39 C =3.789 067 =2.204 949 =0.981 067 159.2330 24.6458
40 H =4.366 570 =2.511 893 =0.100 281 31.3527 0.5023
41 H =4.470 337 =1.692 837 =1.668 944 30.8863 0.9687
42 H =3.422 449 =3.110 711 =1.475 723 30.8963 0.9587
43 N =1.270 914 1.457 147 =0.575 806 — —
44 C =2.105 087 2.295 691 =1.424 227 138.8344 45.0444
45 H =1.486 553 2.743 927 =2.206 653 29.8152 2.0398
46 H =2.887 815 1.709 864 =1.910 243 29.0309 2.8241
47 H =2.584 119 3.113 690 =0.852 303 30.5616 1.2934
48 N 2.184 409 0.685 204 =1.114 859 — —
49 H 2.728 131 1.521 614 =0.894 848 31.4332 0.4218
119
S-I.4 Nankakurine – Originally Proposed Diastereomer (202b)
Fig. S24 202b – Conformer 1
SCF Energy - E(RM062X) =775.099 320 833
SCF Energy from NMR - E(RB3LYP) =775.608 400 202
Sum of Electronic and Thermal Free Energies =774.683 058 000
Table S24 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
202b – Conformer 1
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 3.223 133 =0.352 241 =1.729 853 158.6616 25.2172
2 C 4.221 783 =0.797 804 =0.662 242 152.0739 31.8049
3 C 3.474 683 =1.271 521 0.578 532 138.3552 45.5236
4 H 2.648 936 =1.221 314 =2.077 232 30.3233 1.5317
5 H 3.745 763 0.051 009 =2.603 809 30.3651 1.4899
6 H 4.864 703 =1.601 314 =1.036 975 30.2914 1.5636
7 H 4.868 256 0.047 173 =0.390 360 30.5565 1.2985
Continued on next page
120
Table S24 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
8 H 4.177 121 =1.514 718 1.381 848 29.1765 2.6785
9 H 2.929 932 =2.198 988 0.335 254 28.7866 3.0684
10 C =0.511 629 =1.154 535 0.875 633 145.6992 38.1796
11 C 0.524 006 =0.863 308 =0.226 068 149.0196 34.8592
12 C 1.547 980 0.246 739 0.114 225 124.3013 59.5775
13 C 0.844 653 1.456 789 0.786 871 133.6557 50.2231
14 C 0.040 286 1.019 210 2.013 626 148.7503 35.1285
15 C =1.088 765 0.120 247 1.521 802 141.2419 42.6369
16 H 0.000 317 =1.705 122 1.680 121 30.0884 1.7666
17 H 0.002 526 =0.570 496 =1.139 964 30.0334 1.8216
18 H 1.052 838 =1.797 085 =0.450 886 29.6615 2.1935
19 H 1.640 733 2.151 158 1.085 262 30.7133 1.1417
20 H 0.656 301 0.496 639 2.754 402 30.0714 1.7836
21 H =0.370 659 1.905 071 2.514 499 30.4872 1.3678
22 H =1.710 005 =0.190 083 2.373 440 30.4056 1.4494
23 C =0.114 235 2.242 550 =0.114 683 121.0340 62.8448
24 C =2.021 340 0.894 434 0.571 542 113.6533 70.2255
25 H =0.447 384 3.133 094 0.458 349 29.8615 1.9935
26 H 0.401 935 2.617 825 =1.004 053 28.7956 3.0594
27 C =1.646 612 =2.044 440 0.347 844 138.0381 45.8407
28 H =2.222 647 =2.431 150 1.202 340 30.6854 1.1696
29 H =1.226 944 =2.915 635 =0.173 522 30.3528 1.5022
30 C =2.622 082 =1.304 523 =0.578 647 156.6115 27.2673
31 H =2.086 766 =0.997 809 =1.487 482 29.9332 1.9218
32 C =3.145 740 =0.042 342 0.114 317 140.5781 43.3007
33 H =2.473 526 1.726 019 1.154 790 29.9079 1.9471
34 H =3.862 543 0.476 260 =0.531 413 29.7713 2.0837
35 H =3.703 902 =0.343 105 1.013 044 31.0387 0.8163
36 C =3.776 299 =2.216 866 =0.990 653 159.2443 24.6345
37 H =4.348 352 =2.531 430 =0.109 046 31.3476 0.5074
38 H =4.462 829 =1.703 325 =1.672 182 30.8858 0.9692
39 H =3.408 290 =3.118 075 =1.492 497 30.8960 0.9590
40 N =1.275 524 1.469 375 =0.560 960 — —
41 C =2.121 019 2.315 066 =1.391 757 138.7108 45.1680
42 H =1.509 095 2.784 680 =2.166 914 29.8076 2.0474
43 H =2.898 022 1.729 542 =1.887 063 29.0256 2.8294
44 H =2.607 450 3.116 575 =0.803 447 30.5241 1.3309
45 C 2.274 349 0.706 781 =1.161 786 141.3799 42.4989
Continued on next page
121
Table S24 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
46 H 2.852 466 1.610 648 =0.920 098 30.7110 1.1440
47 H 1.531 854 0.986 084 =1.916 715 30.1047 1.7503
48 N 2.590 390 =0.208 919 1.071 891 — —
49 H 2.141 759 =0.540 735 1.921 581 30.0988 1.7562
Fig. S25 202b – Conformer 2
SCF Energy - E(RM062X) =775.099 688 816
SCF Energy from NMR - E(RB3LYP) =775.608 371 720
Sum of Electronic and Thermal Free Energies =774.683 128 000
Table S25 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
202b – Conformer 2
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 3.531 665 0.766 649 =1.180 100 159.0466 24.8322
2 C 4.394 708 =0.316 223 =0.525 883 151.9852 31.8936
Continued on next page
122
Table S25 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
3 C 3.684 367 =0.918 502 0.683 817 138.8082 45.0706
4 H 4.004 743 1.124 078 =2.101 055 30.4442 1.4108
5 H 3.454 497 1.632 651 =0.509 271 30.2724 1.5826
6 H 4.583 326 =1.114 612 =1.255 650 30.4541 1.4009
7 H 5.365 218 0.089 469 =0.220 962 30.2830 1.5720
8 H 3.639 838 =0.169 107 1.491 582 28.8817 2.9733
9 H 4.252 251 =1.770 140 1.071 252 29.2713 2.5837
10 C =0.832 467 =1.459 664 0.417 153 145.3608 38.5180
11 C 0.153 707 =1.087 619 =0.705 010 134.2315 49.6473
12 C 1.441 804 =0.375 375 =0.251 442 124.4487 59.4301
13 C 1.122 902 0.717 779 0.816 271 149.7566 34.1222
14 C 0.343 087 0.114 577 1.986 347 149.1169 34.7619
15 C =1.013 729 =0.333 452 1.453 769 141.1181 42.7607
16 H =0.416 482 =2.320 086 0.963 184 30.0188 1.8362
17 H =0.352 732 =0.436 848 =1.420 967 29.5619 2.2931
18 H 0.448 603 =2.000 792 =1.239 409 30.8957 0.9593
19 H 2.068 992 1.127 900 1.185 012 29.4449 2.4101
20 H 0.876 392 =0.726 683 2.445 099 30.0314 1.8236
21 H 0.211 856 0.873 393 2.768 307 30.4649 1.3901
22 H =1.620 240 =0.733 593 2.278 238 30.3717 1.4833
23 C 0.316 291 1.918 490 0.310 252 120.0618 63.8170
24 C =1.797 476 0.867 473 0.890 932 113.6276 70.2512
25 H 0.254 693 2.650 605 1.143 000 29.7171 2.1379
26 H 0.835 735 2.423 150 =0.511 226 29.0101 2.8449
27 C =2.192 134 =1.883 896 =0.157 916 138.3172 45.5616
28 H =2.777 719 =2.371 620 0.636 232 30.7248 1.1302
29 H =2.045 579 =2.631 220 =0.949 706 30.4401 1.4149
30 C =3.020 633 =0.709 765 =0.697 910 156.6639 27.2149
31 H =2.497 559 =0.270 628 =1.558 195 29.9607 1.8943
32 C =3.154 913 0.371 854 0.378 508 140.3694 43.5094
33 H =1.976 158 1.571 526 1.732 740 29.9408 1.9142
34 H =3.771 994 1.199 350 0.012 234 29.7752 2.0798
35 H =3.692 072 =0.054 745 1.238 254 31.0275 0.8275
36 C =4.394 271 =1.185 999 =1.167 227 159.2025 24.6763
37 H =4.956 597 =1.616 384 =0.329 399 31.3380 0.5170
38 H =4.981 610 =0.357 414 =1.577 095 30.8941 0.9609
39 H =4.302 599 =1.954 991 =1.941 683 30.9266 0.9284
40 N =1.029 322 1.570 941 =0.150 773 — —
Continued on next page
123
Table S25 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
41 C =1.708 547 2.777 733 =0.601 080 138.6087 45.2701
42 H =1.062 999 3.312 141 =1.303 547 29.8061 2.0489
43 H =2.639 107 2.535 939 =1.118 439 29.0182 2.8368
44 H =1.941 839 3.458 454 0.239 965 30.4929 1.3621
45 C 2.137 092 0.216 282 =1.488 934 144.1875 39.6913
46 H 1.500 508 0.986 255 =1.937 524 30.0859 1.7691
47 H 2.227 808 =0.591 452 =2.228 618 30.7675 1.0875
48 N 2.360 227 =1.408 745 0.286 970 — —
49 H 1.925 770 =1.882 006 1.074 990 29.8572 1.9978
Fig. S26 202b – Conformer 3
SCF Energy - E(RM062X) =775.099 602 704
SCF Energy from NMR - E(RB3LYP) =775.608 116 205
Sum of Electronic and Thermal Free Energies =774.683 137 000
124
Table S26 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
202b – Conformer 3
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 3.507 383 0.777 493 =1.183 669 158.9692 24.9096
2 C 4.385 056 =0.304 968 =0.550 286 150.4503 33.4285
3 C 3.697 207 =0.914 038 0.674 278 137.8756 46.0032
4 H 3.963 113 1.145 038 =2.109 480 30.3779 1.4771
5 H 3.433 350 1.638 660 =0.505 862 30.1303 1.7247
6 H 4.560 008 =1.099 879 =1.288 862 30.5988 1.2562
7 H 5.364 043 0.097 867 =0.266 496 30.3524 1.5026
8 H 3.667 767 =0.177 418 1.486 214 29.0332 2.8218
9 H 4.271 922 =1.767 248 1.048 782 29.2337 2.6213
10 C =0.845 231 =1.461 062 0.449 458 145.4845 38.3943
11 C 0.157 353 =1.112 165 =0.664 089 133.6556 50.2232
12 C 1.436 826 =0.377 046 =0.219 640 123.8876 59.9912
13 C 1.118 824 0.714 224 0.842 286 148.0034 35.8754
14 C 0.327 781 0.118 870 2.008 003 149.0256 34.8532
15 C =1.028 858 =0.319 802 1.467 961 140.6460 43.2328
16 H =0.438 867 =2.313 762 1.011 540 29.8440 2.0110
17 H =0.339 408 =0.490 801 =1.412 181 29.6609 2.1941
18 H 0.459 128 =2.040 338 =1.172 408 31.0361 0.8189
19 H 2.064 698 1.120 587 1.216 486 29.6004 2.2546
20 H 0.858 001 =0.729 484 2.451 430 29.6345 2.2205
21 H 0.196 987 0.880 351 2.787 745 30.5657 1.2893
22 H =1.646 829 =0.705 030 2.291 229 30.3698 1.4852
23 C 0.324 931 1.914 671 0.318 916 120.3498 63.5290
24 C =1.798 467 0.878 864 0.881 713 113.5418 70.3370
25 H 0.251 781 2.650 300 1.147 309 29.7482 2.1068
26 H 0.856 977 2.415 093 =0.496 936 28.9973 2.8577
27 C =2.200 745 =1.881 960 =0.137 608 138.4283 45.4505
28 H =2.799 320 =2.356 379 0.654 983 30.7429 1.1121
29 H =2.050 800 =2.639 854 =0.918 921 30.4581 1.3969
30 C =3.015 131 =0.708 986 =0.701 141 156.6745 27.2043
31 H =2.479 287 =0.283 661 =1.560 603 29.9685 1.8865
32 C =3.153 651 0.386 359 0.360 730 140.3227 43.5561
33 H =1.981 472 1.595 551 1.711 917 29.9547 1.9003
34 H =3.761 618 1.213 379 =0.021 650 29.7777 2.0773
35 H =3.702 603 =0.026 608 1.219 694 31.0307 0.8243
36 C =4.386 819 =1.181 100 =1.180 203 159.1507 24.7281
Continued on next page
125
Table S26 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
37 H =4.961 342 =1.597 590 =0.343 607 31.3390 0.5160
38 H =4.963 889 =0.353 460 =1.606 285 30.8975 0.9575
39 H =4.292 188 =1.959 956 =1.944 410 30.9299 0.9251
40 N =1.013 408 1.564 002 =0.160 071 — —
41 C =1.682 292 2.765 551 =0.639 077 138.5913 45.2875
42 H =1.024 199 3.287 859 =1.339 057 29.8033 2.0517
43 H =2.605 140 2.518 188 =1.167 556 29.0198 2.8352
44 H =1.927 327 3.459 331 0.187 841 30.4933 1.3617
45 C 2.114 230 0.214 479 =1.472 702 142.5925 41.2863
46 H 1.467 984 0.972 429 =1.929 489 29.9582 1.8968
47 H 2.207 947 =0.600 168 =2.206 593 30.8610 0.9940
48 N 2.328 832 =1.383 572 0.413 732 — —
49 H 2.392 233 =2.172 312 =0.229 992 31.6829 0.1721
Fig. S27 202b – Conformer 4
SCF Energy - E(RM062X) =775.099 299 709
SCF Energy from NMR - E(RB3LYP) =775.608 223 098
Sum of Electronic and Thermal Free Energies =774.683 162 000
126
Table S27 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
202b – Conformer 4
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 3.189 954 =0.403 037 =1.739 592 158.6029 25.2759
2 C 4.211 311 =0.807 192 =0.677 235 150.3382 33.5406
3 C 3.490 576 =1.256 488 0.594 110 137.6573 46.2215
4 H 2.615 892 =1.286 502 =2.049 746 30.1708 1.6842
5 H 3.692 684 =0.023 445 =2.635 665 30.2864 1.5686
6 H 4.863 230 =1.609 432 =1.041 508 30.3816 1.4734
7 H 4.850 955 0.054 970 =0.441 249 30.7012 1.1538
8 H 4.209 060 =1.459 877 1.394 594 29.1494 2.7056
9 H 2.963 192 =2.198 221 0.399 139 28.9244 2.9306
10 C =0.530 552 =1.152 428 0.906 816 145.6340 38.2448
11 C 0.520 381 =0.894 855 =0.188 259 146.7334 37.1454
12 C 1.539 219 0.225 434 0.116 322 124.0282 59.8506
13 C 0.849 060 1.446 413 0.781 894 133.3025 50.5763
14 C 0.045 452 1.026 201 2.013 235 148.7728 35.1060
15 C =1.095 639 0.139 045 1.528 336 140.6666 43.2122
16 H =0.032 746 =1.695 003 1.723 385 29.9794 1.8756
17 H 0.013 862 =0.638 463 =1.121 127 30.1244 1.7306
18 H 1.052 803 =1.835 212 =0.373 417 29.8212 2.0338
19 H 1.650 101 2.141 413 1.074 141 30.8306 1.0244
20 H 0.669 873 0.489 701 2.733 435 29.5702 2.2848
21 H =0.353 010 1.918 794 2.512 729 30.6264 1.2286
22 H =1.724 956 =0.150 933 2.381 453 30.3911 1.4639
23 C =0.096 716 2.235 871 =0.128 564 120.7847 63.0941
24 C =2.015 130 0.910 143 0.562 845 113.5966 70.2822
25 H =0.428 911 3.131 633 0.436 802 29.8304 2.0246
26 H 0.425 856 2.602 257 =1.017 749 28.8062 3.0488
27 C =1.671 265 =2.035 026 0.378 778 138.1100 45.7688
28 H =2.258 207 =2.406 508 1.232 663 30.7048 1.1502
29 H =1.257 325 =2.916 756 =0.129 627 30.3701 1.4849
30 C =2.632 180 =1.295 756 =0.563 276 156.7578 27.1210
31 H =2.087 334 =1.004 218 =1.471 505 29.9415 1.9135
32 C =3.147 036 =0.020 598 0.112 114 140.5183 43.3605
33 H =2.461 411 1.754 717 1.131 891 29.9234 1.9316
34 H =3.856 347 0.497 084 =0.542 632 29.7739 2.0811
35 H =3.711 654 =0.305 423 1.012 022 31.0348 0.8202
36 C =3.792 886 =2.200 451 =0.973 817 159.1941 24.6847
Continued on next page
127
Table S27 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
37 H =4.374 305 =2.499 531 =0.092 928 31.3508 0.5042
38 H =4.469 353 =1.687 398 =1.665 739 30.8891 0.9659
39 H =3.430 778 =3.110 889 =1.463 185 30.9023 0.9527
40 N =1.257 946 1.462 738 =0.573 842 — —
41 C =2.092 541 2.300 724 =1.423 360 138.6620 45.2168
42 H =1.472 085 2.756 212 =2.200 171 29.8089 2.0461
43 H =2.868 536 1.712 053 =1.916 494 29.0193 2.8357
44 H =2.579 700 3.112 773 =0.850 317 30.5188 1.3362
45 C 2.243 799 0.665 373 =1.184 395 139.8079 44.0709
46 H 2.824 485 1.575 750 =0.969 046 30.7938 1.0612
47 H 1.493 847 0.930 164 =1.938 444 29.9998 1.8552
48 N 2.527 461 =0.274 078 1.109 185 — —
49 H 3.059 363 0.529 424 1.445 185 31.7205 0.1345
128
S-I.5 Normal trans-Menthide (203b)
Fig. S28 203b – Conformer 1
SCF Energy - E(RM062X) =542.169 990 504
SCF Energy from NMR - E(RB3LYP) =542.553 134 970
Sum of Electronic and Thermal Free Energies =541.937 504 000
Table S28 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
203b – Conformer 1
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =0.857 662 =0.409 469 0.349 807 94.9056 88.7020
2 C 2.245 895 =0.377 236 =0.204 793 146.4929 37.1147
3 C 1.381 435 =1.619 213 0.027 254 140.7721 42.8355
4 C =0.079 989 =1.487 457 =0.401 047 145.1562 38.4514
5 H 2.257 574 =0.153 014 =1.280 775 30.1207 1.7442
6 H 1.833 479 =2.462 325 =0.507 661 29.9770 1.8879
7 H 1.419 337 =1.870 212 1.097 757 30.5819 1.2830
8 H =0.146 784 =1.278 651 =1.475 889 30.1355 1.7294
9 H =0.584 640 =2.445 722 =0.231 107 30.1413 1.7236
10 C 0.543 647 1.525 568 =0.169 542 =2.2084 185.8160
11 O 0.638 831 2.613 479 =0.702 544 — —
12 O =0.634 142 0.892 917 =0.242 703 — —
13 H =0.530 494 =0.367 329 1.397 622 27.5596 4.3053
14 C =2.374 984 =0.619 072 0.337 307 143.0604 40.5472
15 H =2.536 059 =1.582 316 0.839 873 30.2113 1.6536
Continued on next page
129
Table S28 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
16 C =2.941 794 =0.706 420 =1.081 500 168.5560 15.0516
17 H =4.026 128 =0.846 035 =1.042 713 31.1850 0.6799
18 H =2.738 992 0.217 624 =1.632 136 30.8946 0.9703
19 H =2.515 762 =1.543 014 =1.642 677 30.7411 1.1238
20 C =3.083 543 0.469 715 1.144 366 161.5150 22.0926
21 H =4.151 756 0.248 719 1.225 914 30.9190 0.9459
22 H =2.672 226 0.545 929 2.156 598 30.9769 0.8880
23 H =2.973 471 1.442 792 0.656 367 30.6763 1.1886
24 C 1.702 198 0.862 802 0.537 509 137.1302 46.4774
25 H 2.479 379 1.626 342 0.603 021 29.5338 2.3311
26 H 1.416 391 0.583 570 1.559 011 29.2478 2.6171
27 C 3.681 586 =0.643 546 0.249 331 157.2322 26.3754
28 H 4.331 558 0.207 277 0.026 063 30.7399 1.1250
29 H 3.711 896 =0.821 004 1.330 900 31.0827 0.7822
30 H 4.088 461 =1.527 840 =0.250 343 30.8001 1.0648
Fig. S29 203b – Conformer 2
SCF Energy - E(RM062X) =542.169 535 189
SCF Energy from NMR - E(RB3LYP) =542.552 804 001
Sum of Electronic and Thermal Free Energies =541.937 459 000
130
Table S29 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
203b – Conformer 2
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 0.912 188 =0.061 797 =0.327 385 94.1342 89.4734
2 C =2.131 115 =0.600 844 0.318 150 146.4012 37.2064
3 C =1.005 620 =1.638 471 0.322 171 140.7964 42.8112
4 C 0.383 146 =1.097 326 0.661 880 152.0900 31.5176
5 H =2.208 921 =0.163 231 1.323 355 30.1210 1.7439
6 H =1.263 758 =2.427 953 1.037 274 29.9534 1.9115
7 H =0.970 553 =2.112 397 =0.670 166 30.6839 1.1810
8 H 0.387 609 =0.649 688 1.663 526 30.4668 1.3981
9 H 1.085 307 =1.937 640 0.688 250 30.0265 1.8384
