Conformations and Conformational Processes of Hexahydrobenzazocines by NMR and DFT Studies

Article abstract of DOI:10.1021/acs.joc.5b01687

Conformational processes that occur in hexahydrobenzazocines have been studied with the ¹H and ¹³C dynamic nuclear magnetic resonance (DNMR) spectroscopy. The coalescence effects are assigned to two different conformational processes: the ring-inversion of the ground-state conformations and the interconversion between two different conformers. The barriers for these processes are in the range of 42-52 and 42-43 kJ mol^-1, respectively. Molecular modeling on the density functional theory (DFT) level and the gauge invariant atomic orbitals (GIAO)-DFT calculations of isotropic shieldings and coupling constants for the set of low-energy conformations were compared with the experimental NMR data. The ground-state of all compounds in solution is the boat-chair (BC) conformation. The BC form adopts two different conformations because the nitrogen atom can be in the boat or chair parts of the BC structure. These two conformers are engaged in the interconversion process.

Full text of DOI:10.1021/acs.joc.5b01687

Article
pubs.acs.org/joc
Conformations and Conformational Processes of
Hexahydrobenzazocines by NMR and DFT Studies
Bogdan Musielak,† Tad A. Holak,†,‡ and Barbara Rys*,†
†Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland
‡Malopolska Centre for Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland
S
* Supporting Information
ABSTRACT: Conformational processes that occur in hex-
1
ahydrobenzazocines have been studied with the H and 13C
dynamic nuclear magnetic resonance (DNMR) spectroscopy.
The coalescence effects are assigned to two different
conformational processes: the ring-inversion of the ground-
state conformations and the interconversion between two
different conformers. The barriers for these processes are in
the range of 42−52 and 42−43 kJ mol−1, respectively.
Molecular modeling on the density functional theory (DFT)
level and the gauge invariant atomic orbitals (GIAO)-DFT
calculations of isotropic shieldings and coupling constants for
the set of low-energy conformations were compared with the
experimental NMR data. The ground-state of all compounds
in solution is the boat−chair (BC) conformation. The BC form adopts two different conformations because the nitrogen atom
can be in the boat or chair parts of the BC structure. These two conformers are engaged in the interconversion process.
are in the range 38−100 and 36−105 kJ mol−1 for the inversion
INTRODUCTION
■
and interconversion processes, respectively.7 Studies carried out
Organic compounds that contain the N-heterocyclic eight-
membered ring have mostly been considered as potential drugs
using DNMR and X-ray of the benzo[b]azocines with the N-
benzoyl moiety showed that these derivatives adopt the BC
conformation in both solution and solid states, and the
due to their affinity for the opioid receptor and their structural
similarity to the benzomorphan system.1 Modification of the
activation energy for the ring inversion is in the range of 69.9−
structure of these compounds, by introducing an oxygen atom
71.1 kJ mol−1.8 In the case of dibenzoazocine the preferred
to the heterocyclic ring, retains analgesic properties, and these
structures are classified as non-narcotic analgesics.2 Benzazo-
conformations are different, and their geometry depends on the
cines have been shown to have antitumor activity3 and also can
N-substituent and on the localization of benzene rings. These
be effective against the HIV virus.4
molecules can adopt the BC, twist−boat, boat, and chair
forms.9 Conformational processes in 2,5-benzoxazocine de-
rivatives studied by Glaser showed that nefopan adopts only the
boat−boat (BB) and twist−chair−chair (TCC) states.10
In the present investigation, the conformational behavior of
benzazocine derivatives 1−3 (Scheme 1) has been described.
One of the main methods used for studying the conforma-
tional behavior of cyclic chemical systems is the variable-
temperature (VT) NMR spectroscopy combined with
prediction of NMR parameters derived from the computation-
ally generated conformers using the -gauge invariant atomic
orbitals-density functional theory (GIAO-DFT) calculations.
Azacyclooctane is the simplest eight-membered ring which
contains the nitrogen atom and conformational studies by the
dynamic 13C NMR showed that azacyclooctane adopts the
boat−chair (BC) and crown conformations in solution.