10 C =0.896 596 1.578 934 =0.168 467 =1.7396 185.3472
11 O =1.239 999 2.704 436 0.134 805 — —
12 O 0.393 953 1.255 228 =0.013 802 — —
13 H 0.599 998 =0.317 206 =1.348 802 27.6042 4.2607
14 C 2.436 134 0.103 970 =0.324 505 144.4800 39.1276
15 H 2.634 885 0.984 455 =0.948 679 29.8770 1.9879
16 C 3.120 669 =1.099 328 =0.974 840 162.9034 20.7042
17 H 4.194 553 =0.913 015 =1.065 693 30.7923 1.0726
18 H 2.994 604 =2.006 518 =0.374 247 31.1739 0.6910
19 H 2.724 585 =1.294 227 =1.976 839 30.9414 0.9235
20 C 2.992 732 0.370 088 1.075 088 167.5501 16.0575
21 H 4.056 979 0.616 006 1.014 613 31.0858 0.7791
22 H 2.475 673 1.204 588 1.557 071 30.5366 1.3283
23 H 2.891 890 =0.515 124 1.712 769 31.2633 0.6016
24 C =1.869 538 0.544 627 =0.683 086 137.1137 46.4939
25 H =2.796 532 1.087 884 =0.875 273 29.5191 2.3458
26 H =1.518 416 0.129 611 =1.635 900 29.2486 2.6163
27 C =3.462 795 =1.271 282 =0.021 568 157.2482 26.3594
28 H =4.291 335 =0.559 975 0.039 408 30.7420 1.1229
29 H =3.436 064 =1.677 141 =1.039 735 31.0846 0.7803
30 H =3.667 366 =2.097 161 0.666 424 30.7994 1.0655
131
Fig. S30 203b – Conformer 3
SCF Energy - E(RM062X) =542.168 628 918
SCF Energy from NMR - E(RB3LYP) =542.552 439 622
Sum of Electronic and Thermal Free Energies =541.937 340 000
Table S30 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
203b – Conformer 3
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =0.919 386 =0.224 788 0.017 890 91.8084 91.7992
2 C 2.227 146 =0.493 680 =0.160 400 146.5522 37.0554
3 C 1.213 257 =1.638 636 =0.223 456 140.7742 42.8334
4 C =0.160 514 =1.276 542 =0.788 993 147.3639 36.2437
5 H 2.408 496 =0.127 801 =1.180 893 30.1030 1.7619
6 H 1.641 222 =2.448 502 =0.825 322 29.9760 1.8889
7 H 1.083 126 =2.038 757 0.793 167 30.6243 1.2406
8 H =0.072 922 =0.905 656 =1.818 372 30.4555 1.4094
9 H =0.761 728 =2.188 517 =0.832 854 29.6701 2.1948
10 C 0.743 543 1.571 859 =0.051 946 =1.7224 185.3300
11 O 1.023 186 2.697 939 =0.413 321 — —
12 O =0.470 841 1.099 578 =0.360 664 — —
13 H =0.741 064 =0.355 337 1.095 608 28.0945 3.7704
14 C =2.434 500 =0.229 269 =0.216 889 144.6951 38.9125
15 H =2.599 242 =0.181 926 =1.302 631 30.1780 1.6869
16 C =3.098 073 0.984 122 0.439 856 162.0719 21.5357
Continued on next page
132
Table S30 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
17 H =4.181 971 0.940 724 0.298 557 31.0121 0.8528
18 H =2.900 019 0.985 800 1.519 044 31.3781 0.4868
19 H =2.732 381 1.924 006 0.023 525 30.1759 1.6890
20 C =3.064 276 =1.513 895 0.330 511 162.1505 21.4571
21 H =4.148 616 =1.481 806 0.192 682 30.8441 1.0208
22 H =2.696 234 =2.416 858 =0.161 839 30.7016 1.1633
23 H =2.868 027 =1.605 871 1.405 569 31.3125 0.5524
24 C 1.719 895 0.690 796 0.689 521 137.3621 46.2455
25 H 2.554 339 1.340 706 0.958 774 29.5363 2.3286
26 H 1.271 456 0.314 742 1.617 048 29.2578 2.6071
27 C 3.551 378 =0.995 882 0.416 001 157.3501 26.2575
28 H 4.312 639 =0.210 707 0.402 047 30.7383 1.1266
29 H 3.415 485 =1.320 798 1.454 319 31.0892 0.7757
30 H 3.925 853 =1.848 088 =0.159 117 30.8033 1.0616
Fig. S31 203b – Conformer 4
SCF Energy - E(RM062X) =542.165 252 005
SCF Energy from NMR - E(RB3LYP) =542.545 413 963
Sum of Electronic and Thermal Free Energies =541.932 246 000
133
Table S31 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
203b – Conformer 4
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 0.914 812 =0.107 380 =0.807 131 92.4804 91.1272
2 C =1.790 772 =0.906 698 0.726 880 150.2969 33.3107
3 C =0.657 947 =1.849 009 0.303 046 150.2422 33.3654
4 C 0.120 140 =1.405 495 =0.935 389 155.7061 27.9015
5 H =2.228 730 =1.331 565 1.638 190 29.8767 1.9882
6 H 0.033 459 =1.977 971 1.146 135 29.7748 2.0901
7 H =1.089 295 =2.837 122 0.103 890 30.2842 1.5807
8 H 0.831 546 =2.191 170 =1.210 409 29.9755 1.8894
9 H =0.553 263 =1.296 555 =1.792 985 29.7094 2.1555
10 C =0.916 408 1.395 728 =0.027 461 =1.6231 185.2307
11 O =1.498 475 2.443 718 =0.229 524 — —
12 O 0.059 675 1.064 481 =0.884 947 — —
13 H 1.497 840 0.006 078 =1.728 375 28.0662 3.7987
14 C 1.916 637 =0.023 462 0.352 758 149.9747 33.6329
15 H 1.399 149 =0.162 025 1.307 604 29.3594 2.5055
16 C 2.607 986 1.341 342 0.369 413 162.4368 21.1708
17 H 3.348 511 1.379 827 1.173 502 30.9903 0.8746
18 H 3.127 064 1.517 541 =0.580 189 31.1966 0.6683
19 H 1.896 591 2.157 566 0.519 540 30.4991 1.3658
20 C 2.946 422 =1.149 547 0.219 027 162.2537 21.3539
21 H 3.720 923 =1.040 074 0.983 316 30.8883 0.9766
22 H 2.493 774 =2.137 853 0.339 033 30.7528 1.1121
23 H 3.434 568 =1.112 360 =0.762 339 31.3458 0.5191
24 C =1.288 917 0.491 994 1.130 641 135.4092 48.1984
25 H =0.440 489 0.410 019 1.816 587 28.8990 2.9659
26 H =2.083 654 1.025 636 1.655 533 29.2401 2.6248
27 C =2.902 925 =0.808 473 =0.320 327 164.9915 18.6161
28 H =3.731 821 =0.199 204 0.052 846 30.7889 1.0760
29 H =2.550 275 =0.347 797 =1.249 714 30.7105 1.1544
30 H =3.289 654 =1.802 560 =0.565 148 31.0496 0.8153
134
S-I.6 Normal cis-Carvomenthide (204a)
Fig. S32 204a – Conformer 1
SCF Energy - E(RM062X) =542.169 260 511
SCF Energy from NMR - E(RB3LYP) =542.548 839 790
Sum of Electronic and Thermal Free Energies =541.935 530 000
Table S32 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
204a – Conformer 1
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =2.055 131 =0.327 730 0.109 051 100.9720 82.6356
2 C 0.274 970 0.914 930 1.266 550 140.5636 43.0440
3 C 0.999 288 =0.399 149 0.885 769 138.1549 45.4527
4 C 0.028 421 =1.586 084 0.926 571 147.1657 36.4419
5 C =1.119 496 =1.518 524 =0.080 958 148.3533 35.2543
6 H =0.425 689 0.722 447 2.087 010 28.9935 2.8714
7 H 1.742 705 =0.571 535 1.677 420 30.5060 1.3589
8 H 0.581 600 =2.518 929 0.782 370 29.7326 2.1323
9 H =0.401 237 =1.638 689 1.935 873 30.2907 1.5742
10 H =0.748 484 =1.500 506 =1.114 152 30.1042 1.7607
Continued on next page
135
Table S32 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
11 H =1.724 899 =2.426 303 0.019 996 30.2878 1.5771
12 C =0.462 949 1.541 626 0.105 097 =1.3645 184.9721
13 O =0.140 604 2.606 945 =0.381 136 — —
14 O =1.497 656 0.890 467 =0.447 697 — —
15 H =2.241 423 =0.157 444 1.176 915 27.3433 4.5216
16 C =3.376 194 =0.511 273 =0.615 990 159.1524 24.4552
17 H =3.996 541 0.382 031 =0.515 055 30.4933 1.3716
18 H =3.198 050 =0.697 917 =1.679 397 30.5235 1.3414
19 H =3.914 132 =1.364 067 =0.195 075 30.8182 1.0467
20 H 0.985 283 1.667 899 1.608 816 29.0190 2.8459
21 C 1.782 507 =0.266 740 =0.438 210 149.4261 34.1815
22 H 1.078 730 0.013 209 =1.236 606 30.3061 1.5588
23 C 2.843 946 0.834 080 =0.339 291 160.4138 23.1938
24 H 3.545 914 0.611 062 0.474 020 31.4098 0.4551
25 H 3.416 469 0.896 542 =1.269 553 30.9610 0.9039
26 H 2.403 477 1.817 255 =0.155 002 30.1582 1.7067
27 C 2.441 843 =1.588 626 =0.840 795 161.2666 22.3410
28 H 3.071 316 =1.968 142 =0.025 952 31.3759 0.4890
29 H 1.707 934 =2.359 965 =1.090 401 30.5995 1.2654
30 H 3.079 881 =1.441 302 =1.717 324 31.0051 0.8598
Fig. S33 204a – Conformer 2
136
SCF Energy - E(RM062X) =542.164 392 485
SCF Energy from NMR - E(RB3LYP) =542.544 841 222
Sum of Electronic and Thermal Free Energies =541.930 683 000
Table S33 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
204a – Conformer 2
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 1.982 353 =0.542 589 =0.188 145 102.0054 81.6022
2 C =0.174 012 0.930 545 =1.333 792 139.6398 43.9678
3 C =1.105 414 =0.230 149 =0.920 861 140.4514 43.1562
4 C =0.344 999 =1.551 893 =0.708 200 152.6906 30.9170
5 C 0.898 408 =1.545 676 0.191 589 144.3578 39.2498
6 H 0.489 669 0.597 069 =2.139 331 28.7803 3.0846
7 H =1.726 249 =0.393 582 =1.811 362 30.0766 1.7883
8 H =1.043 553 =2.309 211 =0.332 673 29.8129 2.0520
9 H =0.024 045 =1.902 271 =1.698 104 30.1893 1.6756
10 H 0.650 742 =1.377 116 1.244 140 29.9035 1.9614
11 H 1.348 197 =2.543 741 0.135 067 30.2169 1.6480
12 C 0.652 507 1.509 875 =0.212 054 =2.8714 186.4790
13 O 0.446 095 2.610 506 0.258 970 — —
14 O 1.657 213 0.784 306 0.300 854 — —
15 H 2.101 461 =0.488 433 =1.277 171 27.2050 4.6599
16 C 3.318 341 =0.872 959 0.452 254 159.3255 24.2821
17 H 4.053 109 =0.096 152 0.229 263 30.4674 1.3975
18 H 3.205 938 =0.950 210 1.537 960 30.5375 1.3274
19 H 3.686 460 =1.827 354 0.068 278 30.8330 1.0319
20 H =0.776 010 1.757 238 =1.715 083 29.4151 2.4498
21 C =2.096 838 0.170 373 0.199 231 145.7069 37.9007
22 H =2.345 479 1.227 802 0.031 323 29.8498 2.0151
23 C =3.394 980 =0.633 799 0.073 836 158.3263 25.2813
24 H =3.204 696 =1.706 131 0.200 211 30.8003 1.0646
25 H =4.112 128 =0.333 080 0.844 018 30.9180 0.9469
26 H =3.863 074 =0.485 246 =0.904 419 31.0493 0.8156
27 C =1.560 150 0.042 047 1.629 202 161.4196 22.1880
28 H =1.421 963 =1.011 724 1.896 712 31.2378 0.6271
29 H =0.610 919 0.562 359 1.783 792 30.5920 1.2729
30 H =2.285 213 0.466 635 2.330 423 30.9932 0.8717
137
Fig. S34 204a – Conformer 3
SCF Energy - E(RM062X) =542.164 222 687
SCF Energy from NMR - E(RB3LYP) =542.544 090 829
Sum of Electronic and Thermal Free Energies =541.930 083 000
Table S34 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
204a – Conformer 3
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 2.065 495 =0.121 331 =0.202 303 102.2069 81.4007
2 C =0.467 219 0.620 451 =1.298 259 146.5638 37.0438
3 C =0.988 637 =0.771 408 =0.873 821 140.2793 43.3283
4 C 0.146 897 =1.790 310 =0.673 764 145.9931 37.6145
5 C 1.338 912 =1.396 715 0.208 185 144.5956 39.0120
6 H 0.246 294 0.488 103 =2.119 980 29.0608 2.8041
7 H =1.535 932 =1.119 023 =1.760 469 29.9164 1.9485
8 H =0.286 270 =2.721 010 =0.286 340 29.9812 1.8837
9 H 0.550 018 =2.029 882 =1.666 773 29.8931 1.9718
10 H 1.063 309 =1.287 999 1.261 658 29.7847 2.0802
11 H 2.067 040 =2.214 618 0.160 045 30.1471 1.7178
Continued on next page
138
Table S34 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
12 C 0.186 492 1.445 595 =0.215 483 =3.5721 187.1797
13 O =0.307 042 2.463 898 0.227 175 — —
14 O 1.367 578 1.053 747 0.283 483 — —
15 H 2.142 257 =0.048 443 =1.294 019 27.2424 4.6225
16 C 3.450 963 =0.028 524 0.411 328 159.3275 24.2801
17 H 3.915 539 0.929 439 0.167 459 30.4690 1.3959
18 H 3.386 746 =0.122 113 1.499 681 30.5238 1.3411
19 H 4.080 345 =0.834 452 0.026 267 30.8186 1.0463
20 H =1.290 249 1.227 953 =1.676 417 29.1566 2.7083
21 C =2.049 203 =0.756 598 0.252 496 143.0121 40.5955
22 H =2.513 896 =1.752 290 0.212 781 30.0133 1.8516
23 C =1.510 636 =0.581 375 1.677 034 163.3878 20.2198
24 H =0.922 228 0.334 764 1.792 934 30.8878 0.9771
25 H =2.350 073 =0.517 299 2.377 101 31.1389 0.7260
26 H =0.893 093 =1.429 316 1.983 828 30.6868 1.1781
27 C =3.148 255 0.272 253 =0.030 568 159.8772 23.7304
28 H =2.780 503 1.293 300 0.117 615 30.3791 1.4858
29 H =3.519 701 0.188 457 =1.058 228 30.9461 0.9188
30 H =3.992 741 0.121 041 0.648 514 30.8754 0.9895
Fig. S35 204a – Conformer 4
SCF Energy - E(RM062X) =542.163 494 264
SCF Energy from NMR - E(RB3LYP) =542.546 004 235
Sum of Electronic and Thermal Free Energies =541.931 402 000
139
Table S35 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
204a – Conformer 4
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 2.304 665 =0.569 330 =0.218 367 102.7965 80.8111
2 C =0.257 854 0.743 061 0.571 561 142.3522 41.2554
3 C =0.876 035 =0.174 422 =0.502 740 136.9666 46.6410
4 C =0.100 464 =1.487 454 =0.636 863 149.0473 34.5603
5 C 1.334 701 =1.315 590 =1.131 097 145.8154 37.7922
6 H =0.967 133 1.517 757 0.867 365 29.3512 2.5137
7 H =0.818 127 0.347 861 =1.469 802 30.3811 1.4838
8 H =0.102 196 =2.019 655 0.323 244 29.7538 2.1111
9 H =0.628 351 =2.132 656 =1.348 991 30.4171 1.4478
10 H 1.774 942 =2.305 891 =1.296 124 29.9429 1.9220
11 H 1.332 613 =0.807 271 =2.103 339 29.8063 2.0586
12 C 0.967 485 1.504 579 0.117 892 =2.6991 186.3067
13 O 0.970 483 2.717 931 0.039 768 — —
14 O 2.095 533 0.867 830 =0.225 609 — —
15 H 3.289 554 =0.631 067 =0.687 861 27.2731 4.5918
16 C 2.440 424 =1.117 993 1.195 287 165.1893 18.4183
17 H 3.161 514 =0.519 756 1.757 433 30.4186 1.4463
18 H 1.499 641 =1.141 968 1.746 721 29.9445 1.9204
19 H 2.816 891 =2.143 456 1.135 384 30.8712 0.9937
20 H =0.019 302 0.162 302 1.467 967 29.4581 2.4068
21 C =2.375 834 =0.427 716 =0.225 926 143.2827 40.3249
22 H =2.683 950 =1.204 181 =0.940 001 30.2027 1.6622
23 C =2.646 994 =0.955 235 1.186 238 167.2360 16.3716
24 H =2.424 851 =0.191 469 1.940 175 31.4317 0.4332
25 H =3.702 909 =1.222 110 1.292 358 31.0930 0.7719
26 H =2.053 420 =1.845 117 1.417 133 30.7917 1.0732
27 C =3.229 939 0.811 477 =0.504 833 160.4172 23.1904
28 H =3.007 016 1.622 546 0.197 051 30.8619 1.0030
29 H =3.064 066 1.187 301 =1.519 443 30.9776 0.8873
30 H =4.292 889 0.572 471 =0.399 448 30.8954 0.9695
140
Fig. S36 204a – Conformer 5
SCF Energy - E(RM062X) =542.163 420 262
SCF Energy from NMR - E(RB3LYP) =542.545 837 090
Sum of Electronic and Thermal Free Energies =541.931 194 000
Table S36 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
204a – Conformer 5
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 2.097 508 =0.984 012 =0.215 801 102.6984 80.9092
2 C 0.037 371 1.040 575 0.537 683 133.7876 49.8200
3 C =0.889 425 0.199 083 =0.362 946 137.1544 46.4532
4 C =0.492 663 =1.279 081 =0.350 343 158.4283 25.1793
5 C 0.885 650 =1.549 602 =0.952 112 145.9129 37.6947
6 H =0.432 700 2.001 874 0.757 659 29.4802 2.3847
7 H =0.781 744 0.568 586 =1.394 203 30.3071 1.5578
8 H =0.533 103 =1.663 539 0.677 099 30.2321 1.6328
9 H =1.223 345 =1.855 995 =0.926 674 30.2157 1.6492
10 H 1.044 105 =2.633 025 =1.005 002 29.9352 1.9297
11 H 0.917 043 =1.177 033 =1.983 538 29.9266 1.9383
12 C 1.371 394 1.394 628 =0.080 404 =2.4276 186.0352
13 O 1.680 037 2.547 455 =0.313 063 — —
14 O 2.261 154 0.446 622 =0.405 469 — —
15 H 2.983 203 =1.358 104 =0.735 385 27.2675 4.5974
16 C 2.227 941 =1.381 588 1.248 057 165.1819 18.4257
Continued on next page
141
Table S36 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
17 H 3.134 174 =0.942 757 1.672 302 30.4170 1.4479
18 H 1.375 289 =1.081 249 1.858 555 29.9568 1.9081
19 H 2.312 510 =2.470 756 1.306 753 30.8919 0.9730
20 H 0.202 277 0.532 513 1.492 815 28.9616 2.9033
21 C =2.363 603 0.441 482 0.033 956 142.8225 40.7851
22 H =2.514 111 1.528 656 =0.018 825 30.1584 1.7065
23 C =3.337 559 =0.200 875 =0.957 114 160.2623 23.3453
24 H =3.340 293 =1.292 365 =0.868 315 30.9244 0.9405
25 H =4.357 504 0.145 137 =0.762 904 30.7830 1.0819
26 H =3.082 597 0.057 240 =1.990 554 30.9724 0.8925
27 C =2.685 739 =0.005 297 1.462 926 167.6379 15.9697
28 H =2.590 750 =1.091 754 1.567 020 31.2474 0.6175
29 H =2.030 531 0.467 769 2.201 290 30.9162 0.9487
30 H =3.716 690 0.260 301 1.716 756 31.0947 0.7702
Fig. S37 204a – Conformer 6
SCF Energy - E(RM062X) =542.165 745 134
SCF Energy from NMR - E(RB3LYP) =542.546 978 417
Sum of Electronic and Thermal Free Energies =541.933 151 000
142
Table S37 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
204a – Conformer 6
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =2.076 727 =0.484 595 0.349 955 104.8322 78.7754
2 C 0.414 186 0.713 125 0.856 392 146.0696 37.5380
3 C 0.856 309 =0.657 455 0.255 316 141.1340 42.4736
4 C 0.025 982 =1.053 576 =0.974 369 149.2078 34.3998
5 C =1.410 196 =1.453 078 =0.622 844 144.0410 39.5666
6 H 0.045 036 0.584 389 1.879 461 29.0562 2.8087
7 H 0.683 855 =1.426 080 1.021 939 30.0904 1.7745
8 H 0.010 122 =0.227 174 =1.695 985 30.2841 1.5808
9 H 0.514 873 =1.891 861 =1.483 423 30.4706 1.3943
10 H =2.014 278 =1.516 304 =1.535 314 30.1433 1.7216