Differences in the energies between the BC and crown
conformers is ΔE = 5 kJ mol−1 and the barrier of
interconversion is ΔG⧧ = 44 kJ mol−1.5 For the BC
conformation, the barrier for the ring inversion, which is
equal ΔG⧧ = 31 kJ mol−1, was also established.5 The
dominating BC conformation was observed for the N-methyl
and N-tosyl derivatives.6 Favored conformations for benzazo-
cinone derivatives studied with VT NMR are the twist−boat−
chair, BC, and twist−boat conformations. The energy barriers
Scheme 1. Structure of the Investigating Compounds with
a
the Numbering Scheme
a
The numbering does not correspond to the IUPAC nomenclature.
This is done for the sake of better comparability of the systems.
Received: July 21, 2015
© XXXX American Chemical Society
A
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The preferred ground-state conformations in the solution were
explored with the dynamic 1H and 13C NMR spectroscopy and
by molecular modeling methods carried out at the density
functional theory (DFT) level.
two different spatial arrangements of the nitrogen atom, suffix
(a) or (b) is added to the descriptor of the conformation (the
former corresponds to the substitution of the carbon atom with
its lower number).
Dynamic NMR Studies and Conformational Processes.
All 1H NMR signals of 1a−c become broadened with
decreasing temperature. Their coalescences are observed at
180 K for 1a, in the range of 220−200 K for 1b, and for the
compound with the isopropyl substituent at the nitrogen atom
at 240−200 K (Figure 1, Supporting Information Figures S25
and S27). The signals become sharp below the coalescence
temperature only for the N-alkylated compounds, and in the
case of 1a the signals were still broaden at these temperatures.
The changes in line shapes of the NMR signals are also
observed between 300 and 170 K in the 13C NMR spectra of
1a,b (Supporting Information Figures S26 and S28). Lowering
the temperature causes broadening of all carbon signals. 13C
spectra of 1c show sharp signals throughout the range of
temperatures, with the exception of the signal from carbons C-
12 and C-13 (δ = 22.6 ppm at 300 K), which split into two
signals below 200 K (Figure 2). The assignment of the proton
and carbon signals was carried out using the COSY, HSQC,
and HMBC spectra recorded at 300 K and at the lowest
temperature of the temperature-dependent measurements.
The data above can be interpreted as follows: the molecules
are frozen in their chiral ground-state conformations at 170 K.
The racemization of the chiral eight-membered ring, during
which hydrogen atoms in methylene groups interconvert their
stereochemical positions, occurs on raising the temperature.
Furthermore, another conformational process for 1a and 1b,
namely the interconversion between two different conforma-
RESULTS AND DISCUSSION
■
Synthesis. All isomers of benzazocines were synthesized by
the reduction of appropriate benzazocinones with lithium
aluminum hydride in ethyl ether. Lactams were obtained by the
Schmidt reaction of a ketone with sodium azide in the acidic
condition.7a Their N-alkyl derivatives were prepared by the
reaction of lactams with methyl iodide or isopropyl bromide
(4) in the presence of sodium hydride in the DMF solution.
The N-isopropyl derivatives (5,6) were synthesized according
to the procedure described by Johenstone.11
Nomenclature of Conformers. The conformational
terminology for the medium-sized rings proposed by
Hendrickson is used throughout the paper.12 For the parent
hydrocarbon, cis-cyclooctene, two conformers BC and BB were
found.13 However, replacement of the methylene group at C-1
or C-6 by nitrogen in the BC conformer of the carbocyclic ring
leads to two different conformations (Scheme 2). The same is
Scheme 2. BC Conformations of cis-Cyclooctene and
Hexahydroazocine
1
tions, can also be considered, but in neither H nor 13C NMR
spectra the presence of the second conformer could be
detected.
true for the bezoannulated analogues 1−3 and for other
conformations of the eight membered-ring. To distinguish the
1
Figure 1. Temperature dependence of H NMR spectra of 1c in CD2Cl2 (300−170 K).
B
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Figure 2. Temperature dependence of 13C NMR spectra of 1c in CD2Cl2 (300−170 K).
1
Figure 3. Experimental (left) and fitted (right) line shapes of the H6 proton along with the calculated rates (s−1) obtained from the H DNMR
measurements for 1a in CD2Cl2.