11 H =1.420 261 =2.444 351 =0.153 737 30.2020 1.6629
12 C =0.651 302 1.453 884 0.074 538 =1.9229 185.5305
13 O =0.481 268 2.561 097 =0.393 432 — —
14 O =1.853 939 0.876 228 =0.088 783 — —
15 H =1.643 812 =0.597 625 1.349 990 27.2339 4.6310
16 C =3.579 255 =0.665 136 0.430 696 161.3390 22.2686
17 H =4.016 174 0.028 395 1.152 792 30.3899 1.4750
18 H =4.031 674 =0.488 545 =0.549 228 30.6809 1.1840
19 H =3.808 428 =1.687 869 0.741 961 30.7178 1.1471
20 H 1.253 191 1.407 187 0.912 357 29.4091 2.4558
21 C 2.369 194 =0.681 702 =0.051 964 142.6631 40.9445
22 H 2.579 414 =1.693 468 =0.426 423 30.2030 1.6619
23 C 2.773 125 0.312 626 =1.143 807 168.1073 15.5003
24 H 2.537 210 1.343 263 =0.854 277 31.0951 0.7698
25 H 3.851 564 0.259 431 =1.322 697 31.2341 0.6308
26 H 2.266 704 0.105 906 =2.090 996 30.8868 0.9781
27 C 3.209 281 =0.479 394 1.211 326 160.8121 22.7955
28 H 3.100 985 0.535 145 1.610 475 30.9600 0.9049
29 H 2.919 063 =1.185 598 1.996 762 31.0789 0.7860
30 H 4.270 688 =0.631 636 0.992 629 30.9205 0.9444
143
Fig. S38 204a – Conformer 7
SCF Energy - E(RM062X) =542.165 698 992
SCF Energy from NMR - E(RB3LYP) =542.546 816 347
Sum of Electronic and Thermal Free Energies =541.932 836 000
Table S38 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
204a – Conformer 7
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =2.004 242 =0.675 639 0.257 835 104.7445 78.8631
2 C 0.169 525 0.929 209 1.017 768 138.3358 45.2718
3 C 0.905 585 =0.348 918 0.506 771 140.9627 42.6449
4 C 0.305 845 =0.881 024 =0.803 472 157.8956 25.7120
5 C =1.073 835 =1.517 340 =0.610 268 144.1054 39.5022
6 H =0.287 657 0.742 112 1.995 425 28.5826 3.2823
7 H 0.776 696 =1.131 719 1.267 268 30.1568 1.7081
8 H 0.235 291 =0.065 231 =1.534 204 30.6877 1.1772
9 H 0.975 202 =1.625 486 =1.245 574 30.2602 1.6047
10 H =1.546 986 =1.684 349 =1.584 896 30.1350 1.7299
11 H =0.970 869 =2.494 985 =0.123 896 30.3256 1.5393
12 C =0.909 160 1.478 673 0.106 912 =1.4856 185.0932
13 O =0.878 612 2.600 136 =0.357 050 — —
14 O =1.967 516 0.702 502 =0.182 550 — —
15 H =1.677 010 =0.710 096 1.302 604 27.2441 4.6208
16 C =3.452 943 =1.111 894 0.171 597 161.3388 22.2688
Continued on next page
144
Table S38 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
17 H =4.082 382 =0.501 670 0.823 313 30.3986 1.4663
18 H =3.812 671 =1.019 301 =0.857 053 30.6848 1.1801
19 H =3.538 322 =2.157 893 0.478 386 30.7193 1.1456
20 H 0.876 259 1.750 069 1.151 868 29.5222 2.3427
21 C 2.422 119 =0.072 283 0.402 958 142.4021 41.2055
22 H 2.708 726 0.426 064 1.339 842 30.2754 1.5895
23 C 3.236 549 =1.364 436 0.310 256 161.0799 22.5277
24 H 3.039 825 =1.897 763 =0.625 891 30.9176 0.9473
25 H 4.307 701 =1.141 361 0.340 039 30.8613 1.0036
26 H 3.007 341 =2.039 141 1.141 759 31.0334 0.8315
27 C 2.764 357 0.866 706 =0.757 023 167.0320 16.5756
28 H 2.603 092 0.369 802 =1.719 924 31.3165 0.5484
29 H 2.155 654 1.777 468 =0.742 790 30.6446 1.2203
30 H 3.816 337 1.164 045 =0.709 490 31.1165 0.7484
Fig. S39 204a – Conformer 8
SCF Energy - E(RM062X) =542.161 921 458
SCF Energy from NMR - E(RB3LYP) =542.544 682 644
Sum of Electronic and Thermal Free Energies =541.929 255 000
145
Table S39 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
204a – Conformer 8
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 2.262 643 =0.769 533 =0.237 074 103.0430 80.5646
2 C =0.034 810 0.897 345 0.636 696 136.8196 46.7880
3 C =0.908 528 =0.066 762 =0.194 215 135.6202 47.9874
4 C =0.269 343 =1.456 473 =0.254 281 151.1870 32.4206
5 C 1.105 158 =1.490 097 =0.923 057 145.7829 37.8247
6 H =0.608 151 1.776 676 0.929 153 29.0907 2.7742
7 H =0.983 219 0.320 127 =1.223 416 30.8443 1.0206
8 H =0.212 744 =1.872 302 0.762 333 30.3216 1.5433
9 H =0.915 364 =2.127 195 =0.827 217 29.9557 1.9092
10 H 1.418 778 =2.535 905 =1.021 707 29.9107 1.9542
11 H 1.023 912 =1.092 333 =1.942 555 29.8988 1.9661
12 C 1.176 570 1.457 249 =0.074 764 =1.5131 185.1207
13 O 1.259 030 2.635 920 =0.361 533 — —
14 O 2.208 890 0.671 250 =0.407 881 — —
15 H 3.161 967 =1.006 816 =0.810 957 27.2734 4.5915
16 C 2.531 328 =1.166 669 1.208 094 165.3263 18.2813
17 H 3.380 507 =0.599 314 1.596 439 30.4101 1.4548
18 H 1.677 394 =1.015 430 1.869 550 29.9268 1.9381
19 H 2.787 663 =2.229 959 1.233 455 30.8808 0.9841
20 H 0.276 352 0.393 113 1.557 078 29.4249 2.4400
21 C =2.338 957 =0.080 454 0.398 811 144.4375 39.1701
22 H =2.239 223 =0.167 917 1.491 809 30.7329 1.1320
23 C =3.081 850 1.221 548 0.077 076 159.9284 23.6792
24 H =3.258 701 1.290 453 =1.002 865 31.3435 0.5214
25 H =4.054 628 1.241 627 0.577 572 30.9108 0.9541
26 H =2.533 254 2.116 235 0.382 373 30.4032 1.4617
27 C =3.182 250 =1.260 403 =0.094 585 161.3709 22.2367
28 H =3.207 569 =1.284 067 =1.191 222 31.3235 0.5414
29 H =2.804 552 =2.222 713 0.259 293 30.5854 1.2795
30 H =4.212 283 =1.156 157 0.260 005 30.9741 0.8908
146
S-I.7 Normal trans-Carvomenthide (204b)
Fig. S40 204b – Conformer 1
SCF Energy - E(RM062X) =542.168 496 435
SCF Energy from NMR - E(RB3LYP) =542.551 625 328
Sum of Electronic and Thermal Free Energies =541.936 203 000
Table S40 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
204b – Conformer 1
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 2.122 385 =0.523 656 0.292 566 101.7056 81.9020
2 C =0.425 554 0.745 873 0.633 425 145.2387 38.3689
3 C =0.943 615 =0.258 234 =0.422 757 137.1790 46.4286
4 C =0.138 409 =1.560 578 =0.394 293 143.4141 40.1935
5 C 1.353 278 =1.402 395 =0.690 473 142.9742 40.6334
6 H 1.776 910 =0.697 302 1.319 277 27.3507 4.5142
7 H =1.181 238 1.499 912 0.858 411 29.4730 2.3919
8 H =0.812 019 0.197 746 =1.415 613 30.3403 1.5246
9 H =0.250 092 =2.031 528 0.591 928 30.1035 1.7614
10 H =0.568 719 =2.254 968 =1.125 348 30.2510 1.6139
11 H 1.817 720 =2.394 598 =0.675 621 30.0032 1.8617
12 H 1.509 702 =0.993 560 =1.697 368 30.2589 1.6060
13 C 0.775 824 1.517 104 0.145 834 =3.1892 186.7968
14 O 0.726 076 2.696 780 =0.140 374 — —
15 O 1.946 429 0.883 315 =0.012 145 — —
16 C 3.621 340 =0.749 593 0.213 851 159.1872 24.4204
Continued on next page
147
Table S40 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
17 H 4.149 303 =0.056 668 0.872 750 30.4775 1.3874
18 H 3.857 157 =1.772 977 0.515 305 30.8251 1.0398
19 H 3.970 709 =0.595 802 =0.811 680 30.5357 1.3292
20 C =2.456 972 =0.522 955 =0.255 163 143.6497 39.9579
21 H =2.693 970 =1.352 553 =0.936 017 30.2383 1.6266
22 C =2.839 234 =0.955 721 1.163 350 167.4817 16.1259
23 H =2.675 671 =0.142 490 1.879 701 31.4642 0.4007
24 H =3.900 810 =1.218 255 1.203 598 31.1362 0.7287
25 H =2.268 048 =1.826 222 1.499 531 30.8266 1.0383
26 C =3.297 378 0.679 814 =0.690 433 160.6420 22.9656
27 H =3.133 358 1.543 491 =0.036 671 30.8250 1.0399
28 H =3.056 646 0.981 686 =1.714 645 30.9807 0.8842
29 H =4.363 451 0.435 604 =0.647 972 30.9113 0.9536
30 H =0.187 503 0.219 767 1.565 142 29.4934 2.3715
Fig. S41 204b – Conformer 2
SCF Energy - E(RM062X) =542.168 389 401
SCF Energy from NMR - E(RB3LYP) =542.551 370 060
Sum of Electronic and Thermal Free Energies =541.936 133 000
148
Table S41 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
204b – Conformer 2
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 1.998 079 =0.722 052 0.357 293 101.5874 82.0202
2 C =0.195 151 1.110 832 0.549 906 137.0237 46.5839
3 C =0.976 258 0.098 184 =0.319 902 137.6292 45.9784
4 C =0.469 111 =1.330 665 =0.104 202 152.4833 31.1243
5 C 1.003 606 =1.544 146 =0.458 021 143.3184 40.2892
6 H 1.683 140 =0.662 854 1.406 484 27.3668 4.4981
7 H =0.769 640 2.032 988 0.661 422 29.6138 2.2511
8 H =0.807 403 0.363 141 =1.374 770 30.2423 1.6226
9 H =0.620 172 =1.610 825 0.947 442 30.5332 1.3317
10 H =1.067 697 =2.023 411 =0.704 596 30.0668 1.7981
11 H 1.247 941 =2.600 806 =0.302 652 30.0001 1.8648
12 H 1.183 775 =1.329 682 =1.519 645 30.3680 1.4969
13 C 1.114 875 1.520 402 =0.076 082 =2.9691 186.5767
14 O 1.304 079 2.627 901 =0.538 345 — —
15 O 2.112 153 0.628 334 =0.159 060 — —
16 C 3.406 409 =1.283 495 0.281 151 159.1620 24.4456
17 H 4.108 158 =0.631 920 0.806 605 30.4905 1.3744
18 H 3.433 958 =2.274 829 0.739 885 30.8289 1.0360
19 H 3.720 618 =1.370 204 =0.763 450 30.5354 1.3295
20 C =2.494 101 0.252 142 =0.072 167 142.6093 40.9983
21 H =2.726 526 1.304 180 =0.288 286 30.1224 1.7425
22 C =3.321 262 =0.604 972 =1.033 551 160.4254 23.1822
23 H =3.242 068 =1.669 801 =0.790 363 30.9554 0.9095
24 H =4.379 108 =0.332 134 =0.968 907 30.7994 1.0655
25 H =2.997 214 =0.466 528 =2.070 628 30.9799 0.8850
26 C =2.903 383 =0.026 048 1.377 018 167.7908 15.8168
27 H =2.736 217 =1.075 884 1.641 412 31.2656 0.5993
28 H =2.352 922 0.597 765 2.088 335 30.9611 0.9038
29 H =3.969 764 0.180 233 1.511 503 31.1100 0.7549
30 H =0.020 939 0.699 603 1.550 799 29.0086 2.8563
149
Fig. S42 204b – Conformer 3
SCF Energy - E(RM062X) =542.167 141 614
SCF Energy from NMR - E(RB3LYP) =542.550 372 752
Sum of Electronic and Thermal Free Energies =541.934 520 000
Table S42 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
204b – Conformer 3
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 2.142 659 =0.593 717 0.306 707 102.0999 81.5077
2 C =0.233 064 0.934 500 0.723 419 139.9874 43.6202
3 C =0.980 613 =0.131 631 =0.113 250 135.8838 47.7238
4 C =0.273 106 =1.486 530 =0.007 856 145.1380 38.4696
5 C 1.187 150 =1.498 698 =0.465 275 142.9449 40.6627
6 H 1.909 499 =0.605 721 1.378 225 27.3167 4.5482
7 H =0.882 124 1.781 284 0.944 934 29.2391 2.6258
8 H =0.973 480 0.181 015 =1.169 819 30.8168 1.0481
9 H =0.327 117 =1.829 254 1.036 847 30.6413 1.2236
10 H =0.810 690 =2.224 839 =0.609 141 29.8122 2.0527
11 H 1.564 238 =2.523 517 =0.374 550 29.9891 1.8758
12 H 1.259 718 =1.228 915 =1.527 276 30.3423 1.5226
13 C 0.957 915 1.522 265 0.007 463 =1.9837 185.5913
14 O 0.959 281 2.649 377 =0.446 034 — —
15 O 2.057 761 0.775 703 =0.162 081 — —
16 C 3.595 022 =0.982 815 0.098 514 159.2483 24.3593
17 H 4.257 943 =0.270 173 0.594 255 30.4899 1.3750
18 H 3.773 796 =1.978 063 0.512 381 30.8293 1.0356
19 H 3.830 610 =0.998 744 =0.969 954 30.5446 1.3203
Continued on next page
150
Table S42 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
20 C =2.459 420 =0.185 276 0.340 108 144.1613 39.4463
21 H =2.463 596 =0.198 704 1.441 045 30.7460 1.1189
22 C =3.225 535 1.052 929 =0.139 235 160.1732 23.4344
23 H =3.305 758 1.038 801 =1.232 672 31.3456 0.5193
24 H =4.239 741 1.059 680 0.271 307 30.9135 0.9514
25 H =2.744 795 1.992 165 0.146 292 30.3754 1.4895
26 C =3.192 414 =1.437 179 =0.151 863 161.6617 21.9459
27 H =3.107 496 =1.529 217 =1.241 865 31.3640 0.5009
28 H =2.805 946 =2.354 097 0.299 641 30.6177 1.2472
29 H =4.256 330 =1.366 990 0.094 556 30.9847 0.8802
30 H 0.073 374 0.491 564 1.678 327 29.4210 2.4439
Fig. S43 204b – Conformer 4
SCF Energy - E(RM062X) =542.164 337 332
SCF Energy from NMR - E(RB3LYP) =542.543 500 218
Sum of Electronic and Thermal Free Energies =541.931 298 000
151
Table S43 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
204b – Conformer 4
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =2.009 190 =0.507 958 =0.635 952 102.5076 81.1000
2 C =0.024 602 0.843 067 1.158 642 137.7345 45.8731
3 C 0.829 936 =0.407 395 0.864 811 137.9671 45.6405
4 C =0.057 485 =1.641 904 0.659 809 153.7936 29.8140
5 C =0.935 129 =1.592 801 =0.589 961 151.7196 31.8880
6 H =2.570 417 =0.661 064 =1.561 172 27.2750 4.5899
7 H =0.820 817 0.588 516 1.863 814 29.0455 2.8194
8 H 1.417 032 =0.586 423 1.777 380 30.5580 1.3069
9 H 0.569 927 =2.537 120 0.609 228 29.8975 1.9674
10 H =0.688 251 =1.768 924 1.548 677 29.9325 1.9324
11 H =0.314 924 =1.491 848 =1.488 541 29.6320 2.2329
12 H =1.467 458 =2.546 205 =0.688 292 30.2696 1.5953
13 C =0.628 615 1.493 703 =0.068 829 =1.3381 184.9457
14 O =0.352 444 2.633 497 =0.388 685 — —
15 O =1.474 311 0.823 443 =0.865 926 — —
16 C =3.012 019 =0.522 735 0.509 967 165.1863 18.4213
17 H =3.750 945 0.269 078 0.365 539 30.4303 1.4346
18 H =3.532 484 =1.484 877 0.504 438 30.9047 0.9602
19 H =2.555 061 =0.397 994 1.492 613 29.8777 1.9872
20 C 1.843 874 =0.157 825 =0.272 653 150.3335 33.2741
21 H 1.291 186 0.123 705 =1.181 789 30.2457 1.6192
22 C 2.786 667 0.999 291 0.075 400 160.4932 23.1144
23 H 3.317 873 0.788 565 1.012 111 31.4008 0.4641
24 H 3.534 234 1.130 746 =0.712 585 30.9769 0.8880
25 H 2.254 329 1.947 425 0.187 416 30.2175 1.6474
26 C 2.659 654 =1.414 557 =0.587 710 161.2276 22.3800
27 H 3.150 092 =1.789 952 0.319 331 31.3554 0.5095
28 H 2.043 446 =2.219 941 =0.997 298 30.5684 1.2965
29 H 3.438 963 =1.186 495 =1.320 968 30.9845 0.8804
30 H 0.578 766 1.621 978 1.625 840 28.9064 2.9585
152
S-I.8 Abnormal cis-Carvomenthide (205a)
Fig. S44 205a – Conformer 1
SCF Energy - E(RM062X) =542.164 619 571
SCF Energy from NMR - E(RB3LYP) =542.544 017 109
Sum of Electronic and Thermal Free Energies =541.931 279 000
Table S44 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
205a – Conformer 1
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =1.905 425 0.417 034 0.236 772 140.1980 43.4096
2 C =0.890 383 1.506 432 =0.177 001 151.8476 31.7600
3 C 0.321 235 1.629 499 0.747 149 147.6298 35.9778
4 C 1.194 004 0.370 113 0.838 145 133.6748 49.9328
5 C 0.404 488 =0.797 930 1.434 280 110.2317 73.3759
6 H =1.993 616 0.426 040 1.331 499 29.0793 2.7856
7 H =0.580 174 1.333 593 =1.215 862 30.2808 1.5841
8 H =1.427 824 2.460 731 =0.172 089 30.4274 1.4375
9 H 0.929 717 2.482 300 0.431 896 29.7080 2.1569
10 H =0.038 809 1.867 716 1.757 006 30.2667 1.5982
11 H 1.990 609 0.582 628 1.567 864 30.6219 1.2430
12 H 1.074 294 =1.561 679 1.829 852 27.3954 4.4695
Continued on next page
153
Table S44 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
13 H =0.243 814 =0.461 462 2.250 346 27.4509 4.4140
14 C =1.424 755 =0.965 415 =0.174 454 =5.7268 189.3344
15 O =1.946 793 =1.613 170 =1.057 677 — —
16 O =0.373 442 =1.513 700 0.457 366 — —
17 C =3.277 696 0.687 231 =0.375 648 162.9619 20.6457
18 H =3.992 487 =0.097 297 =0.117 966 30.6775 1.1874
19 H =3.657 605 1.643 853 =0.007 652 31.0531 0.8118
20 H =3.207 234 0.736 379 =1.465 744 30.6055 1.2594
21 C 1.886 624 =0.017 271 =0.485 751 153.5849 30.0227
22 H 1.114 266 =0.261 880 =1.227 566 30.1582 1.7067
23 C 2.720 634 1.141 663 =1.038 411 161.3452 22.2624
24 H 2.103 499 1.996 734 =1.327 610 30.5953 1.2696
25 H 3.447 958 1.483 580 =0.291 313 31.3681 0.4968
26 H 3.275 526 0.819 590 =1.924 701 30.9699 0.8950
27 C 2.766 695 =1.258 342 =0.307 666 161.1646 22.4430
28 H 3.508 802 =1.092 817 0.483 602 31.3011 0.5638
29 H 2.179 284 =2.143 769 =0.050 104 30.3313 1.5336
30 H 3.306 957 =1.477 359 =1.233 455 30.9122 0.9527
Fig. S45 205a – Conformer 2
154
SCF Energy - E(RM062X) =542.158 664 695
SCF Energy from NMR - E(RB3LYP) =542.540 917 545
Sum of Electronic and Thermal Free Energies =541.926 295 000
Table S45 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
205a – Conformer 2
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 2.007 276 0.832 462 =0.109 601 134.3871 49.2205
2 C 0.833 531 1.421 723 =0.911 356 149.6918 33.9158
3 C =0.574 726 1.179 021 =0.369 364 158.7669 24.8407
4 C =0.991 588 =0.293 534 =0.377 466 132.6224 50.9852
5 C =0.122 159 =1.129 858 0.558 146 104.0576 79.5500
6 H 2.921 158 1.201 870 =0.582 661 28.8329 3.0320
7 H 1.008 333 2.502 648 =0.960 171 30.1060 1.7589
8 H 0.891 661 1.050 174 =1.942 425 30.0651 1.7998
9 H =0.654 692 1.578 982 0.649 874 30.2057 1.6592
10 H =1.270 151 1.758 620 =0.985 263 30.2066 1.6583
11 H =0.837 635 =0.692 102 =1.391 845 30.2510 1.6139