Table 1. Experimental Barriers for Dynamic Processes (kJ mol−1) in Molecules 1−3 from DNMR
compound
1a
51
1b
45
1c
46
2a
44
2b
43
2c
3a
3b
3c
inversion barrier
2
2
2
2
1
−
major
45
minor
49
major
42
major
48
minor
52 1
2
5
1
2
interconversion
barrier
major→minor 43
1
major→minor 43
1
minor→major 42
1
minor→major 43
1
The estimation of free energy barriers for the observed ring
inversion processes is illustrated in Figure 3 where the
temperature dependence of the H6 signal with the rate
constant is shown. The free enthalpy of activation is calculated
based on the Eyring equation and are ΔG⧧= 51, 45, and 46 kJ
mol−1 for 1a, 1b, and 1c, respectively. The values of the energy
C
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Figure 4. 1H and 13C NMR spectra of two conformers of 3a in the CD2Cl2 solution at 180 K. The assignments of the signals from the major and
minor conformers are marked in red and blue, respectively.
1
Figure 5. H and 13C NMR spectra of two conformers of 3c in CD2Cl2 at 180 K. The assignments of the signals from the major and minor
conformers are marked in red and blue, respectively.
barriers of conformational processes for the investigated
hexahydrobenzazocines are summarized in Table 1.
to be seen in the NMR spectra at these temperatures. This is in
contrast to 2b for which the energy difference between two
conformers is sufficiently low resulting in the observance the
signals in both the 1H and 13C NMR spectra at 170 K. The split
Coalescence processes are observed in hexahydrobenzo[c]-
1
azocines 2 in both H and 13C NMR spectra. Changes in the
1
line shapes are seen for all signals. The signals of 2a and 2c are
still broaden in the NMR spectra at the lowest temperature.
This is in contrast to those of 2b, for which sharp and well-
separated signals are seen at 170 K (Supporting Information
Figures S31−S36). Our interpretation of these observations is
that lowering the temperature reduces the rate of the inversion
of the major conformer of the N-heterocyclic ring in 2’s. This
process is accompanied by a second process which is the
interconversion between two different conformers. The differ-
ence in the energy between the two conformers is too high for
2a and 2c for the NMR signals of the higher energy conformer
in the H spectral signals of the lower populated conformer
reveals that the process of interconversion of the minor
conformer is inhibited. The ratio of the conformers at 170 K is
equal 2:1 (determined from the 1H NMR spectra). The energy
barriers of the eight-membered-ring inversion of 2a,b are
similar, and they are equal to approximately 43−44 kJ mol−1
(Table 1).
1
The line-shapes of the NMR signals in both H and 13C
NMR spectra were monitored for all hexahydrobenzo[d]-
azocines (Supporting Information Figures S37−S42). All
aliphatic carbon resonances are broadened in the spectra
D
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recorded at 300 K, and with the temperature lowering they split
into two nearly equally intense signals in the spectra of 3a and
3c. Only one set of sharp signals is observed for 3b, and there is
no evidence of the existence of the second conformer even at
temperatures lower than 180 K. In contrast to the carbon
spectra, there is a raised baseline in the 1H NMR in the range δ
= 7.33−7.00 and 3.60−1.15 ppm at 180 K, which suggests the
presence of the second conformer. Distribution of the
conformers for compounds 3a and 3c is 1:0.8 (Figures 4 and
5). The multiplet at δ = 1.68 ppm (H-5) of 3a (Supporting
Information Figure S37) in the spectra measured at 300 K splits
into three signals at 180 K, whereas the signal at δ = 1.43 ppm
is a combination of two signals from the H5′-protons of
different conformers. The signals of H5 for the first conformer
are at δ = 1.43 and 1.95 ppm and correlate with the signal at δ =
34.2 ppm in the HSQC spectrum, while for the second one
they are at δ = 1.43 and 1.85 ppm and they connect to the
signal at δ = 33.7 ppm of the HSQC spectrum (Supporting
Information Figure S43). Separate signals of the diastereotopic
protons of both conformers are present in the proton spectra
(i.e., the protons are magnetically nonequivalent). This spectral
feature can be interpreted similarly to that for 2: the inversion
of the ground-state conformation and the interconversion
between two different conformers. A similar situation is
observed in the NMR spectra of 3c (Supporting Information
Figure S44). The energy barriers for the conformational
processes in 3 are summarized in Table 1.
cyclooctene and benzazocines 1 (Supporting Information Table
S1). It is worth noting that the twist−chair (TC) conformation
found in 1a, populated at 6% in the “solvent model”, has not
been found for cis-cyclooctene (Supporting Information Table
S2).