12 H 0.038 398 =0.633 310 1.519 052 27.2697 4.5952
13 H =0.602 522 =2.091 202 0.754 590 27.8750 3.9899
14 C 2.163 873 =0.675 201 =0.246 891 =4.7326 188.3402
15 O 3.215 176 =1.170 763 =0.602 140 — —
16 O 1.149 035 =1.516 990 0.003 060 — —
17 C 2.058 627 1.291 359 1.356 402 167.5349 16.0727
18 H 2.963 600 0.917 468 1.842 258 30.4906 1.3743
19 H 2.085 201 2.384 898 1.379 761 30.8884 0.9765
20 H 1.197 916 0.969 079 1.944 575 30.1811 1.6838
21 C =2.482 533 =0.516 515 =0.032 119 145.3002 38.3074
22 H =2.650 298 =1.600 243 =0.104 299 30.0352 1.8297
23 C =2.844 352 =0.083 680 1.392 878 166.5511 17.0565
24 H =2.238 098 =0.594 586 2.147 844 31.1062 0.7587
25 H =2.712 627 0.996 052 1.522 514 31.1589 0.7060
26 H =3.893 842 =0.314 485 1.600 666 31.1043 0.7606
27 C =3.412 697 0.155 816 =1.044 372 160.1220 23.4856
28 H =3.402 686 1.245 425 =0.936 366 30.8976 0.9673
29 H =3.125 695 =0.088 076 =2.072 785 30.9724 0.8925
30 H =4.443 210 =0.178 746 =0.890 219 30.8078 1.0571
155
Fig. S46 205a – Conformer 3
SCF Energy - E(RM062X) =542.158 493 639
SCF Energy from NMR - E(RB3LYP) =542.540 986 250
Sum of Electronic and Thermal Free Energies =541.926 197 000
Table S46 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
205a – Conformer 3
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 2.136 246 0.603 034 =0.192 058 134.4397 49.1679
2 C 1.143 321 1.204 678 =1.201 740 149.4707 34.1369
3 C =0.311 870 1.332 213 =0.754 916 149.2368 34.3708
4 C =1.005 716 =0.007 720 =0.498 085 132.5612 51.0464
5 C =0.365 318 =0.760 700 0.665 076 110.1393 73.4683
6 H 3.128 089 0.692 559 =0.643 180 28.8437 3.0212
7 H 1.523 495 2.202 576 =1.448 649 30.1301 1.7348
8 H 1.186 764 0.616 884 =2.127 523 29.9523 1.9126
9 H =0.371 078 1.958 190 0.145 275 29.7587 2.1062
10 H =0.861 566 1.866 774 =1.538 743 30.4212 1.4437
11 H =0.882 218 =0.636 274 =1.392 985 30.3138 1.5511
12 H =0.162 336 =0.098 616 1.511 257 27.5405 4.3244
13 H =1.021 482 =1.558 006 1.017 362 27.7181 4.1468
Continued on next page
156
Table S46 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
14 C 2.003 653 =0.902 390 =0.010 179 =4.9593 188.5669
15 O 2.954 491 =1.642 696 =0.168 348 — —
16 O 0.835 749 =1.476 209 0.317 734 — —
17 C 2.198 420 1.350 515 1.149 402 167.5304 16.0772
18 H 2.987 258 0.934 987 1.781 800 30.4868 1.3781
19 H 2.435 590 2.400 469 0.953 180 30.8753 0.9896
20 H 1.262 468 1.322 484 1.709 649 30.1818 1.6831
21 C =2.525 711 0.171 575 =0.271 525 144.0643 39.5433
22 H =2.865 312 0.863 491 =1.054 067 30.2265 1.6384
23 C =3.296 955 =1.138 062 =0.456 399 160.4714 23.1362
24 H =3.088 008 =1.586 718 =1.432 632 30.8514 1.0135
25 H =3.041 803 =1.872 438 0.315 549 30.7919 1.0730
26 H =4.374 278 =0.956 830 =0.388 645 30.8558 1.0091
27 C =2.860 587 0.801 284 1.085 647 166.3115 17.2961
28 H =2.612 189 0.121 447 1.908 947 31.5108 0.3541
29 H =2.325 738 1.742 039 1.247 608 30.6856 1.1793
30 H =3.932 485 1.011 661 1.149 377 31.0708 0.7941
Fig. S47 205a – Conformer 4
SCF Energy - E(RM062X) =542.160 145 896
SCF Energy from NMR - E(RB3LYP) =542.540 171 877
Sum of Electronic and Thermal Free Energies =541.926 339 000
157
Table S47 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
205a – Conformer 4
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =1.838 755 0.594 849 0.237 352 141.6817 41.9259
2 C =0.716 745 1.424 264 =0.425 186 148.1818 35.4258
3 C 0.574 349 1.561 566 0.392 079 152.6104 30.9972
4 C 1.278 150 0.276 983 0.867 935 137.0764 46.5312
5 C 0.328 881 =0.695 029 1.559 402 105.7452 77.8624
6 H =1.841 737 0.801 869 1.314 814 28.9269 2.9380
7 H =0.527 501 1.017 602 =1.423 910 30.1757 1.6892
8 H =1.115 348 2.433 408 =0.577 991 30.3544 1.5105
9 H 1.285 701 2.169 555 =0.179 464 29.7708 2.0941
10 H 0.326 606 2.146 790 1.287 505 30.1590 1.7059
11 H 1.942 344 0.592 695 1.686 102 30.3298 1.5351
12 H 0.903 432 =1.471 657 2.067 537 27.6466 4.2183
13 H =0.288 885 =0.184 505 2.305 929 27.1633 4.7016
14 C =1.558 047 =0.882 346 0.030 169 =5.5380 189.1456
15 O =2.205 985 =1.586 467 =0.716 012 — —
16 O =0.513 265 =1.441 310 0.661 842 — —
17 C =3.204 221 0.952 162 =0.343 452 163.5024 20.1052
18 H =3.992 832 0.322 451 0.074 549 30.6798 1.1851
19 H =3.433 184 1.997 336 =0.119 801 31.0708 0.7941
20 H =3.205 126 0.819 733 =1.428 965 30.6682 1.1967
21 C 2.199 428 =0.417 366 =0.165 472 145.0504 38.5572
22 H 2.405 884 =1.422 710 0.228 718 29.8416 2.0233
23 C 1.606 770 =0.583 023 =1.568 875 160.6382 22.9694
24 H 0.643 259 =1.099 334 =1.563 200 30.6157 1.2492
25 H 1.479 352 0.391 489 =2.053 794 31.1155 0.7494
26 H 2.294 245 =1.167 267 =2.188 795 30.9474 0.9175
27 C 3.537 149 0.323 341 =0.267 148 157.9734 25.6342
28 H 3.389 428 1.348 046 =0.628 108 30.7753 1.0896
29 H 4.040 769 0.375 118 0.703 351 31.0013 0.8636
30 H 4.205 825 =0.180 821 =0.971 949 30.9211 0.9438
158
Fig. S48 205a – Conformer 5
SCF Energy - E(RM062X) =542.157 349 822
SCF Energy from NMR - E(RB3LYP) =542.539 920 978
Sum of Electronic and Thermal Free Energies =541.924 665 000
Table S48 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
205a – Conformer 5
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 2.117 892 0.726 086 =0.150 466 134.7655 48.8421
2 C 0.965 842 1.408 661 =0.906 978 149.8664 33.7412
3 C =0.431 846 1.348 122 =0.290 271 151.4980 32.1096
4 C =1.026 639 =0.059 883 =0.209 530 131.7684 51.8392
5 C =0.166 347 =0.962 016 0.673 727 107.0765 76.5311
6 H 3.035 398 0.984 277 =0.686 287 28.8467 3.0182
7 H 1.250 062 2.462 138 =1.011 050 30.1094 1.7555
8 H 0.924 667 0.997 808 =1.924 013 30.0217 1.8432
9 H =0.425 687 1.794 495 0.715 110 30.3757 1.4892
10 H =1.078 379 1.980 975 =0.904 697 29.9963 1.8686
11 H =1.043 213 =0.493 887 =1.221 928 30.6613 1.2036
12 H 0.120 357 =0.440 625 1.591 945 27.6167 4.2482
13 H =0.715 647 =1.857 812 0.962 614 27.7094 4.1555
14 C 2.105 445 =0.791 458 =0.252 700 =5.0930 188.7006
15 O 3.082 060 =1.409 746 =0.627 342 — —
Continued on next page
159
Table S48 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
16 O 1.005 732 =1.503 406 0.037 733 — —
17 C 2.305 513 1.220 578 1.292 628 167.4136 16.1940
18 H 3.182 128 0.751 185 1.746 788 30.4686 1.3963
19 H 2.469 999 2.302 046 1.271 702 30.8657 0.9992
20 H 1.444 279 1.030 591 1.934 937 30.1812 1.6837
21 C =2.474 442 =0.086 040 0.343 919 149.2472 34.3604
22 H =2.410 773 =0.010 969 1.441 058 30.7956 1.0693
23 C =3.333 222 1.080 571 =0.152 502 161.7564 21.8512
24 H =2.978 140 2.047 134 0.212 925 30.6307 1.2342
25 H =3.344 378 1.111 455 =1.248 988 31.2964 0.5685
26 H =4.365 320 0.953 393 0.188 292 30.9871 0.8778
27 C =3.174 967 =1.402 138 =0.015 046 159.9687 23.6389
28 H =3.333 354 =1.453 703 =1.098 614 31.2739 0.5910
29 H =2.603 951 =2.286 569 0.280 068 30.4918 1.3731
30 H =4.153 757 =1.461 619 0.470 325 30.8856 0.9793
Fig. S49 205a – Conformer 6
SCF Energy - E(RM062X) =542.160 100 797
SCF Energy from NMR - E(RB3LYP) =542.539 573 001
Sum of Electronic and Thermal Free Energies =541.925 874 000
160
Table S49 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
205a – Conformer 6
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 1.900 491 0.340 272 =0.295 821 141.7129 41.8947
2 C 1.053 930 1.396 176 0.448 510 148.0961 35.5115
3 C =0.218 808 1.857 168 =0.274 344 146.3933 37.2143
4 C =1.243 104 0.792 515 =0.707 941 138.0291 45.5785
5 C =0.598 545 =0.360 232 =1.470 559 111.8138 71.7938
6 H 1.887 197 0.565 783 =1.369 523 28.8870 2.9779
7 H 0.841 477 1.018 490 1.453 779 30.0411 1.8238
8 H 1.690 597 2.277 708 0.583 168 30.2986 1.5663
9 H =0.728 637 2.599 194 0.352 841 29.9539 1.9110
10 H 0.103 095 2.389 155 =1.179 441 29.8678 1.9971
11 H =1.862 584 1.276 923 =1.477 802 30.2170 1.6479
12 H =1.360 193 =0.966 653 =1.961 525 27.3492 4.5157
13 H 0.075 925 0.017 679 =2.245 847 27.3294 4.5355
14 C 1.286 883 =1.031 489 =0.081 194 =5.3216 188.9292
15 O 1.795 455 =1.889 549 0.609 908 — —
16 O 0.097 772 =1.307 226 =0.640 005 — —
17 C 3.345 420 0.348 238 0.195 913 163.4816 20.1260
18 H 3.931 660 =0.443 607 =0.275 680 30.6731 1.1918
19 H 3.804 075 1.312 589 =0.037 715 31.0653 0.7996
20 H 3.382 743 0.198 036 1.278 455 30.6765 1.1884
21 C =2.245 434 0.364 327 0.392 175 144.5890 39.0186
22 H =2.849 342 1.261 852 0.588 033 30.0042 1.8607
23 C =3.194 806 =0.726 728 =0.110 967 160.3968 23.2108
24 H =3.621 571 =0.472 141 =1.087 735 30.8990 0.9659
25 H =2.674 297 =1.686 650 =0.203 794 30.6469 1.2180
26 H =4.020 229 =0.865 182 0.593 642 30.7920 1.0729
27 C =1.631 625 =0.051 583 1.733 908 161.9697 21.6379
28 H =0.943 860 =0.896 105 1.624 233 30.9017 0.9632
29 H =1.098 616 0.775 448 2.210 279 30.5531 1.3118
30 H =2.429 678 =0.360 303 2.417 317 31.0465 0.8184
161
Fig. S50 205a – Conformer 7
SCF Energy - E(RM062X) =542.160 414 157
SCF Energy from NMR - E(RB3LYP) =542.540 979 083
Sum of Electronic and Thermal Free Energies =541.927 954 000
Table S50 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
205a – Conformer 7
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =2.042 015 0.503 283 0.336 448 143.0289 40.5787
2 C =1.030 875 1.586 086 =0.137 160 149.6777 33.9299
3 C 0.370 966 1.091 689 =0.510 465 159.9780 23.6296
4 C 1.153 847 0.461 222 0.647 229 134.9334 48.6742
5 C 0.315 220 =0.605 646 1.363 920 108.3262 75.2814
6 H =2.066 106 0.492 907 1.431 389 28.7579 3.1070
7 H =1.461 118 2.067 990 =1.021 766 30.5200 1.3449
8 H =0.958 327 2.356 915 0.638 559 30.0018 1.8631
9 H 0.289 023 0.374 202 =1.337 158 30.5828 1.2821
10 H 0.936 941 1.942 825 =0.900 562 30.3287 1.5362
11 H 1.335 222 1.250 489 1.391 862 30.1598 1.7051
12 H 0.956 993 =1.337 703 1.859 456 27.8188 4.0461
13 H =0.332 114 =0.162 808 2.124 065 27.1659 4.6990
14 C =1.600 445 =0.884 333 =0.094 982 =3.9626 187.5702
15 O =2.195 561 =1.567 854 =0.900 623 — —
16 O =0.480 149 =1.389 834 0.455 112 — —
17 C =3.450 955 0.801 070 =0.166 335 163.6585 19.9491
18 H =4.174 707 0.080 028 0.220 979 30.7556 1.1093
19 H =3.747 987 1.802 679 0.157 491 30.9206 0.9443
Continued on next page
162
Table S50 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
20 H =3.483 254 0.765 339 =1.258 474 30.7045 1.1604
21 C 2.537 263 =0.086 483 0.231 861 143.9978 39.6098
22 H 3.018 766 =0.417 982 1.163 289 30.1116 1.7533
23 C 2.458 628 =1.298 455 =0.701 303 165.7822 17.8254
24 H 1.872 716 =2.113 635 =0.267 234 30.5944 1.2705
25 H 2.002 837 =1.033 080 =1.661 159 31.0978 0.7671
26 H 3.465 101 =1.676 585 =0.907 244 31.0899 0.7750
27 C 3.421 204 1.003 725 =0.378 540 160.7841 22.8235
28 H 3.065 868 1.290 842 =1.374 026 31.0252 0.8397
29 H 3.439 850 1.902 104 0.248 504 31.0277 0.8372
30 H 4.448 950 0.644 036 =0.487 916 30.8579 1.0070
Fig. S51 205a – Conformer 8
SCF Energy - E(RM062X) =542.160 579 831
SCF Energy from NMR - E(RB3LYP) =542.541 311 139
Sum of Electronic and Thermal Free Energies =541.927 588 000
Table S51 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
205a – Conformer 8
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 2.064 214 =0.452 806 0.392 273 142.9824 40.6252
2 C 1.262 458 =1.541 598 =0.377 261 149.4797 34.1279
Continued on next page
163
Table S51 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
3 C =0.119 500 =1.125 899 =0.890 694 151.3412 32.2664
4 C =1.133 270 =0.763 363 0.200 616 134.7055 48.9021
5 C =0.531 916 0.232 515 1.200 016 115.1821 68.4255
6 H 1.945 568 =0.618 244 1.468 523 28.7425 3.1224
7 H 1.864 870 =1.839 909 =1.242 053 30.5327 1.3322
8 H 1.170 762 =2.425 816 0.263 754 29.9010 1.9639
9 H =0.004 968 =0.280 778 =1.581 882 30.2593 1.6056
10 H =0.532 936 =1.948 334 =1.484 124 30.4517 1.4132
11 H =1.341 812 =1.677 753 0.775 208 30.2751 1.5898
12 H =1.306 057 0.807 172 1.711 958 27.6317 4.2332
13 H 0.057 264 =0.278 000 1.964 850 27.4432 4.4217
14 C 1.516 660 0.936 222 0.110 576 =4.1323 187.7399
15 O 2.126 904 1.798 767 =0.484 509 — —
16 O 0.280 142 1.231 546 0.554 575 — —
17 C 3.551 971 =0.520 436 0.062 971 163.6116 19.9960
18 H 4.125 630 0.196 832 0.654 712 30.7636 1.1013
19 H 3.925 587 =1.526 402 0.274 587 30.9211 0.9438
20 H 3.719 543 =0.302 588 =0.995 131 30.6906 1.1743
21 C =2.472 931 =0.285 057 =0.401 675 145.9759 37.6317
22 H =2.703 429 =0.975 536 =1.225 335 30.3384 1.5265
23 C =3.611 484 =0.385 996 0.616 709 159.8148 23.7928
24 H =3.715 026 =1.407 022 0.998 158 31.0576 0.8073
25 H =3.440 801 0.279 417 1.471 154 30.9294 0.9355
26 H =4.563 096 =0.093 940 0.161 726 30.8786 0.9863
27 C =2.404 550 1.131 827 =0.980 319 164.8734 18.7342
28 H =2.238 389 1.871 356 =0.188 986 31.1805 0.6844
29 H =1.600 039 1.244 183 =1.712 586 30.6662 1.1987
30 H =3.348 951 1.380 404 =1.474 330 31.0891 0.7758
164
Fig. S52 205a – Conformer 9
SCF Energy - E(RM062X) =542.160 224 026
SCF Energy from NMR - E(RB3LYP) =542.541 035 379
Sum of Electronic and Thermal Free Energies =541.927 132 000
Table S52 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
205a – Conformer 9
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 2.128 294 0.256 322 =0.507 482 142.6059 41.0017
2 C 1.152 568 1.471 649 =0.517 757 150.5802 33.0274
3 C =0.194 850 1.266 256 0.183 877 151.7950 31.8126
4 C =1.146 074 0.297 407 =0.536 315 132.7391 50.8685
5 C =0.358 694 =0.919 297 =1.023 929 112.8632 70.7444
6 H 2.193 161 =0.159 504 =1.520 204 28.7397 3.1252
7 H 1.664 815 2.302 295 =0.021 820 30.5386 1.3263
8 H 0.980 508 1.784 252 =1.554 267 29.9378 1.9271
9 H =0.021 398 0.908 831 1.209 304 30.7199 1.1450
10 H =0.682 055 2.240 174 0.282 456 30.0584 1.8065
11 H =1.531 027 0.799 704 =1.438 177 30.8003 1.0646
12 H =1.009 262 =1.743 133 =1.315 952 27.4732 4.3917
13 H 0.267 276 =0.669 018 =1.883 914 27.3822 4.4827
14 C 1.620 601 =0.879 009 0.367 716 =4.2805 187.8881
15 O 2.213 759 =1.307 432 1.334 297 — —
16 O 0.454 228 =1.462 704 0.033 045 — —
17 C 3.531 593 0.668 856 =0.073 753 163.0175 20.5901
18 H 4.228 123 =0.171 330 =0.118 388 30.7117 1.1532
19 H 3.896 041 1.462 500 =0.731 954 30.9278 0.9371
Continued on next page
165
Table S52 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
20 H 3.518 433 1.047 796 0.951 942 30.7134 1.1515
21 C =2.354 037 =0.105 331 0.336 133 148.0367 35.5709
22 H =1.981 707 =0.783 931 1.117 615 30.2267 1.6382
23 C =2.996 421 1.106 136 1.019 457 161.7042 21.9034
24 H =2.325 446 1.585 660 1.736 284 30.6104 1.2545
25 H =3.290 402 1.854 770 0.272 559 31.4391 0.4258
26 H =3.898 007 0.801 109 1.559 341 31.0196 0.8453
27 C =3.421 959 =0.837 489 =0.483 166 160.4196 23.1880
28 H =3.820 195 =0.174 509 =1.261 110 31.4341 0.4308
29 H =3.043 268 =1.739 988 =0.969 982 30.4262 1.4387
30 H =4.255 618 =1.137 581 0.158 851 30.8920 0.9729
166
S-I.9 Abnormal trans-Carvomenthide (205b)
Fig. S53 205b – Conformer 1
SCF Energy - E(RM062X) =542.163 734 082
SCF Energy from NMR - E(RB3LYP) =542.545 617 507
Sum of Electronic and Thermal Free Energies =541.930 878 000
Table S53 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
205b – Conformer 1
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 1.870 093 0.581 393 0.447 566 140.8188 42.7888
2 C 0.891 314 1.447 605 =0.377 237 146.6269 36.9807
3 C =0.590 631 1.225 840 =0.071 370 152.5309 31.0767
4 C =1.098 159 =0.188 717 =0.365 630 134.0328 49.5748
5 C =0.334 062 =1.243 723 0.434 604 104.6113 78.9963
6 H 1.133 998 2.494 660 =0.166 617 30.1422 1.7227
7 H 1.088 310 1.292 226 =1.446 303 30.4352 1.4297
8 H =0.764 601 1.458 772 0.988 272 30.4120 1.4529
9 H =1.170 204 1.949 539 =0.653 621 30.0205 1.8444
10 H =0.911 470 =0.410 300 =1.427 195 30.2542 1.6107
11 H =0.164 904 =0.932 839 1.471 351 27.4679 4.3970
12 H =0.890 394 =2.183 635 0.450 009 27.8288 4.0361
13 C 1.990 360 =0.801 103 =0.168 664 =5.4704 189.0780
14 O 3.004 039 =1.210 825 =0.694 578 — —
15 O 0.919 757 =1.612 177 =0.168 718 — —
16 C =2.617 692 =0.358 004 =0.135 336 145.4479 38.1597
17 H =2.853 712 =1.388 569 =0.435 923 30.0203 1.8446
18 C =3.030 938 =0.197 930 1.331 871 166.7126 16.8950
Continued on next page
167
Table S53 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
19 H =2.500 347 =0.893 589 1.989 963 31.1263 0.7386
20 H =2.841 803 0.820 389 1.688 081 31.1665 0.6984
21 H =4.102 588 =0.390 739 1.442 476 31.1076 0.7573
22 C =3.440 450 0.576 533 =1.024 833 160.2474 23.3602
23 H =3.358 321 1.617 520 =0.694 932 30.9418 0.9231
24 H =3.114 143 0.522 721 =2.068 990 30.9874 0.8775
25 H =4.499 064 0.302 102 =0.984 218 30.8259 1.0390
26 C 3.247 561 1.233 337 0.534 225 163.2771 20.3305
27 H 3.956 339 0.599 538 1.071 331 30.6658 1.1991
28 H 3.648 455 1.416 942 =0.466 635 30.6675 1.1974
29 H 3.164 689 2.189 968 1.056 477 31.0500 0.8149
30 H 1.465 012 0.467 928 1.461 665 29.0759 2.7890
Fig. S54 205b – Conformer 2
SCF Energy - E(RM062X) =542.163 578 052
SCF Energy from NMR - E(RB3LYP) =542.545 705 624
Sum of Electronic and Thermal Free Energies =541.930 800 000
Table S54 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
205b – Conformer 2
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =1.952 121 =0.545 803 0.327 558 141.0895 42.5181
Continued on next page
168
Table S54 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
2 C =1.154 167 =1.341 606 =0.730 250 146.3249 37.2827
3 C 0.347 411 =1.446 257 =0.464 149 143.4994 40.1082
4 C 1.095 638 =0.110 421 =0.437 402 133.9752 49.6324
5 C 0.541 045 0.830 569 0.631 619 110.5671 73.0405
6 H =1.572 856 =2.353 409 =0.755 311 30.1590 1.7059
7 H =1.337 414 =0.904 657 =1.720 849 30.3356 1.5293
8 H 0.495 106 =1.961 065 0.495 304 30.0025 1.8624
9 H 0.795 505 =2.083 546 =1.235 384 30.2230 1.6419
10 H 0.943 683 0.389 828 =1.405 342 30.3370 1.5279
11 H 0.332 787 0.302 444 1.568 864 27.7421 4.1228
12 H 1.246 053 1.634 557 0.848 315 27.6678 4.1971
13 C =1.831 024 0.943 802 0.058 987 =5.6819 189.2895
14 O =2.760 200 1.632 446 =0.307 862 — —
15 O =0.635 596 1.539 167 0.200 817 — —
16 C 2.618 179 =0.318 906 =0.260 515 144.9722 38.6354
17 H 2.890 141 =1.149 323 =0.926 125 30.2761 1.5888
18 C 3.418 985 0.906 857 =0.707 357 160.6349 22.9727
19 H 3.186 973 1.175 531 =1.742 601 30.8613 1.0036
20 H 3.208 781 1.777 767 =0.076 616 30.7630 1.1019
21 H 4.492 857 0.706 470 =0.639 308 30.8723 0.9926
22 C 3.008 048 =0.717 675 1.167 871 166.4409 17.1667
23 H 2.837 228 0.107 650 1.868 989 31.5241 0.3408
24 H 2.447 365 =1.587 386 1.523 541 30.7125 1.1524
25 H 4.072 634 =0.966 571 1.211 972 31.0985 0.7664
26 C =3.422 624 =0.954 693 0.334 624 163.3525 20.2551
27 H =4.000 107 =0.357 322 1.043 509 30.6765 1.1884
28 H =3.862 488 =0.821 126 =0.657 740 30.6629 1.2020
29 H =3.505 610 =2.008 431 0.612 959 31.0461 0.8188
30 H =1.520 494 =0.749 512 1.316 272 29.0682 2.7967
169
Fig. S55 205b – Conformer 3
SCF Energy - E(RM062X) =542.162 592 398
SCF Energy from NMR - E(RB3LYP) =542.544 760 534
Sum of Electronic and Thermal Free Energies =541.929 880 000
Table S55 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
205b – Conformer 3
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 1.985 793 0.557 603 0.375 962 141.3243 42.2833
2 C 1.018 010 1.419 012 =0.465 273 146.4985 37.1091
3 C =0.452 193 1.372 112 =0.046 332 144.9448 38.6628
4 C =1.117 943 =0.004 020 =0.145 563 133.0241 50.5835
5 C =0.362 102 =1.037 516 0.691 438 107.4091 76.1985
6 H 1.361 237 2.456 151 =0.386 595 30.1504 1.7145
7 H 1.119 083 1.140 133 =1.522 695 30.4042 1.4607
8 H =0.540 337 1.730 761 0.990 884 30.6028 1.2621
9 H =0.996 337 2.085 182 =0.672 138 29.7922 2.0727
10 H =1.085 150 =0.338 488 =1.194 376 30.7116 1.1533
11 H =0.082 886 =0.620 127 1.666 113 27.7905 4.0744
12 H =0.974 952 =1.920 161 0.872 302 27.6207 4.2442
13 C 1.940 367 =0.881 310 =0.103 038 =5.6122 189.2198
14 O 2.874 126 =1.436 035 =0.643 278 — —
15 O 0.799 976 =1.576 827 0.037 347 — —
16 C =2.600 091 0.005 227 0.305 723 149.0898 34.5178
17 H =2.610 140 =0.015 176 1.407 036 30.8063 1.0586
Continued on next page
170
Table S55 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
18 C =3.360 023 1.256 310 =0.144 237 161.8707 21.7369
19 H =2.981 736 2.167 756 0.324 768 30.6568 1.2081
20 H =3.291 947 1.376 910 =1.232 428 31.3266 0.5383
21 H =4.418 841 1.161 680 0.115 535 31.0002 0.8647
22 C =3.339 825 =1.233 958 =0.212 277 160.1452 23.4624
23 H =3.421 313 =1.187 290 =1.304 549 31.2808 0.5841
24 H =2.838 902 =2.171 219 0.044 150 30.4493 1.4156
25 H =4.353 133 =1.275 886 0.198 353 30.8966 0.9683
26 C 3.414 273 1.088 501 0.294 330 163.3999 20.2077
27 H 4.108 996 0.450 871 0.845 173 30.6630 1.2019
28 H 3.747 777 1.132 519 =0.746 297 30.6788 1.1861
29 H 3.452 114 2.096 597 0.715 166 31.0569 0.8080
30 H 1.656 054 0.580 923 1.422 640 29.0244 2.8405
Fig. S56 205b – Conformer 4
SCF Energy - E(RM062X) =542.159 715 149
SCF Energy from NMR - E(RB3LYP) =542.539 307 334
Sum of Electronic and Thermal Free Energies =541.925 785 000
171
Table S56 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
205b – Conformer 4
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =1.888 046 0.463 261 =0.511 212 133.8130 49.7946
2 C =0.757 967 1.481 899 =0.749 386 155.5131 28.0945
3 C 0.214 277 1.704 729 0.407 860 153.7684 29.8392
4 C 1.014 910 0.458 344 0.809 598 132.9585 50.6491
5 C 0.105 177 =0.600 259 1.431 443 109.9798 73.6278
6 H =0.206 353 1.191 046 =1.651 556 29.8354 2.0295
7 H =1.248 428 2.433 484 =0.984 472 30.4831 1.3818
8 H 0.900 718 2.513 084 0.137 347 29.9133 1.9516
9 H =0.336 048 2.060 846 1.287 896 29.9852 1.8797
10 H 1.692 930 0.758 971 1.623 616 30.5793 1.2856
11 H 0.688 089 =1.318 718 2.008 508 27.4733 4.3916
12 H =0.624 096 =0.146 119 2.107 030 27.2643 4.6006
13 C =1.441 033 =0.992 536 =0.450 729 =5.1760 188.7836
14 O =1.881 855 =1.817 229 =1.227 216 — —
15 O =0.573 695 =1.434 732 0.474 034 — —
16 C 1.895 302 =0.122 137 =0.317 004 154.2387 29.3689
17 H 1.243 572 =0.473 353 =1.128 602 30.0807 1.7842
18 C 2.833 726 0.942 106 =0.892 009 161.4703 22.1373
19 H 2.289 692 1.751 312 =1.387 255 30.5520 1.3129
20 H 3.447 953 1.382 678 =0.096 611 31.3355 0.5294
21 H 3.507 736 0.495 712 =1.629 248 30.9435 0.9214
22 C 2.703 879 =1.325 949 0.176 062 161.3073 22.3003
23 H 3.314 579 =1.049 615 1.044 811 31.3139 0.5510
24 H 2.060 248 =2.163 227 0.459 398 30.3926 1.4723
25 H 3.378 281 =1.678 645 =0.609 877 30.9119 0.9530
26 C =2.811 272 0.824 248 0.663 651 167.7184 15.8892
27 H =3.635 399 0.109 658 0.736 921 30.5199 1.3450
28 H =2.300 030 0.854 381 1.627 005 30.0764 1.7885
29 H =3.235 207 1.816 420 0.482 666 30.9199 0.9450
30 H =2.507 554 0.475 525 =1.411 758 28.8305 3.0344
172
Fig. S57 205b – Conformer 5
SCF Energy - E(RM062X) =542.161 614 596
SCF Energy from NMR - E(RB3LYP) =542.541 053 565
Sum of Electronic and Thermal Free Energies =541.927 499 000
Table S57 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
205b – Conformer 5
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C 1.502 087 0.611 453 0.581 018 142.7210 40.8866
2 C 0.640 311 1.414 413 =0.423 796 152.1622 31.4454
3 C =0.254 505 0.555 170 =1.320 885 156.4561 27.1515
4 C =1.150 224 =0.444 753 =0.576 611 136.7659 46.8417
5 C =0.322 374 =1.487 084 0.210 596 108.0889 75.5187
6 H 0.041 708 2.133 775 0.146 783 29.9730 1.8919
7 H 1.317 437 1.996 023 =1.059 952 30.7309 1.1340
8 H =0.881 217 1.207 532 =1.935 474 30.0931 1.7718
9 H 0.373 582 =0.001 120 =2.026 112 30.3121 1.5528
10 H =1.721 472 =0.984 162 =1.345 471 30.2502 1.6147
11 H =0.293 775 =1.246 981 1.278 386 27.7940 4.0709
12 H =0.751 655 =2.484 106 0.109 536 27.4436 4.4213
13 C 1.948 176 =0.683 618 =0.072 910 =4.5023 188.1099
14 O 3.075 700 =0.889 774 =0.468 327 — —
15 O 1.026 403 =1.648 148 =0.264 033 — —
16 C =2.177 252 0.214 106 0.366 985 147.3377 36.2699
Continued on next page
173
Table S57 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
17 H =1.624 517 0.683 089 1.196 191 30.2352 1.6297
18 C =2.996 358 1.298 238 =0.336 598 160.9672 22.6404
19 H =2.384 163 2.153 831 =0.634 565 30.5141 1.3508
20 H =3.475 378 0.892 627 =1.236 310 31.3057 0.5592
21 H =3.785 441 1.667 253 0.325 793 30.9707 0.8942
22 C =3.119 351 =0.840 493 0.959 362 161.1783 22.4293
23 H =3.681 172 =1.335 428 0.157 828 31.3871 0.4778
24 H =2.585 007 =1.612 418 1.521 492 30.8091 1.0558
25 H =3.840 607 =0.375 721 1.638 296 30.9065 0.9584
26 C 2.698 005 1.422 774 1.066 107 164.8698 18.7378
27 H 3.274 857 0.874 575 1.815 057 30.7622 1.1027
28 H 3.361 522 1.662 479 0.231 510 30.7043 1.1606
29 H 2.347 590 2.357 872 1.512 244 30.9646 0.9003
30 H 0.879 796 0.353 011 1.444 041 28.8748 2.9901
174
S-I.10 Normal Lactone of β-Pinene (206)
Fig. S58 206 – Conformer 1
SCF Energy - E(RM062X) =501.635 899 100
SCF Energy from NMR - E(RB3LYP) =501.975 408 400
Sum of Electronic and Thermal Free Energies =501.450 490 000
Table S58 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
206 – Conformer 1
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =0.496 124 =0.504 913 =1.081 236 95.0974 88.5102
2 C 1.788 127 =0.396 856 =0.136 537 =2.5374 186.1450
3 O 2.790 865 =1.042 224 0.093 129 — —
4 O 0.849 500 =0.978 317 =0.905 720 — —
5 C =1.272 166 =0.314 349 0.246 733 135.0936 48.5140
6 C =0.819 271 =1.116 860 1.458 847 163.3260 20.2816
7 H 0.244 906 =1.012 551 1.686 374 30.8750 0.9899
8 H =1.377 132 =0.795 292 2.345 238 31.1767 0.6882
9 H =1.018 803 =2.181 480 1.298 483 31.1015 0.7634
10 C =2.766 945 =0.538 718 0.013 080 154.7181 28.8895
Continued on next page
175
Table S58 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
11 H =3.334 684 =0.202 034 0.886 681 30.7964 1.0685
12 H =3.135 027 0.010 159 =0.858 991 30.3526 1.5123
13 H =2.974 386 =1.602 830 =0.141 956 30.7759 1.0890
14 C =0.657 250 1.000 486 =1.360 635 155.4110 28.1966
15 H 0.184 164 1.517 625 =1.826 136 29.6821 2.1828
16 H =1.548 068 1.179 417 =1.964 973 29.2984 2.5665
17 C =0.911 611 1.204 279 0.155 756 138.2349 45.3727
18 H =1.727 461 1.882 399 0.427 964 29.7029 2.1620
19 C 0.358 244 1.584 108 0.914 107 156.4086 27.1990
20 H 0.272 429 1.262 211 1.957 403 29.8890 1.9759
21 H 0.451 605 2.674 739 0.933 372 30.0725 1.7924
22 C 1.667 878 1.050 420 0.311 001 144.5429 39.0647
23 H 2.486 187 1.197 637 1.017 279 29.1063 2.7586
24 H 1.922 250 1.634 877 =0.580 960 28.8373 3.0276
25 H =0.914 188 =1.206 124 =1.805 746 27.5547 4.3102
176
S-I.11 Abnormal Lactone of β-Pinene (207)
Fig. S59 207 – Conformer 1
SCF Energy - E(RM062X) =501.634 249 141
SCF Energy from NMR - E(RB3LYP) =501.973 754 661
Sum of Electronic and Thermal Free Energies =501.448 041 000
Table S59 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
207 – Conformer 1
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =0.221 474 =0.743 948 =0.832 199 125.6433 57.9643
2 C 1.121 626 =1.077 428 =0.229 616 =1.6233 185.2309
3 O 1.515 809 =2.224 881 =0.161 389 — —
4 C =1.197 509 =0.151 801 0.248 351 137.6390 45.9686
5 C =0.963 053 =0.501 796 1.712 993 161.4246 22.1830
6 H =1.616 750 0.105 944 2.349 030 31.1786 0.6863
7 H =1.207 787 =1.555 048 1.887 448 31.0260 0.8389
8 H 0.067 568 =0.338 892 2.036 879 30.4130 1.4519
9 C =2.644 295 =0.483 637 =0.119 002 153.6197 29.9879
Continued on next page
177
Table S59 – continued from previous page
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
10 H =3.327 339 0.096 546 0.511 075 30.8395 1.0254
11 H =2.871 865 =0.253 614 =1.163 694 30.0830 1.7819
12 H =2.844 953 =1.547 002 0.047 417 30.7275 1.1374
13 C =0.367 332 0.593 557 =1.600 395 161.6493 21.9583
14 H 0.500 771 0.989 021 =2.129 518 29.5067 2.3582
15 H =1.190 187 0.516 776 =2.311 695 29.4810 2.3839
16 C =0.799 969 1.263 711 =0.274 050 138.1865 45.4211
17 H =1.629 536 1.977 010 =0.328 554 29.7054 2.1595
18 C 0.381 900 1.896 242 0.465 169 151.6682 31.9394
19 H 0.201 319 1.889 868 1.545 296 29.3414 2.5235
20 H 0.468 628 2.948 382 0.168 461 30.1174 1.7475
21 C 1.743 199 1.286 406 0.153 913 113.1358 70.4718
22 O 1.877 878 =0.135 170 0.365 187 — —
23 H 2.496 457 1.710 084 0.818 854 27.6139 4.2510
24 H 2.047 227 1.502 159 =0.872 941 27.0235 4.8414
25 H =0.561 607 =1.648 655 =1.339 428 28.9960 2.8689
Fig. S60 207 – Conformer 2
178
SCF Energy - E(RM062X) =501.626 888 110
SCF Energy from NMR - E(RB3LYP) =501.967 201 057
Sum of Electronic and Thermal Free Energies =501.441 868 000
Table S60 Cartesian Coordinates, Isotropic Shielding Tensors and Scaled NMR Shifts for
207 – Conformer 2
Center Atom Cartesian Coordinates NMR Scaled
# Type X Y Z Shielding Tensor NMR Shifts
1 C =0.147 254 =0.997 579 =0.550 244 123.6353 59.9723
2 C 1.282 459 =0.982 149 =0.067 140 =6.1618 189.7694
3 O 1.919 221 =2.003 805 0.088 049 — —
4 C =1.187 994 =0.194 094 0.294 482 138.8110 44.7966
5 C =1.007 619 =0.106 376 1.812 176 157.2783 26.3293
6 H =1.385 801 0.850 762 2.189 376 30.5464 1.3185
7 H =1.573 544 =0.903 654 2.304 005 30.7893 1.0756
8 H 0.030 363 =0.214 237 2.133 601 30.6301 1.2348
9 C =2.596 533 =0.722 257 0.003 887 150.8277 32.7799
10 H =3.336 518 =0.063 513 0.472 054 30.6540 1.2109
11 H =2.813 317 =0.765 092 =1.067 203 30.2082 1.6567
12 H =2.720 547 =1.726 937 0.420 586 30.8059 1.0590
13 C =0.357 440 0.034 355 =1.688 248 150.3092 33.2984
14 H 0.534 214 0.343 615 =2.239 772 30.2567 1.6082
15 H =1.117 065 =0.302 667 =2.394 184 29.3695 2.4954
16 C =0.898 746 1.029 290 =0.633 852 136.6651 46.9425
17 H =1.791 219 1.593 936 =0.925 981 29.6819 2.1830
18 C 0.184 456 2.010 738 =0.194 041 148.2542 35.3534
19 H =0.238 031 2.764 441 0.481 178 29.7772 2.0877
20 H 0.526 502 2.544 730 =1.088 003 29.5372 2.3277
21 C 1.388 243 1.431 579 0.546 541 110.5938 73.0138
22 O 1.946 635 0.187 883 0.067 953 — —
23 H 1.169 954 1.302 992 1.607 088 27.0351 4.8298
24 H 2.227 562 2.123 308 0.468 558 27.4667 4.3982
25 H =0.396 838 =2.041 356 =0.750 681 28.8261 3.0388
179
S-II Calculated and Experimental NMR Chemical Shifts
S-II.1 Carvomenthones (201) . . . . . . . . . . . . . . . . . . . . . . . . . . 181
S-II.2 Nankakurines (202) . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
S-II.3 Normal Menthides (203) . . . . . . . . . . . . . . . . . . . . . . . . . 184
S-II.4 Normal Carvomenthides (204) . . . . . . . . . . . . . . . . . . . . . 186
S-II.5 Abnormal Carvomenthides (205) . . . . . . . . . . . . . . . . . . . . 188
S-II.6 Normal Lactone of β-Pinene (206) . . . . . . . . . . . . . . . . . . . 190
S-II.7 Abnormal Lactone of β-Pinene (207) . . . . . . . . . . . . . . . . . . 191
All calculated shifts were obtained using the methods described in 2.2.1. Statistical
analysis was executed according to the method and equations described in 2.4.1. Any
experimental shifts that were assigned as a range of shifts are given in bold. For any analysis
of these shifts, the average value of the range was used. Any shifts assignments that were
incomplete were matched with the closest computed chemical shift in the corresponding
structure, and are provided in italics. If there was more than one distinct set of unknown
shifts, a superscript italicsa will be applied. Assigned shifts in italics and within the same
superscript group can be switched with other shifts within italics and part of the same
superscript group (e.g., shifts in italicsa can be switched with other shifts in italicsa, but
not with those in italicsb).