1
The calculated H and 13C spectral NMR parameters of the
lowest-energy BCb of 1 are in good agreement with the
experimental NMR data. The correlation coefficients are 0.9984
and 0.9987 for proton NMR spectra of 1a,c and 1b,
respectively. The largest discrepancy between the calculated
and experimental chemical shifts has not exceeded 0.20 ppm,
with the average difference smaller than 0.08 ppm. Similarly,
close agreement has been found for the 13C NMR chemical
shifts (Supporting Information Tables S11−S14). Thus, the
matching of the calculated and experimental spectra allowed us
to postulate that the conformation observed in the solution for
molecules 1 are the same as the global minimum, i.e., the BCb
conformation, found by molecular modeling. Additional
arguments for validation of the BCb conformation came from
the coupling constants in the proton NMR spectra. Simulation
of the line shapes of the aliphatic signals in the 1H spectrum of
1b at 180 K (using program from the TopSpin package)14
allowed accurate determination of the experimental geminal
and vicinal coupling constants and their comparison with
calculated values (Table 2). The analysis performed for the
Table 2. Comparison of the Values of Coupling Constants
1
Computational Studies. The conformational space of the
molecules of hexahydrobenzazocines was explored using the
DFT with the hybrid B3LYP functional using 6-311G++(d,p)
basis sets in energy window of 40 kJ mol−1. Theoretical
obtained from H NMR spectra (Jexp) and Calculated (Jcalcd
)
using the GIAO/DFT Method for the BCb Conformer of 1b
hydrogen
atom
Jexp (Hz)
Jcalcd (Hz)
1
chemical shifts of H and 13C nuclei were calculated for all
3
3
H3′
2J = 15.1; J = 13.9; 9.0; 5.7; 2J = 13.9; J = 11.4; 8.1; 4.0;
conformers using the DFT-GIAO at the same combination of
functional and basis sets. That the five conformers of 1a have
the population above 1% (Supporting Information Table S2).
Energy difference between two lowest-energy minima is equal
ΔE = 1.22 kJ mol−1 for isolated molecules and ΔE = 0.94 kJ
mol−1 in dichloromethane. However, the population of the first
conformer (BCb) was approximately 15% lower than that of
the BBa. This difference is due to the fact that the free energy
value of the second conformer is less than the first. The
calculations performed for 1b and 1c showed that their
conformational space is not complicated and the global minima
of the BCb are well separated from all other conformers,
leading to the population higher than 90% for the BCb. Three
rotamers were found for the dominant conformer 1c, which
have different energies depending on the position of the
isopropyl substituent at the nitrogen atom. The lowest-energy
conformation adopted by 1 is virtually the same and can be
described as the boat−chair (BCb) (Figure 6). This was
established by comparing the endocyclic dihedral angles of cis-
4.1
2J = 15.1; J = 11.1; 3.2; 0.0; 2J = 13.9; J = 9.8; 4.1; 2.3;
0.0 0.4
2J = 14.8; J = 14.7; 9.0; 3.9; 2J = 13.2; J = 11.2; 8.1; 3.0;
3.2 0.4
2J = 14.8; J = 11.1; 4.3; 4.1; 2J = 13.2; J = 9.8; 3.9; 3.3;
3.0 0.4
2J = 14.8; 3J = 14.7; 11.1; 3.0; 2J = 12.7; 3J = 11.2; 11.1; 3.3;
0.4
3
3
H3″
H4′
H4″
H5′
H5″
3
3
3
3
1.6
1.7
3
3
2J = 14.8; J = 4.3; 4.2; 4.2;
2J = 12.7; J = 6.1; 3.9; 3.0;
3.9
1.8
NMR signals shows that the whole set of coupling constants is
in excellent agreement with the geometry of the global
minimum conformation of 1b found by the DFT calculation.
The small differences between the values of the calculated and
experimental coupling constants may result from the broad-
ening of the signals due at the decreased temperature and
increased viscosity of the solvent.
1
In the H NMR spectra chemical shift of proton H3′ is
observed at the lower frequency when increasing the steric
bulkiness at the nitrogen atom (1a δH3′ = 1.03 ppm, 1b δH3′
=
0.65 ppm, and 1c δH3′ = 0.53 ppm) because of the steric
hindrance forces the H3′ atom above the aromatic ring, thereby
a ring current effect shields atoms H3′.
Our molecular modeling predicted that the lowest-energy
conformation of compound 2 in the solution is the BC form
(Supporting Information Figures S53−S55). In the case of 2a
and 2c the conformers that are preferred are those of the BCa
form, while in 2b this is the BCb conformation. Comparison of
the spectral NMR parameters obtained for the experiments at
the lowest temperature and calculated data for compounds 2a
Figure 6. Lowest-energy conformers BCb of 1a (left), 1b (center),
and 1c (right) as calculated by the DFT methods.