180
S-II.1 Carvomenthones (201)
O
1
2
345
6
7
8
9
10
Hβ Hα
O
1
2
345
6
7
8
9
10
Hβ Hα
201a 201b
Table S61 Calculated and Experimental 1H Shifts (in ppm) for carvomenthones 201
Position
Computed Experimental
201a 201b 201a 201b
2 2.47 2.48 2.45 2.33
3 α 1.87 1.29 1.87 1.30
3 β 1.70 2.12 1.60–1.75 2.10
4 α 1.69 1.87 1.60–1.75 1.86
4 β 1.88 1.55 1.60–1.75 1.44
5 1.61 1.55 1.60–1.75 1.51–1.61
6 α 2.36 2.33 2.28–2.38 2.40
6 β 2.51 2.24 2.28–2.38 2.06
7 1.45 1.51 1.49 1.51–1.61
8 Me 0.90 0.91 0.91 0.90
9 Me 0.88 0.89 0.89 0.89
10 Me 1.06 0.92 1.10 1.01
Table S62 Calculated and Experimental 13C Shifts (in ppm) for carvomenthones 201
Position
Computed Experimental
201a 201b 201a 201b
1 232.16 230.49 215.30 213.70
2 51.87 51.15 44.40 45.00
3 36.69 40.92 31.50 35.20
4 30.08 33.99 25.00 29.00
5 52.15 54.11 44.90 46.70
6 47.62 50.36 43.10 45.50
7 36.85 39.59 30.70 32.90
8 21.22 21.36 20.14 19.70
9 21.37 20.72 20.07 19.40
10 18.30 16.39 16.00 14.50
181
S-II.2 Nankakurines (202)
1
2
3
4
5 6 7
N
8
9
10 11 12
H
N
13 14
15 16
17
CH3
CH3
1
2
3
4
5 6 7
N
8
9
10 11 12
13 14
15 16
NH
17
CH3
CH3
202a 202b
Table S63 Calculated and Experimental43 1H Shifts (in ppm) for nankakurines 202
Position
Computed Experimental
202a 202b 202a 202b
1 R 2.73 2.75 2.82a 2.66a
1 S 2.79 2.76 2.82a 2.76a
2 R 1.40 1.34 1.58b 1.16a
2 S 1.38 1.38 1.53b 1.28a
3 R 1.50 1.49 1.57 1.66–1.75a
3 S 1.52 1.55 1.57 1.66–1.75a
4 R 1.44 1.38 1.66 1.66–1.75a
4 S 1.62 1.43 1.66 1.54–1.43a
6 R 1.93 1.97 2.29c 2.58a
6 S 1.52 1.45 1.64c 1.66–1.75a
7 1.78 1.83 1.85 1.82–1.95a
8 R 1.42 1.41 1.49d 1.43–1.54a
8 S 1.11 1.10 1.20d 1.16a
9 R 3.03 2.91 3.00e 2.87a
9 S 1.96 2.02 2.14e 1.82–1.95a
10 1.75 1.67 1.81 1.43–1.54a
11 R 1.79 1.99 1.83f 2.39a
11 S 1.41 1.28 1.53f 1.15a
12 1.43 1.43 1.53 1.43–1.54a
13 1.88 1.88 2.03 1.66–1.75a
14 R 0.78 0.78 0.89g 0.82a
14 S 2.04 2.04 2.02g 1.82–1.95a
15 1.87 1.86 1.95 2.21a
16 Me 0.76 0.76 0.85 0.79b
17 Me 2.05 2.04 2.12 1.93b
182
Table S64 Calculated and Experimental43 13C Shifts (in ppm) for nankakurines 202
Position
Computed Experimental
202a 202b 202a 202b
1 45.42 45.46 41.00 —
2 32.00 32.44 26.30 —
3 25.11 24.80 20.90 22.60a
4 39.42 41.64 34.60 —
5 59.34 59.46 56.10 56.50a
6 45.77 42.83 40.00 —
7 39.35 38.08 34.50 —
8 45.39 45.40 41.90 —
9 62.13 63.07 58.50 56.10a
10 41.70 42.37 37.40 —
11 36.01 34.71 32.50 —
12 42.78 42.72 36.90 —
13 69.96 70.02 65.10 63.30a
14 43.23 43.18 40.00 —
15 26.95 26.95 22.00 23.00a
16 24.43 24.43 23.00 22.90a
17 44.96 44.98 43.40 —
183
S-II.3 Normal Menthides (203)
O
O
1
2
3 4
5
6 7 8
9
10
Hβ Hα
O
O
1
2
3 4
5
6 7 8
9
10
Hβ Hα
203a 203b
Table S65 Calculated and Experimental 1H Shifts (in ppm) for normal menthides 203
Position
Computed Experimental
203a 203b 203a 203b
2 α — 2.34 2.54 2.47
2 β — 2.61 2.89 2.54
3 — 1.75 2.18 1.85
4 α — 1.90 1.69–1.80 1.95
4 β — 1.24 1.69–1.80 1.29
5 α — 1.52 1.69–1.80 1.60
5 β — 1.91 1.69–1.80 1.85
6 — 4.13 4.02 4.05
7 — 1.78 1.87 1.85
8 Me — 0.94 0.98 0.98
9 Me — 0.94 0.98 0.97
10 Me — 0.99 1.05 1.04
184
Table S66 Calculated and Experimental 13C Shifts (in ppm) for normal menthides 203
Position
Computed Experimental
203a 203b 203a 203b
1 — 185.51 174.50 174.80
2 — 46.42 40.80 42.30
3 — 37.12 26.70 30.20a
4 — 42.82 34.30a 37.20
5 — 35.42 26.74a 30.70
6 — 89.91 84.90 84.50
7 — 39.56 33.30 33.10a
8 — 18.94 17.30 18.10
9 — 19.85 17.70 16.80
10 — 26.32 18.50 23.70
185
S-II.4 Normal Carvomenthides (204)
O
O
1
2
3 4
5
6
7
8
9
10
Hβ Hα
O
O
1
2
3 4
5
6
7
8
9
10
Hβ Hα
204a 204b
Table S67 Calculated and Experimental 1H Shifts (in ppm) for normal carvomenthides
204
Position
Computed Experimental
204a 204b 204a 204b
2 α 2.88 2.35 2.80 2.42–2.51
2 β 2.79 2.59 2.76 2.42–2.51
3 1.41 1.53 1.51–1.57 1.57
4 α 1.56 1.73 1.98 1.82
4 β 2.04 1.53 1.58–1.65 1.47
5 α 1.59 1.55 1.66-1.80 1.65
5 β 1.76 1.87 1.66-1.80 1.91
6 4.54 4.51 4.44 4.42
7 1.57 1.64 1.58–1.62 1.69
8 Me 1.00 0.85 1.02 0.87
9 Me 0.87 0.86 0.90 0.90
10 Me 1.26 1.25 1.35 1.35
186
Table S68 Calculated and Experimental 13C Shifts (in ppm) for normal carvomenthides
204
Position
Computed Experimental
204a 204b 204a 204b
1 185.05 186.60 174.20 175.60
2 42.81 42.44 38.30 38.00
3 45.12 46.33 38.70 40.20
4 35.63 36.02 30.00 31.10
5 35.84 40.46 32.00 35.70
6 82.14 81.92 76.30 76.50
7 35.15 40.36 28.90 33.40
8 22.56 19.85 20.60 18.60
9 22.05 19.72 20.30 18.40
10 24.07 24.41 22.20 22.40
187
S-II.5 Abnormal Carvomenthides (205)
O
O
1
2
3
4
5
6
7
8
9
10
Hβ
Hα
O
O
1
2
3
4
5
6
7
8
9
10
Hβ
Hα
205a 205b
Table S69 Calculated and Experimental 1H Shifts (in ppm) for abnormal carvomenthides
205
Position
Computed Experimental
205a 205b 205a 205b
2 2.81 2.80 2.75 2.72
3 α 1.47 1.47 1.52–1.69 1.48–1.60
3 β 1.57 1.72 2.01 1.78
4 α 1.60 1.79 1.52–1.69 1.84–1.88
4 β 2.11 1.59 1.52–1.69 1.48–1.60
5 1.27 1.51 1.42 1.48–1.60
6 α 4.42 4.14 4.30 4.0
6 β 4.45 4.23 4.36 4.07
7 1.71 1.62 1.73 1.68
8 Me 0.89 0.88 0.91 0.91
9 Me 1.01 0.87 1.01 0.90
10 Me 1.09 1.07 1.20 1.20
188
Table S70 Calculated and Experimental 13C Shifts (in ppm) for abnormal carvomenthides
205
Position
Computed Experimental
205a 205b 205a 205b
1 189.23 189.17 178.10 178.10
2 43.30 42.59 37.60 37.10
3 31.93 37.04 30.50 31.90
4 35.44 35.79 28.10 31.08a
5 49.87 49.72 43.60 44.60
6 73.36 76.14 69.60 71.60
7 30.64 37.76 25.60 31.12a
8 22.15 20.14 20.75a 19.40
9 22.39 20.88 20.82a 19.20
10 20.57 20.25 18.60 18.40
189
S-II.6 Normal Lactone of β-Pinene (206)
O
O
1
2
3
4 5
6
7
89Hβ
Hα
206
Table S71 Calculated and Experimental 1H Shifts (in ppm) for normal lactone of β-
pinene 206
Position Computed Experimental
2 α 3.03 2.93
2 β 2.76 2.83
3 α 1.79 1.95
3 β 1.98 1.87
4 2.16 2.28
5 anti 2.57 2.65
5 syn 2.18 2.11
6 4.31 4.33
8 Me 1.22 1.30
9 Me 0.81 0.89
Table S72 Calculated and Experimental 13C Shifts (in ppm) for normal lactone of β-
pinene 206
Position Computed Experimental
1 186.15 174.90
2 39.06 33.90
3 27.20 27.20
4 45.37 40.90
5 28.20 26.30
6 88.51 83.90
7 48.51 43.00
8 28.89 27.20
9 20.28 18.30
190
S-II.7 Abnormal Lactone of β-Pinene (207)
O
O
1
2
3
4
5
6 7
Hβ Hα
8
9
207
Table S73 Calculated and Experimental 1H Shifts (in ppm) for abnormal lactone of β-
pinene 207
Position Computed Experimental
2 2.87 2.94
3 anti 2.38 2.45
3 syn 2.36 2.30
4 2.16 2.26
5 α 1.75 1.86
5 β 2.52 2.46
6 α 4.84 4.69
6 β 4.25 4.32
8 1.31 1.38
9 0.99 1.04
Table S74 Calculated and Experimental 13C Shifts (in ppm) for abnormal lactone of
β-pinene 207
Position Computed Experimental
1 185.24 174.50
2 57.97 53.10
3 21.97 19.70
4 45.42 40.80
5 31.94 27.40
6 70.48 66.10
7 45.97 40.30
8 29.99 28.40
9 22.19 20.60
191
S-III Calculated Geometries and Free Energies for
Benzyne, Related Compounds and Reactions
S-III.1 Benzyne (301) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
S-III.2 1,4,6-tridecatriyne (310a) . . . . . . . . . . . . . . . . . . . . . . . . 196
S-III.3 1,5,7-tridecatriyne (310b) . . . . . . . . . . . . . . . . . . . . . . . . 198
S-III.4 1,6,8-tridecatriyne (310c) . . . . . . . . . . . . . . . . . . . . . . . . 200
S-III.5 3-hexylbenzynocyclopropane (311a) . . . . . . . . . . . . . . . . . . 202
S-III.6 3-pentylbenzynocyclobutane (311b) . . . . . . . . . . . . . . . . . . 204
S-III.7 3-butylbenzynocyclopentane (311c) . . . . . . . . . . . . . . . . . . 206
S-III.8 1,3,6-heptatriyne (312a) . . . . . . . . . . . . . . . . . . . . . . . . . 207
S-III.9 1,3,7-octatriyne (312b) . . . . . . . . . . . . . . . . . . . . . . . . . 208
S-III.10 1,3,8-nonatriyne (312c) . . . . . . . . . . . . . . . . . . . . . . . . . 209
S-III.11 Benzynocyclopropane (313a) . . . . . . . . . . . . . . . . . . . . . . 210
S-III.12 Benzynocyclobutane (313b) . . . . . . . . . . . . . . . . . . . . . . . 211
S-III.13 Benzynocyclopentane (313c) . . . . . . . . . . . . . . . . . . . . . . 212
S-III.14 Benzynocyclobutane Ring Opened Diene (314) . . . . . . . . . . . . 213
S-III.15 Benzocyclobutane (315) . . . . . . . . . . . . . . . . . . . . . . . . . 214
S-III.16 Benzocyclobutane Ring Opened Diene (316) . . . . . . . . . . . . . 215
S-III.17 N-Methylimidazole (317) . . . . . . . . . . . . . . . . . . . . . . . . 216
S-III.18 Benzene N-heterocyclic Carbene Zwitterionic Intermediate (324) . . 218
S-III.19 Benzene N-heterocyclic Carbene (317a) . . . . . . . . . . . . . . . . 221
S-III.20 Proton Transfer Transition State for Benzene N-heterocyclic Carbene
(from 324 to 317a) . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
S-III.21 Dinitrogen (318) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
S-III.22 1,2-diazabenzene (318a) . . . . . . . . . . . . . . . . . . . . . . . . . 228
S-III.23 Carbon Dioxide (319) . . . . . . . . . . . . . . . . . . . . . . . . . . 229
S-III.24 Benzo-β-Lactone (319a) . . . . . . . . . . . . . . . . . . . . . . . . . 230
S-III.25 Benzodioxole Carbene (319b) . . . . . . . . . . . . . . . . . . . . . . 231
S-III.26 Transition State Leading to 319b . . . . . . . . . . . . . . . . . . . . 232
S-III.27 Carbon Disulfide (320) . . . . . . . . . . . . . . . . . . . . . . . . . 234
S-III.28 Benzodithioate (320a) . . . . . . . . . . . . . . . . . . . . . . . . . . 235
S-III.29 Benzodithiolane Carbene (320b) . . . . . . . . . . . . . . . . . . . . 236
S-III.30 Methyl Isocyanate (321) . . . . . . . . . . . . . . . . . . . . . . . . . 237
S-III.31 Benzo-β-Lactam (321a) . . . . . . . . . . . . . . . . . . . . . . . . . 238
S-III.32 Benzoxazole Carbene (321b) . . . . . . . . . . . . . . . . . . . . . . 239
192
S-III.33 Methyl Isothiocyanate (322) . . . . . . . . . . . . . . . . . . . . . . 240
S-III.34 Benzo-β-Thiolactam (322a) . . . . . . . . . . . . . . . . . . . . . . . 241
S-III.35 Benzothiazole Carbene (322b) . . . . . . . . . . . . . . . . . . . . . 242
S-III.36 Benzo-β-Thioimidate (322c) . . . . . . . . . . . . . . . . . . . . . . 243
S-III.37 Carbon Monoxide (323) . . . . . . . . . . . . . . . . . . . . . . . . . 245
S-III.38 Benzocyclopropanone (323a) . . . . . . . . . . . . . . . . . . . . . . 246
All geometries extracted are in the standard (x,y,z) coordinate system. Energies reported
(in hartrees) indicate the level of theory they are obtained at. Energies reported include:
1) energies from optimizations (SCF Energy), 2) Gibb’s free energy (Sum of Electronic
and Thermal Free Energies). Entries corresponding to transition states will also report
calculated imaginary frequencies.
S-III.1 Benzyne (301)
Fig. S61 Optimized Geometry of 301 - Solvation in CHCl3
SCF Energy - E(RM062X) =230.822 458 591
Sum of Electronic and Thermal Free Energies - E(RM062X) =230.773 291 000
Table S75 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 301 - Solvation in CHCl3
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 0.000 000 0.623 314 =1.232 873
2 C 0.000 000 =0.623 314 =1.232 873
Continued on next page
193
Table S75 – continued from previous page
Center Atom Cartesian Coordinates
# Type X Y Z
3 C 0.000 000 =1.465 161 =0.132 318
4 C 0.000 000 =0.703 794 1.053 181
5 C 0.000 000 0.703 794 1.053 181
6 C 0.000 000 1.465 161 =0.132 318
7 H 0.000 000 =2.548 206 =0.133 237
8 H 0.000 000 =1.226 935 2.005 298
9 H 0.000 000 1.226 935 2.005 298
10 H 0.000 000 2.548 206 =0.133 237
194
Fig. S62 Optimized Geometry of 301 - No Solvation
SCF Energy - E(RM062X) =230.819 701 209
Sum of Electronic and Thermal Free Energies - E(RM062X) =230.770 387 000
Table S76 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 301 - No Solvation
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 0.000 000 0.623 079 =1.233 101
2 C 0.000 000 =0.623 079 =1.233 101
3 C 0.000 000 =1.462 378 =0.132 632
4 C 0.000 000 =0.703 335 1.053 729
5 C 0.000 000 0.703 335 1.053 729
6 C 0.000 000 1.462 378 =0.132 632
7 H 0.000 000 =2.545 664 =0.133 965
8 H 0.000 000 =1.226 371 2.005 995
9 H 0.000 000 1.226 371 2.005 995
10 H 0.000 000 2.545 664 =0.133 965
195
S-III.2 1,4,6-tridecatriyne (310a)
Fig. S63 Optimized Geometry of 310a
SCF Energy - E(RM062X) =543.924 641 779
Sum of Electronic and Thermal Free Energies - E(RM062X) =543.692 501 000
Table S77 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 310a
Center Atom Cartesian Coordinates
# Type X Y Z
1 C =1.229 515 0.857 913 =0.293 878
2 C =2.362 185 0.426 353 =0.350 933
3 C =3.653 626 =0.057 675 =0.414 545
4 C =4.786 887 =0.482 165 =0.471 014
5 C =6.159 269 =0.998 933 =0.541 807
6 H =6.147 466 =2.083 484 =0.386 498
7 H =6.560 026 =0.829 705 =1.547 390
8 C =7.046 392 =0.372 859 0.449 692
9 C =7.777 186 0.138 664 1.261 891
10 H =8.423 131 0.592 936 1.981 746
11 C 0.148 023 1.344 477 =0.222 202
12 H 0.246 872 1.999 723 0.651 401
13 H 0.353 295 1.962 009 =1.104 679
14 C 1.175 954 0.205 176 =0.135 064
15 H 1.067 712 =0.443 037 =1.012 550
16 H 0.955 877 =0.409 570 0.745 543
17 C 2.605 140 0.735 952 =0.054 008
18 H 2.700 966 1.389 961 0.823 643
19 H 2.811 799 1.361 244 =0.933 487
20 C 3.646 171 =0.378 688 0.030 011
21 H 3.550 625 =1.031 077 =0.849 007
Continued on next page
196
Table S77 – continued from previous page
Center Atom Cartesian Coordinates
# Type X Y Z
22 H 3.435 523 =1.006 299 0.907 035
23 C 5.078 472 0.144 967 0.116 678
24 H 5.174 292 0.797 016 0.996 348
25 H 5.289 054 0.774 370 =0.759 508
26 C 6.122 445 =0.967 431 0.199 391
27 H 6.025 685 =1.617 422 =0.679 739
28 H 5.910 106 =1.595 532 1.074 120
29 C 7.549 358 =0.429 498 0.286 738
30 H 7.673 532 0.201 656 1.173 084
31 H 8.282 063 =1.239 275 0.345 663
32 H 7.790 193 0.178 959 =0.591 423
197
S-III.3 1,5,7-tridecatriyne (310b)
Fig. S64 Optimized Geometry of 310b
SCF Energy - E(RM062X) =543.930 984 550
Sum of Electronic and Thermal Free Energies - E(RM062X) =543.700 572 000
Table S78 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 310b
Center Atom Cartesian Coordinates
# Type X Y Z
1 C =0.182 046 0.875 654 =0.045 783
2 C 0.963 664 0.475 628 =0.064 278
3 C 2.269 138 0.026 157 =0.084 877
4 C 3.413 848 =0.375 152 =0.103 900
5 C 4.804 302 =0.828 449 =0.120 361
6 H 5.023 594 =1.302 017 =1.082 568
7 H 4.950 384 =1.588 303 0.653 936
8 C 5.785 189 0.340 531 0.113 795
9 H 5.565 833 0.813 853 1.075 578
10 H 5.640 238 1.099 328 =0.661 073
11 C 7.176 735 =0.116 990 0.098 234
12 C 8.318 608 =0.510 923 0.082 555
13 H 9.329 954 =0.855 404 0.069 412
14 C =1.574 852 1.322 733 =0.022 589
15 H =1.732 971 1.946 896 0.864 979
16 H =1.758 128 1.962 007 =0.894 410
17 C =2.572 678 0.153 730 =0.018 186
18 H =2.376 311 =0.481 760 0.853 303
19 H =2.404 891 =0.464 052 =0.908 176
20 C =4.018 986 0.641 832 0.010 409
21 H =4.202 896 1.286 693 =0.859 986
22 H =4.174 408 1.266 924 0.900 543
Continued on next page
198
Table S78 – continued from previous page
Center Atom Cartesian Coordinates
# Type X Y Z
23 C =5.029 778 =0.503 231 0.013 982
24 H =4.843 224 =1.150 012 0.882 657
25 H =4.874 557 =1.127 911 =0.876 723
26 C =6.479 980 =0.023 310 0.045 955
27 H =6.664 055 0.623 570 =0.821 412
28 H =6.632 812 0.600 330 0.936 088
29 C =7.480 310 =1.177 551 0.048 493
30 H =7.329 268 =1.821 291 0.921 469
31 H =8.512 010 =0.815 584 0.072 298
32 H =7.361 587 =1.797 209 =0.846 604
199
S-III.4 1,6,8-tridecatriyne (310c)
Fig. S65 Optimized Geometry of 310c
SCF Energy - E(RM062X) =543.933 321 924
Sum of Electronic and Thermal Free Energies - E(RM062X) =543.702 443 000
Table S79 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 310c
Center Atom Cartesian Coordinates
# Type X Y Z
1 C =1.032 978 0.412 340 0.212 160
2 C 0.087 092 =0.010 388 0.012 001
3 C 1.364 537 =0.484 040 =0.213 936
4 C 2.485 641 =0.902 615 =0.417 134
5 C 3.847 806 =1.396 228 =0.631 039
6 H 4.286 547 =0.869 713 =1.486 748
7 H 3.805 576 =2.457 705 =0.895 958
8 C 4.743 055 =1.209 068 0.603 704
9 H 5.729 599 =1.626 070 0.380 055
10 C 5.480 336 1.090 711 =0.031 360
11 C 5.967 872 1.753 617 =0.916 895
12 H 6.397 532 2.346 437 =1.694 975
13 C 4.889 591 0.260 667 1.024 128
14 H 3.906 994 0.667 542 1.289 393
15 H 5.513 962 0.323 840 1.920 770
16 H 4.326 792 =1.770 895 1.445 088
17 C =2.396 248 0.893 719 0.437 212
18 H =2.518 330 1.862 269 =0.062 203
19 H =2.538 008 1.072 372 1.509 796
20 C =3.464 660 =0.087 934 =0.069 544
21 H =3.333 992 =1.052 152 0.435 651
22 H =3.309 727 =0.264 860 =1.140 382
Continued on next page
200
Table S79 – continued from previous page
Center Atom Cartesian Coordinates
# Type X Y Z
23 C =4.877 819 0.437 140 0.170 704
24 H =4.996 549 1.407 195 =0.331 726
25 H =5.020 483 0.622 591 1.244 400
26 C =5.959 100 =0.522 442 =0.323 474
27 H =5.838 196 =1.490 352 0.179 232
28 H =5.812 839 =0.708 107 =1.395 085
29 C =7.369 524 0.011 257 =0.081 037
30 H =7.518 362 0.965 642 =0.596 963
31 H =8.130 216 =0.687 374 =0.440 279
32 H =7.543 913 0.178 925 0.986 989
201
S-III.5 3-hexylbenzynocyclopropane (311a)
Fig. S66 Optimized Geometry of 311a
SCF Energy - E(RM062X) =543.893 715 183
Sum of Electronic and Thermal Free Energies - E(RM062X) =543.659 271 000
Table S80 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 311a
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 2.135 207 =0.073 403 =0.586 437
2 C 3.015 876 =1.042 834 0.007 263
3 C 4.243 412 =0.621 489 0.449 578
4 C 4.759 600 0.682 507 0.387 975
5 C 3.791 941 1.376 029 =0.181 855
6 C 2.615 622 1.249 529 =0.662 930
7 H 2.689 618 =2.074 159 0.087 346
8 C 5.610 326 =0.390 668 0.976 901
9 H 5.767 140 =0.377 475 2.054 737
10 H 6.467 386 =0.733 091 0.398 151
11 C 0.761 714 =0.483 747 =1.049 554
12 H 0.597 626 =0.099 218 =2.063 084
13 H 0.697 280 =1.576 976 =1.100 115
14 C =0.340 983 0.050 967 =0.127 124
15 H =0.253 627 1.143 584 =0.069 135
16 H =0.176 760 =0.332 721 0.888 833
17 C =1.741 401 =0.331 283 =0.600 827
18 H =1.896 982 0.053 485 =1.618 381
19 H =1.817 978 =1.425 579 =0.667 479
20 C =2.845 597 0.196 851 0.313 199
21 H =2.767 860 1.290 983 0.380 284
22 H =2.688 969 =0.187 931 1.330 694
Continued on next page
202
Table S80 – continued from previous page
Center Atom Cartesian Coordinates
# Type X Y Z
23 C =4.248 429 =0.181 185 =0.158 258
24 H =4.326 372 =1.275 574 =0.226 342
25 H =4.405 811 0.203 771 =1.175 772
26 C =5.354 390 0.345 469 0.754 827
27 H =5.275 264 1.438 179 0.821 853
28 H =5.195 799 =0.039 450 1.770 473
29 C =6.750 838 =0.040 297 0.270 853
30 H =6.858 746 =1.129 088 0.222 384
31 H =7.528 742 0.345 121 0.936 054
32 H =6.938 497 0.357 459 =0.732 160
203
S-III.6 3-pentylbenzynocyclobutane (311b)
Fig. S67 Optimized Geometry of 311b
SCF Energy - E(RM062X) =543.953 179 216
Sum of Electronic and Thermal Free Energies - E(RM062X) =543.715 512 000
Table S81 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 311b
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 1.061 720 =0.280 774 =0.543 813
2 C 2.097 167 =1.072 995 0.018 114
3 C 3.356 547 =0.520 047 0.264 036
4 C 3.695 499 0.811 356 =0.006 926
5 C 2.643 233 1.531 205 =0.549 684
6 C 1.522 997 1.016 096 =0.763 694
7 H 1.877 604 =2.112 746 0.247 050
8 C 5.116 311 0.683 365 0.488 642
9 H 5.362 175 1.283 461 1.367 978
10 C 4.750 888 =0.817 598 0.800 593
11 H 4.792 981 =1.077 491 1.861 011
12 H 5.323 215 =1.547 394 0.222 982
13 H 5.891 456 0.813 981 =0.270 259
14 C =0.319 983 =0.798 960 =0.826 653
15 H =0.506 924 =0.757 018 =1.907 338
16 H =0.373 552 =1.853 328 =0.533 718
17 C =1.408 297 =0.000 873 =0.100 822
18 H =1.330 826 1.055 155 =0.392 177
19 H =1.224 074 =0.041 798 0.980 679
20 C =2.813 759 =0.514 370 =0.404 455
21 H =2.884 174 =1.573 123 =0.118 441
Continued on next page
204
Table S81 – continued from previous page
Center Atom Cartesian Coordinates
# Type X Y Z
22 H =2.988 334 =0.473 154 =1.488 692
23 C =3.906 035 0.275 860 0.313 516
24 H =3.834 617 1.335 110 0.029 123
25 H =3.731 684 0.234 091 1.397 899
26 C =5.314 585 =0.232 577 0.010 541
27 H =5.383 673 =1.290 760 0.293 904
28 H =5.487 038 =0.189 807 =1.072 597
29 C =6.396 366 0.565 659 0.735 506
30 H =6.360 876 1.621 178 0.445 732
31 H =6.256 740 0.513 711 1.820 486
32 H =7.396 936 0.187 842 0.506 971
205
S-III.7 3-butylbenzynocyclopentane (311c)
Fig. S68 Optimized Geometry of 311c
SCF Energy - E(RM062X) =230.822 458 591
Sum of Electronic and Thermal Free Energies - E(RM062X) =230.773 291 000
Table S82 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 311c
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 0.000 000 0.623 314 =1.232 873
2 C 0.000 000 =0.623 314 =1.232 873
3 C 0.000 000 =1.465 161 =0.132 318
4 C 0.000 000 =0.703 794 1.053 181
5 C 0.000 000 0.703 794 1.053 181
6 C 0.000 000 1.465 161 =0.132 318
7 H 0.000 000 =2.548 206 =0.133 237
8 H 0.000 000 =1.226 935 2.005 298
9 H 0.000 000 1.226 935 2.005 298
10 H 0.000 000 2.548 206 =0.133 237
206
S-III.8 1,3,6-heptatriyne (312a)
Fig. S69 Optimized Geometry of 312a
SCF Energy - E(RM062X) =268.845 259 196
Sum of Electronic and Thermal Free Energies - E(RM062X) =268.798 457 000
Table S83 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 312a
Center Atom Cartesian Coordinates
# Type X Y Z
1 C =3.635 567 0.505 120 0.000 001
2 H =4.660 573 0.808 234 0.000 002
3 C =2.475 197 0.162 182 0.000 000
4 C =1.151 080 =0.229 330 =0.000 001
5 C 0.009 556 =0.573 817 =0.000 001
6 C 1.414 913 =0.996 431 0.000 000
7 H 1.603 322 =1.622 304 =0.879 292
8 H 1.603 320 =1.622 303 0.879 294
9 C 2.341 992 0.144 291 0.000 001
10 C 3.107 177 1.076 665 0.000 000
11 H 3.783 169 1.904 296 =0.000 003
207
S-III.9 1,3,7-octatriyne (312b)
Fig. S70 Optimized Geometry of 312b
SCF Energy - E(RM062X) =308.147 424 806
Sum of Electronic and Thermal Free Energies - E(RM062X) =308.073 908 000
Table S84 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 312b
Center Atom Cartesian Coordinates
# Type X Y Z
1 C =4.418 652 =0.323 144 0.000 000
2 H =5.465 585 =0.538 161 0.000 001
3 C =3.232 918 =0.080 389 0.000 000
4 C =1.880 667 0.198 568 0.000 000
5 C =0.694 680 0.450 350 0.000 000
6 C 0.741 498 0.722 152 0.000 000
7 H 0.998 260 1.318 580 0.881 086
8 H 0.998 259 1.318 580 =0.881 085
9 C 1.565 541 =0.583 538 0.000 000
10 H 1.306 908 =1.178 604 =0.880 928
11 H 1.306 907 =1.178 603 0.880 929
12 C 3.003 766 =0.305 986 0.000 000
13 C 4.186 402 =0.060 380 0.000 000
14 H 5.233 514 0.152 425 0.000 000
208
S-III.10 1,3,8-nonatriyne (312c)
Fig. S71 Optimized Geometry of 312c
SCF Energy - E(RM062X) =347.445 489 151
Sum of Electronic and Thermal Free Energies - E(RM062X) =347.345 295 000
Table S85 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 312c
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 4.183 101 =0.843 006 0.267 024
2 H 5.138 271 =1.269 963 0.484 938
3 C 3.100 826 =0.360 157 0.020 093
4 C 1.866 915 0.191 260 =0.262 483
5 C 0.785 015 0.677 932 =0.516 240
6 C =0.529 772 1.260 383 =0.788 042
7 H =1.028 586 0.662 065 =1.559 391
8 H =0.394 241 2.266 059 =1.198 671
9 C =1.413 549 1.327 817 0.467 428
10 H =2.360 807 1.801 680 0.193 706
11 C =2.368 939 =0.957 705 0.155 490
12 C =2.928 570 =1.685 840 =0.630 506
13 H =3.422 936 =2.336 026 =1.319 255
14 C =1.687 706 =0.050 858 1.085 773
15 H =0.743 328 =0.508 347 1.402 484
16 H =2.301 060 0.067 966 1.984 320
17 H =0.931 244 1.957 615 1.220 647
209
S-III.11 Benzynocyclopropane (313a)
Fig. S72 Optimized Geometry of 313a
SCF Energy - E(RM062X) =268.819 210 858
Sum of Electronic and Thermal Free Energies - E(RM062X) =268.767 808 000
Table S86 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 313a
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 1.698 241 0.430 919 0.000 000
2 C 0.521 208 1.249 447 0.000 000
3 C =0.693 195 0.613 350 0.000 000
4 C =0.913 011 =0.774 334 0.000 000
5 C 0.297 290 =1.297 776 0.000 000
6 C 1.531 136 =0.962 086 0.000 000
7 H 2.668 279 0.920 313 0.000 000
8 H 0.620 954 2.328 666 0.000 000
9 C =2.096 546 0.132 100 0.000 000
10 H =2.679 984 0.200 655 0.917 020
11 H =2.679 985 0.200 655 =0.917 019
210
S-III.12 Benzynocyclobutane (313b)
Fig. S73 Optimized Geometry of 313b
SCF Energy - E(RM062X) =308.174 513 332
Sum of Electronic and Thermal Free Energies - E(RM062X) =308.094 006 000
Table S87 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 313b
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 2.115 075 0.415 749 =0.000 001
2 C 0.955 283 1.229 928 0.000 000
3 C =0.305 804 0.630 496 0.000 000
4 C =0.515 012 =0.756 068 0.000 000
5 C 0.661 192 =1.487 612 0.000 000
6 C 1.782 229 =0.929 884 0.000 000
7 H 3.112 262 0.838 103 0.000 000
8 H 1.077 320 2.308 887 0.000 000
9 C =2.021 536 =0.654 708 0.000 000
10 H =2.516 286 =1.045 391 0.892 265
11 C =1.803 924 0.905 841 0.000 000
12 H =2.181 013 1.410 671 0.892 423
13 H =2.181 014 1.410 674 =0.892 420
14 H =2.516 286 =1.045 391 =0.892 266
211
S-III.13 Benzynocyclopentane (313c)
Fig. S74 Optimized Geometry of 313c
SCF Energy - E(RM062X) =347.515 496 421
Sum of Electronic and Thermal Free Energies - E(RM062X) =347.406 068 000
Table S88 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 313c
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 2.446 877 0.428 511 =0.055 702
2 C 1.264 196 1.197 070 0.002 938
3 C =0.007 228 0.605 202 0.051 243
4 C =0.199 158 =0.795 994 0.047 858
5 C 1.015 954 =1.453 953 0.001 771
6 C 2.145 790 =0.925 091 =0.050 742
7 H 3.430 434 0.879 335 =0.103 285
8 H 1.349 763 2.280 745 0.002 775
9 C =1.359 927 1.282 080 0.143 651
10 H =1.542 466 1.600 561 1.177 790
11 H =1.437 001 2.168 585 =0.491 176
12 C =1.656 175 =1.161 146 0.123 612
13 H =1.911 822 =1.453 935 1.149 813
14 H =1.921 022 =1.993 653 =0.532 363
15 C =2.344 553 0.164 936 =0.270 209
16 H =3.329 291 0.280 370 0.187 095
17 H =2.473 249 0.188 301 =1.357 179
212
S-III.14 Benzynocyclobutane Ring Opened Diene (314)
Fig. S75 Optimized Geometry of 314
SCF Energy - E(RM062X) =308.155 566 918
Sum of Electronic and Thermal Free Energies - E(RM062X) =308.078 148 000
Table S89 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 314
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 2.096 751 0.056 044 0.088 124
2 C 1.141 650 1.017 539 0.170 882
3 C =0.311 481 0.773 003 0.003 175
4 C =0.844 053 =0.657 688 =0.016 969
5 C 0.296 790 =1.521 514 =0.220 101
6 C 1.481 732 =1.229 833 =0.128 433
7 H 3.156 430 0.248 749 0.190 655
8 H 1.439 278 2.050 394 0.332 940
9 C =2.119 686 =1.009 290 0.201 240
10 H =2.872 475 =0.274 043 0.462 803
11 C =1.133 679 1.821 021 =0.191 491
12 H =0.760 640 2.839 261 =0.152 596
13 H =2.187 945 1.687 358 =0.409 223
14 H =2.422 791 =2.047 409 0.136 858
213
S-III.15 Benzocyclobutane (315)
Fig. S76 Optimized Geometry of 315
SCF Energy - E(RM062X) =309.506 467 462
Sum of Electronic and Thermal Free Energies - E(RM062X) =309.400 165 000
Table S90 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 315
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 0.000 001 0.700 530 =1.910 890
2 C 0.000 001 1.438 902 =0.717 628
3 C 0.000 000 0.696 419 0.453 609
4 C 0.000 000 =0.696 419 0.453 609
5 C =0.000 001 =1.438 902 =0.717 628
6 C =0.000 001 =0.700 530 =1.910 890
7 H 0.000 001 1.224 386 =2.862 243
8 H 0.000 002 2.524 808 =0.733 291
9 C 0.000 001 =0.786 842 1.970 076
10 H 0.890 609 =1.241 092 2.412 264
11 C =0.000 001 0.786 842 1.970 076
12 H 0.890 605 1.241 095 2.412 266
13 H =0.890 609 1.241 092 2.412 264
14 H =0.890 605 =1.241 095 2.412 266
15 H =0.000 002 =2.524 808 =0.733 291
16 H =0.000 001 =1.224 386 =2.862 243
214
S-III.16 Benzocyclobutane Ring Opened Diene (316)
Fig. S77 Optimized Geometry of 316
SCF Energy - E(RM062X) =309.479 988 793
Sum of Electronic and Thermal Free Energies - E(RM062X) =309.376 765 000
Table S91 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 316
Center Atom Cartesian Coordinates
# Type X Y Z
1 C =0.126 135 0.718 371 1.831 334
2 C =0.201 838 1.404 636 0.674 050
3 C =0.007 742 0.746 006 =0.621 634
4 C 0.007 742 =0.746 006 =0.621 634
5 C 0.201 838 =1.404 636 0.674 050
6 C 0.126 135 =0.718 371 1.831 334
7 H =0.233 243 1.231 825 2.781 643
8 H =0.353 285 2.480 755 0.672 423
9 C =0.201 838 =1.482 865 =1.730 190
10 H =0.443 766 =1.031 578 =2.686 574
11 C 0.201 838 1.482 865 =1.730 190
12 H 0.152 136 2.566 680 =1.688 851
13 H 0.443 766 1.031 578 =2.686 574
14 H =0.152 136 =2.566 680 =1.688 851
15 H 0.353 285 =2.480 755 0.672 423
16 H 0.233 243 =1.231 825 2.781 643
215
S-III.17 N-Methylimidazole (317)
Fig. S78 Optimized Geometry of 317 - Solvation in CHCl3
SCF Energy - E(RM062X) =265.435 857 255
Sum of Electronic and Thermal Free Energies - E(RM062X) =265.364 371 000
Table S92 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 317 - Solvation in CHCl3
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 0.224 619 1.109 775 0.000 000
2 C 0.192 413 =1.083 011 0.000 000
3 C 1.501 503 0.605 449 0.000 000
4 H =0.161 817 2.117 691 0.000 000
5 H =0.217 622 =2.083 930 0.000 000
6 H 2.432 494 1.153 566 0.000 000
7 N 1.471 781 =0.768 311 0.000 000
8 N =0.605 092 0.015 716 0.000 000
9 C =2.058 978 0.033 147 0.000 000
10 H =2.419 200 =0.995 544 =0.000 005
11 H =2.429 007 0.542 105 0.891 668
12 H =2.429 008 0.542 115 =0.891 662
216
Fig. S79 Optimized Geometry of 317 - No Solvation
SCF Energy - E(RM062X) =265.427 540 637
Sum of Electronic and Thermal Free Energies - E(RM062X) =265.356 167 000
Table S93 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 317 - No Solvation
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 0.223 174 1.111 161 0.000 000
2 C 0.197 646 =1.081 789 0.000 000
3 C 1.498 968 0.604 915 0.000 000
4 H =0.162 387 2.119 382 0.000 000
5 H =0.209 066 =2.084 374 0.000 000
6 H 2.430 561 1.151 339 0.000 000
7 N 1.471 625 =0.766 216 0.000 000
8 N =0.607 523 0.016 488 0.000 000
9 C =2.056 960 0.030 548 0.000 000
10 H =2.416 102 =0.999 397 0.000 000
11 H =2.434 343 0.536 068 0.891 892
12 H =2.434 343 0.536 069 =0.891 892
217
S-III.18 Benzene N-heterocyclic Carbene Zwitterionic Intermediate
(324)
Fig. S80 Optimized Geometry of 324 - Solvation in CHCl3
SCF Energy - E(RM062X) =496.309 928 520
Sum of Electronic and Thermal Free Energies - E(RM062X) =496.165 269 000
Table S94 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 324 - Solvation in CHCl3
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 0.929 853 0.006 260 =0.026 673
2 C 1.360 312 =1.297 020 =0.284 782
3 C 2.771 300 =1.390 502 =0.233 526
4 C 3.628 544 =0.314 124 0.022 470
5 C 3.101 435 0.953 388 0.283 249
6 C 1.719 410 1.121 681 0.271 215
7 H 3.242 106 =2.359 085 =0.412 470
8 H 4.706 911 =0.458 957 0.028 115
9 H 3.750 884 1.794 437 0.505 578
10 H 1.287 479 2.090 906 0.509 738
11 C =2.524 424 1.129 718 =0.264 030
12 C =1.414 018 =0.722 316 0.176 270
13 C =1.191 474 1.403 970 =0.332 180
14 H =3.387 622 1.755 638 =0.424 625
15 H =1.158 390 =1.744 267 0.407 479
16 H =0.678 135 2.317 546 =0.581 754
17 N =0.518 153 0.234 502 =0.052 888
Continued on next page
218
Table S94 – continued from previous page
Center Atom Cartesian Coordinates
# Type X Y Z
18 N =2.639 899 =0.204 997 0.055 344
19 C =3.892 547 =0.933 552 0.238 263
20 H =3.658 611 =1.974 080 0.456 137
21 H =4.447 272 =0.499 349 1.069 939
22 H =4.481 324 =0.874 341 =0.676 990
Fig. S81 Optimized Geometry of 324 - No Solvation
SCF Energy - E(RM062X) =496.287 575 003
Sum of Electronic and Thermal Free Energies - E(RM062X) =496.144 388 000
Table S95 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 324 - No Solvation
Center Atom Cartesian Coordinates
# Type X Y Z
1 C =0.939 113 0.041 756 =0.001 986
2 C =1.305 663 =1.297 729 =0.069 466
3 C =2.711 128 =1.441 370 =0.063 646
4 C =3.609 219 =0.372 082 =0.004 734
5 C =3.138 252 0.942 295 0.070 230
6 C =1.765 351 1.165 402 0.077 220
7 H =3.137 521 =2.444 437 =0.110 147
8 H =4.681 874 =0.554 657 =0.011 764
9 H =3.826 545 1.779 704 0.128 290
10 H =1.386 250 2.182 500 0.153 319
Continued on next page
219
Table S95 – continued from previous page
Center Atom Cartesian Coordinates
# Type X Y Z
11 C 2.547 299 1.157 215 =0.071 984
12 C 1.389 117 =0.716 990 0.050 875
13 C 1.218 901 1.466 023 =0.086 536
14 H 3.423 315 1.784 531 =0.119 494
15 H 1.058 253 =1.747 982 0.100 565
16 H 0.730 509 2.422 708 =0.157 586
17 N 0.519 484 0.284 380 =0.008 206
18 N 2.631 791 =0.215 303 0.013 910
19 C 3.859 840 =0.996 748 0.060 275
20 H 3.595 823 =2.052 104 0.114 953
21 H 4.446 376 =0.817 614 =0.842 108
22 H 4.440 412 =0.722 833 0.942 548
220
S-III.19 Benzene N-heterocyclic Carbene (317a)
Fig. S82 Optimized Geometry of 317a - Solvation in CHCl3
SCF Energy - E(RM062X) =496.360 959 591
Sum of Electronic and Thermal Free Energies - E(RM062X) =496.215 632 000
Table S96 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 317a - Solvation in CHCl3
Center Atom Cartesian Coordinates
# Type X Y Z
1 C =0.848 126 0.033 551 =0.018 733
2 C =1.429 708 =1.200 421 =0.314 559
3 C =2.814 494 =1.336 477 =0.263 561
4 C =3.622 084 =0.247 533 0.067 711
5 C =3.033 160 0.981 817 0.358 869
6 C =1.646 919 1.125 114 0.324 502
7 H =3.263 912 =2.297 089 =0.494 234
8 H =4.701 043 =0.357 370 0.099 802
9 H =3.650 263 1.833 275 0.627 140
10 H =1.190 030 2.075 023 0.582 815
11 C 2.541 059 1.081 457 =0.354 625
12 C 1.440 445 =0.825 299 0.279 330
13 C 1.217 203 1.343 610 =0.453 990
14 H 3.401 346 1.697 708 =0.566 549
15 H =0.791 376 =2.035 027 =0.580 675
16 H 0.696 088 2.226 453 =0.788 674
17 N 0.567 250 0.176 003 =0.067 570
18 N 2.644 290 =0.228 662 0.089 037
19 C 3.916 915 =0.888 363 0.336 551
Continued on next page
221
Table S96 – continued from previous page
Center Atom Cartesian Coordinates
# Type X Y Z
20 H 3.707 034 =1.903 979 0.667 712
21 H 4.511 539 =0.917 239 =0.579 191
22 H 4.473 054 =0.357 880 1.112 614
Fig. S83 Optimized Geometry of 317a - No Solvation
SCF Energy - E(RM062X) =496.352 403 018
Sum of Electronic and Thermal Free Energies - E(RM062X) =496.206 999 000
Table S97 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 317a - No Solvation
Center Atom Cartesian Coordinates
# Type X Y Z
1 C =0.846 305 0.040 984 =0.015 348
2 C =1.414 006 =1.208 244 =0.270 722
3 C =2.796 850 =1.353 012 =0.230 787
4 C =3.618 559 =0.261 407 0.051 884
5 C =3.043 578 0.980 587 0.308 779
6 C =1.658 711 1.134 510 0.284 293
7 H =3.235 241 =2.325 899 =0.429 568
8 H =4.696 852 =0.379 823 0.075 896
9 H =3.670 705 1.834 762 0.543 670
10 H =1.214 684 2.095 582 0.522 477
11 C 2.543 247 1.102 477 =0.302 257
Continued on next page
222
Table S97 – continued from previous page
Center Atom Cartesian Coordinates
# Type X Y Z
12 C 1.436 322 =0.833 471 0.236 570
13 C 1.220 477 1.371 836 =0.388 166
14 H 3.403 587 1.727 933 =0.485 196
15 H =0.759 629 =2.044 201 =0.488 412
16 H 0.704 608 2.270 853 =0.684 612
17 N 0.567 656 0.189 200 =0.058 047
18 N 2.641 649 =0.228 751 0.075 696
19 C 3.904 385 =0.912 076 0.289 878
20 H 3.676 333 =1.940 169 0.566 769
21 H 4.502 766 =0.902 883 =0.624 967
22 H 4.466 154 =0.432 393 1.095 657
223
S-III.20 Proton Transfer Transition State for Benzene N-heterocyclic
Carbene (from 324 to 317a)
Fig. S84 Optimized Geometry of Transition State to 317a - Solvation in CHCl3
SCF Energy - E(RM062X) =496.291 120 686
Sum of Electronic and Thermal Free Energies - E(RM062X) =496.150 058 000
Imaginary Frequency (cm=1) =1542.040
Table S98 Cartesian Coordinates, Electronic and Free Energies for Optimized Geometry
of Transition State to 317a - Solvation in CHCl3
Center Atomic Cartesian Coordinates
# # X Y Z
1 C 0.688 182 =0.610 905 0.000 000
2 C =0.213 475 =1.680 277 0.000 000
3 C 0.403 965 =2.937 693 0.000 000
4 C 1.800 201 =3.091 742 0.000 000
5 C 2.633 815 =1.973 882 0.000 000
6 C 2.073 278 =0.692 367 0.000 000
7 H =0.204 701 =3.841 766 0.000 000
8 H 2.238 860 =4.086 600 0.000 000
9 H 3.713 061 =2.090 923 0.000 000
10 H 2.708 222 0.189 938 0.000 000
11 C =0.709 313 2.741 563 0.000 000
12 C =1.337 708 0.599 249 0.000 000
13 C 0.422 898 1.981 909 0.000 000
14 H =0.842 600 3.812 426 0.000 000
15 H =1.474 084 =0.675 844 0.000 000
16 H 1.460 905 2.272 893 0.000 000
17 N 0.000 000 0.673 924 0.000 000
Continued on next page
224
Table S98 – continued from previous page
Center Atomic Cartesian Coordinates
# # X Y Z
18 N =1.781 666 1.864 107 0.000 000
19 C =3.184 336 2.262 664 0.000 000
20 H =3.792 215 1.359 766 0.000 000
21 H =3.400 413 2.851 391 0.892 444
22 H =3.400 413 2.851 391 =0.892 444
Fig. S85 Optimized Geometry of Transition State to 317a - No Solvation
SCF Energy - E(RM062X) =496.278 936 384
Sum of Electronic and Thermal Free Energies - E(RM062X) =496.138 018 000
Imaginary Frequency (cm=1) =1261.020
Table S99 Cartesian Coordinates, Electronic and Free Energies for Optimized Geometry
of Transition State to 317a - No Solvation
Center Atomic Cartesian Coordinates
# # X Y Z
1 C 0.685 856 =0.624 414 0.000 000
2 C =0.220 426 =1.683 952 0.000 000
3 C 0.401 700 =2.939 941 0.000 000
4 C 1.795 584 =3.092 316 0.000 000
5 C 2.632 475 =1.976 069 0.000 000
6 C 2.071 544 =0.697 337 0.000 000
7 H =0.207 520 =3.843 151 0.000 000
8 H 2.234 634 =4.087 151 0.000 000
Continued on next page
225
Table S99 – continued from previous page
Center Atomic Cartesian Coordinates
# # X Y Z
9 H 3.711 471 =2.094 541 0.000 000
10 H 2.706 472 0.186 049 0.000 000
11 C =0.701 844 2.745 435 0.000 000
12 C =1.333 289 0.606 320 0.000 000
13 C 0.425 022 1.976 215 0.000 000
14 H =0.827 780 3.817 233 0.000 000
15 H =1.521 149 =0.622 569 0.000 000
16 H 1.465 099 2.258 936 0.000 000
17 N 0.000 000 0.671 969 0.000 000
18 N =1.777 866 1.873 350 0.000 000
19 C =3.178 354 2.268 331 0.000 000
20 H =3.784 079 1.363 420 0.000 000
21 H =3.400 840 2.855 453 0.893 006
22 H =3.400 840 2.855 453 =0.893 006
226
S-III.21 Dinitrogen (318)
Fig. S86 Optimized Geometry of 318
SCF Energy - E(RM062X) =109.492 343 554
Sum of Electronic and Thermal Free Energies - E(RM062X) =109.504 987 000
Table S100 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 318
Center Atom Cartesian Coordinates
# Type X Y Z
1 N 0.000 000 0.000 000 0.549 101
2 N 0.000 000 0.000 000 =0.549 101
227
S-III.22 1,2-diazabenzene (318a)
Fig. S87 Optimized Geometry of 318a
SCF Energy - E(RM062X) =340.285 665 586
Sum of Electronic and Thermal Free Energies - E(RM062X) =340.227 628 000
Table S101 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 318a
Center Atom Cartesian Coordinates
# Type X Y Z
1 C =0.538 256 0.697 781 0.000 000
2 C 0.578 712 1.466 780 0.000 000
3 C 1.785 735 0.691 048 0.000 000
4 C 1.785 735 =0.691 048 0.000 000
5 C 0.578 712 =1.466 780 0.000 000
6 C =0.538 256 =0.697 781 0.000 000
7 H 0.593 769 2.550 131 0.000 000
8 H 2.736 209 1.214 239 0.000 000
9 H 2.736 209 =1.214 239 0.000 000
10 H 0.593 769 =2.550 131 0.000 000
11 N =2.041 018 =0.629 207 0.000 000
12 N =2.041 018 0.629 207 0.000 000
228
S-III.23 Carbon Dioxide (319)
Fig. S88 Optimized Geometry of 319
SCF Energy - E(RM062X) =188.518 377 441
Sum of Electronic and Thermal Free Energies - E(RM062X) =188.527 950 000
Table S102 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 319
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 0.000 000 0.000 000 0.000 000
2 O 0.000 000 0.000 000 =1.162 713
3 O 0.000 000 0.000 000 1.162 713
229
S-III.24 Benzo-β-Lactone (319a)
Fig. S89 Optimized Geometry of 319a
SCF Energy - E(RM062X) =419.406 256 654
Sum of Electronic and Thermal Free Energies - E(RM062X) =419.344 114 000
Table S103 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 319a
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 0.022 367 =0.799 842 0.000 000
2 C 0.273 813 0.561 944 0.000 001
3 C =0.728 881 1.507 713 0.000 000
4 C =2.030 343 0.971 703 0.000 000
5 C =2.259 997 =0.408 255 0.000 000
6 C =1.224 178 =1.368 309 0.000 000
7 H =0.549 140 2.576 386 0.000 001
8 H =2.881 072 1.643 866 =0.000 001
9 H =3.286 559 =0.760 871 0.000 000
10 H =1.417 467 =2.433 408 0.000 001
11 O 1.368 623 =1.215 933 0.000 000
12 C 1.720 288 0.169 751 0.000 000
13 O 2.818 354 0.611 658 0.000 000
230
S-III.25 Benzodioxole Carbene (319b)
Fig. S90 Optimized Geometry of 319b
SCF Energy - E(RM062X) =419.385 969 514
Sum of Electronic and Thermal Free Energies - E(RM062X) =419.322 951 000
Table S104 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 319b
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 0.000 000 =2.071 961 0.702 053
2 C 0.000 000 =0.886 748 1.440 547
3 C 0.000 000 0.273 725 =0.687 588
4 C 0.000 000 =0.886 748 =1.440 547
5 C 0.000 000 =2.071 961 =0.702 053
6 H 0.000 000 =3.019 932 1.229 011
7 H 0.000 000 =0.873 834 2.523 681
8 H 0.000 000 =0.873 834 =2.523 681
9 H 0.000 000 =3.019 932 =1.229 011
10 C 0.000 000 0.273 725 0.687 588
11 C 0.000 000 2.400 636 0.000 000
12 O 0.000 000 1.600 220 =1.075 147
13 O 0.000 000 1.600 220 1.075 147
231
S-III.26 Transition State Leading to 319b
Fig. S91 Optimized Geometry of Transition State to 319b
SCF Energy - E(RM062X) =419.289 219 651
Sum of Electronic and Thermal Free Energies - E(RM062X) =419.232 380 000
Imaginary Frequency (cm=1) =552.720
Table S105 Cartesian Coordinates, Electronic and Free Energies for Optimized Geometry
of Transition State to 319b
Center Atomic Cartesian Coordinates
# # X Y Z
1 C =2.296 944 0.323 485 0.000 000
2 C =1.195 734 1.190 946 0.000 000
3 C 0.205 064 =0.774 939 0.000 000
4 C =0.861 537 =1.666 891 0.000 000
5 C =2.132 634 =1.071 378 0.000 000
6 H =3.298 083 0.742 603 0.000 000
7 H =1.295 238 2.270 414 0.000 000
8 H =0.751 275 =2.746 517 0.000 000
9 H =3.013 895 =1.706 287 0.000 000
10 C 0.000 000 0.503 317 0.000 000
11 C 2.378 737 0.593 488 0.000 000
Continued on next page
232
Table S105 – continued from previous page
Center Atomic Cartesian Coordinates
# # X Y Z
12 O 2.471 120 =0.582 064 0.000 000
13 O 1.500 978 1.438 516 0.000 000
233
S-III.27 Carbon Disulfide (320)
Fig. S92 Optimized Geometry of 320
SCF Energy - E(RM062X) =834.396 762 689
Sum of Electronic and Thermal Free Energies - E(RM062X) =834.412 762 000
Table S106 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 320
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 0.000 000 0.000 000 0.000 000
2 S 0.000 000 0.000 000 1.554 779
3 S 0.000 000 0.000 000 =1.554 779
234
S-III.28 Benzodithioate (320a)
Fig. S93 Optimized Geometry of 320a
SCF Energy - E(RM062X) =1065.320 508 020
Sum of Electronic and Thermal Free Energies - E(RM062X)=1065.265 277 000
Table S107 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 320a
Center Atom Cartesian Coordinates
# Type X Y Z
1 C =0.689 113 0.837 012 0.000 000
2 C =0.163 692 =0.459 559 0.000 000
3 C =0.968 954 =1.584 244 0.000 000
4 C =2.352 931 =1.348 832 0.000 000
5 C =2.866 911 =0.049 840 0.000 000
6 C =2.040 104 1.092 614 0.000 000
7 H =0.558 996 =2.588 846 0.000 000
8 H =3.038 708 =2.188 974 0.000 001
9 H =3.943 806 0.087 335 0.000 000
10 H =2.458 647 2.092 239 =0.000 001
11 C 1.267 130 =0.102 946 0.000 000
12 S 0.901 673 1.682 848 0.000 000
13 S 2.653 803 =0.914 535 0.000 000
235
S-III.29 Benzodithiolane Carbene (320b)
Fig. S94 Optimized Geometry of 320b
SCF Energy - E(RM062X) =1065.309 447 010
Sum of Electronic and Thermal Free Energies - E(RM062X)=1065.253 422 000
Table S108 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 320b
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 0.000 000 0.702 157 =2.588 904
2 C 0.000 000 1.412 000 =1.396 803
3 C 0.000 000 =0.698 296 =0.192 555
4 C 0.000 000 =1.412 000 =1.396 803
5 C 0.000 000 =0.702 157 =2.588 904
6 H 0.000 000 1.239 218 =3.531 468
7 H 0.000 000 2.497 113 =1.395 111
8 H 0.000 000 =2.497 113 =1.395 111
9 H 0.000 000 =1.239 218 =3.531 468
10 C 0.000 000 0.698 296 =0.192 555
11 C 0.000 000 0.000 000 2.366 671
12 S 0.000 000 =1.396 242 1.431 008
13 S 0.000 000 1.396 242 1.431 008
236
S-III.30 Methyl Isocyanate (321)
Fig. S95 Optimized Geometry of 321
SCF Energy - E(RM062X) =207.909 942 935
Sum of Electronic and Thermal Free Energies - E(RM062X) =207.886 645 000
Table S109 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 321
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 1.778 247 0.126 710 0.000 000
2 H 1.984 737 0.722 196 =0.891 280
3 H 2.423 699 =0.750 729 =0.000 003
4 H 1.984 738 0.722 190 0.891 283
5 N 0.407 586 =0.301 774 0.000 000
6 C =0.751 295 =0.038 288 0.000 000
7 O =1.925 999 0.111 028 0.000 000
237
S-III.31 Benzo-β-Lactam (321a)
Fig. S96 Optimized Geometry of 321a
SCF Energy - E(RM062X) =438.838 054 345
Sum of Electronic and Thermal Free Energies - E(RM062X) =438.738 428 000
Table S110 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 321a
Center Atom Cartesian Coordinates
# Type X Y Z
1 C =0.074 646 0.585 757 =0.130 961
2 C =0.235 494 =0.804 284 =0.057 836
3 C =1.462 847 =1.405 939 0.050 828
4 C =2.565 256 =0.518 795 0.093 225
5 C =2.390 713 0.861 267 0.040 138
6 C =1.118 030 1.474 531 =0.071 499
7 H =1.598 233 =2.479 907 0.115 840
8 H =3.568 390 =0.921 791 0.180 062
9 H =3.268 457 1.498 731 0.085 635
10 H =1.004 130 2.551 582 =0.105 302
11 C 1.284 839 =0.884 577 =0.088 177
12 O 2.157 678 =1.696 452 0.050 919
13 N 1.348 176 0.518 654 =0.284 861
14 C 2.367 007 1.419 439 0.215 410
15 H 3.333 400 0.924 392 0.107 398
16 H 2.374 736 2.337 090 =0.374 965
17 H 2.203 260 1.666 556 1.271 246
238
S-III.32 Benzoxazole Carbene (321b)
Fig. S97 Optimized Geometry of 321b
SCF Energy - E(RM062X) =438.837 254 576
Sum of Electronic and Thermal Free Energies - E(RM062X) =438.734 597 000
Table S111 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 321b
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 1.983 719 1.307 387 0.000 000
2 C 0.603 040 1.505 348 0.000 000
3 C 0.378 275 =0.909 786 0.000 000
4 C 1.746 327 =1.126 275 0.000 000
5 C 2.543 529 0.019 360 0.000 000
6 H 2.641 773 2.169 718 0.000 000
7 H 0.169 878 2.499 709 0.000 000
8 H 2.166 532 =2.125 228 0.000 000
9 H 3.622 925 =0.087 960 0.000 000
10 C =0.183 835 0.357 920 0.000 000
11 C =1.856 461 =1.186 803 0.000 000
12 O =0.646 457 =1.821 741 0.000 000
13 N =1.561 595 0.127 197 0.000 000
14 C =2.559 167 1.183 833 0.000 000
15 H =2.444 472 1.803 033 =0.892 268
16 H =3.541 910 0.715 343 =0.000 002
17 H =2.444 474 1.803 030 0.892 271
239
S-III.33 Methyl Isothiocyanate (322)
Fig. S98 Optimized Geometry of 322
SCF Energy - E(RM062X) =530.859 949 538
Sum of Electronic and Thermal Free Energies - E(RM062X) =530.838 987 000
Table S112 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 322
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 2.410 227 0.000 000 =0.000 501
2 H 2.772 848 =0.891 142 =0.515 483
3 H 2.774 671 =0.000 084 1.028 073
4 H 2.772 848 0.891 226 =0.515 337
5 N 0.990 385 0.000 000 0.001 018
6 C =0.179 835 0.000 000 0.000 358
7 S =1.789 714 0.000 000 =0.000 220
240
S-III.34 Benzo-β-Thiolactam (322a)
Fig. S99 Optimized Geometry of 322a
SCF Energy - E(RM062X) =761.779 387 634
Sum of Electronic and Thermal Free Energies - E(RM062X) =761.682 616 000
Table S113 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 322a
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 0.578 434 0.717 828 =0.000 001
2 C 0.355 211 =0.669 518 =0.000 001
3 C 1.371 978 =1.579 520 0.000 000
4 C 2.679 678 =1.017 010 0.000 001
5 C 2.882 992 0.354 824 0.000 001
6 C 1.814 366 1.297 683 0.000 000
7 H 1.216 519 =2.652 891 0.000 000
8 H 3.538 965 =1.678 755 0.000 001
9 H 3.900 813 0.732 223 0.000 001
10 H 1.993 687 2.366 062 0.000 000
11 C =1.130 835 =0.354 753 =0.000 001
12 N =0.830 424 0.986 626 =0.000 002
13 C =1.642 631 2.174 460 0.000 001
14 H =2.687 461 1.859 467 =0.000 002
15 H =1.445 136 2.774 535 0.892 642
16 H =1.445 132 2.774 543 =0.892 633
17 S =2.544 653 =1.164 096 0.000 000
241
S-III.35 Benzothiazole Carbene (322b)
Fig. S100 Optimized Geometry of 322b
SCF Energy - E(RM062X) =761.800 304 962
Sum of Electronic and Thermal Free Energies - E(RM062X) =761.701 104 000
Table S114 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 322b
Center Atom Cartesian Coordinates
# Type X Y Z
1 C =2.330 956 1.119 284 0.000 000
2 C =0.998 953 1.515 854 0.000 001
3 C =0.367 187 =0.836 758 =0.000 001
4 C =1.706 755 =1.229 808 =0.000 002
5 C =2.682 667 =0.239 660 =0.000 002
6 H =3.110 389 1.873 793 0.000 000
7 H =0.730 180 2.566 639 0.000 002
8 H =1.976 730 =2.280 481 =0.000 003
9 H =3.730 302 =0.521 493 =0.000 002
10 C =0.021 825 0.517 171 0.000 001
11 C 2.158 048 =0.395 415 0.000 000
12 N 1.373 979 0.688 155 0.000 001
13 C 1.938 425 2.037 175 0.000 002
14 H 1.611 625 2.576 084 0.892 584
15 H 3.021 607 1.942 225 0.000 002
16 H 1.611 626 2.576 085 =0.892 580
17 S 1.109 758 =1.779 812 =0.000 001
242
S-III.36 Benzo-β-Thioimidate (322c)
Fig. S101 Optimized Geometry of 322c
SCF Energy - E(RM062X) =761.789 676 998
Sum of Electronic and Thermal Free Energies - E(RM062X) =761.693 669 000
Table S115 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 322c
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 0.787 105 0.816 728 0.000 000
2 C 0.061 376 =0.381 634 0.000 000
3 C 0.701 390 =1.612 152 0.000 000
4 C 2.104 594 =1.590 759 0.000 000
5 C 2.813 913 =0.387 725 0.000 000
6 C 2.166 007 0.858 953 0.000 000
7 H 0.167 671 =2.555 747 0.000 000
8 H 2.649 749 =2.528 514 0.000 001
9 H 3.899 155 =0.415 614 0.000 000
10 H 2.726 673 1.786 685 0.000 000
11 C =1.299 325 0.240 500 0.000 000
12 N =2.509 692 =0.075 831 0.000 000
13 C =2.871 393 =1.486 349 0.000 000
14 H =3.486 380 =1.685 217 0.881 119
Continued on next page
243
Table S115 – continued from previous page
Center Atom Cartesian Coordinates
# Type X Y Z
15 H =3.486 384 =1.685 215 =0.881 117
16 H =2.013 461 =2.164 931 =0.000 003
17 S =0.604 449 1.939 625 0.000 000
244
S-III.37 Carbon Monoxide (323)
Fig. S102 Optimized Geometry of 323
SCF Energy - E(RM062X) =113.277 589 723
Sum of Electronic and Thermal Free Energies - E(RM062X) =113.291 541 000
Table S116 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 323
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 0.000 000 0.000 000 =0.646 214
2 O 0.000 000 0.000 000 0.484 660
245
S-III.38 Benzocyclopropanone (323a)
Fig. S103 Optimized Geometry of 323a
SCF Energy - E(RM062X) =344.159 577 518
Sum of Electronic and Thermal Free Energies - E(RM062X) =344.102 041 000
Table S117 Cartesian Coordinates, Electronic and Free Energies of Optimized Geometry
of 323a
Center Atom Cartesian Coordinates
# Type X Y Z
1 C 0.000 000 0.440 326 0.691 810
2 C 0.000 000 0.440 326 =0.691 810
3 C 0.000 000 =0.729 337 =1.467 461
4 C 0.000 000 =1.890 234 =0.713 364
5 C 0.000 000 =1.890 234 0.713 364
6 C 0.000 000 =0.729 337 1.467 461
7 H 0.000 000 =0.742 448 =2.550 957
8 H 0.000 000 =2.851 472 =1.217 981
9 H 0.000 000 =2.851 472 1.217 981
10 H 0.000 000 =0.742 448 2.550 957
11 C 0.000 000 1.690 785 0.000 000
12 O 0.000 000 2.899 261 0.000 000
246
247