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1
Figure 7. Aliphatic parts of the experimental (above) and fitted (below) H NMR spectra of 3b.
and 2c was not possible; therefore the experimental parameters
extracted from the spectra measured at 300 K can be used
(Supporting Information Tables S15, S16, S21, and S22).
These calculated data were compared with the experimental
chemical shifts both individually and as the Boltzmann-
weighted averages. Based on this comparison it has been
established that the investigated structures are involved in the
fast conformational processes leading to the time-averaged
spectra. The equilibrium of compound 2a contains conformers
BCa and BCb, while 2c contains BCa, BBa, and BCb. In both
2a and 2c the BCa conformation dominates (the remaining
conformers are below 10% and do not introduce significant
changes in this statistical evaluation). The assignment of the
major conformer for 2b was straightforward. The spectra
calculated for the BCb conformers of 2b gave the best
agreement with the experimental data obtained at 170 K
(Supporting Information Tables S17 and S18). Determination
of the minor conformer of 2b was impossible because the set of
NMR signals was incomplete in the spectra due to signal
overlap. Therefore, the calculated shielding constants are
compared with the chemical shifts at 300 K. The best statistical
fit was achieved when the spectral parameters used came from
conformers BCb and BCa (Supporting Information Tables S19
and S20). We conclude that in the NMR spectra at 300 K the
averaged signals from conformations BCb and BCa are
observed.
Conformational modeling showed that both the BCa and
BCb conformations are preferred by compounds 3 (Supporting
Information Figures S56−S58). The geometry optimization
with the solvent effect gives very small differences in the ΔG
between the BCa and BCb forms (ΔG = 0.63, −0.06, and 0.59
kJ mol−1 for 3a, 3b, and 3c, respectively), thus their populations
are very similar (Supporting Information Tables S8−S10). The
spectra calculated for these conformers gave the best agreement
with the experimental chemical shifts of the major conformers
for the BCb form in the case of 3a and 3b and of the minor
conformer for the BCa in 3a (Supporting Information Tables
S23−S25). For compound 3c, both the theoretical and
experimental calculations are consistent, and the major
conformer observed in the NMR spectra adopted the BCa,
while a minor the BCb conformation (Supporting Information
Tables S26 and S27).
chemical shifts and shielding constants of their geminal
protons. For example, the largest difference (above 1 ppm) is
observed for signals H4 of the minor conformer 3a (ΔδH4
=
1.36 ppm) and major 3c (ΔδH4 = 1.43 ppm). We also found
similar values ΔσH4 for the BCa conformations, which is 1.19
and 1.11 for 3a and 3c, respectively. In the case of compound
3b we have additional evidence which allowed the correct
assignment of the conformation BCb in the NMR spectra. This
is the comparison of the geminal and vicinal coupling constants
of the isolated proton signals of 3b in the 1H spectrum with the
predicted values obtained from the GIAO-DFT calculation.
Agreement between these two series is excellent (Figure 7 and
Table 3).
SUMMARY REMARKS
■
The structures and conformations of hexahydrobenzazocines
1−3 were determined by variable-temperature NMR spectros-
Table 3. Comparison of the Values of Geminal and Vicinal
Coupling Constants from Experimental and Calculated by
DFT method Spectra for BC Conformers of 3b
hydrogen atom BCbexp Jexp (Hz) BCbcalcd Jcalcd (Hz) BCacalcd Jcalcd (Hz)
H1″
H6″
H6′
H5″
2JH1″‑H1′ = 14.4
3JH1″‑H2′ = 6.0
3JH1″‑H2″ = 14.4
2JH6″‑H6′ = 13.9
3JH6″‑H5′ = 13.0
3JH6″‑H5″ = 1.9
2JH6′‑H6″ = 13.9
3JH6′‑H5′ = 2.4
3JH6′‑H5″ = 5.1
2JH5″‑H5′ = 13.4
3JH5″‑H4′ = 2.0
3JH5″‑H4″ = 4.5
3JH5″‑H6′ = 5.1
3JH5″‑H6″ = 1.9
2JH5′‑H5″ = 13.4
3JH5′‑H4′ = 11.8
3JH5′‑H4″ = 3.3
3JH5′‑H6′ = 2.4
3JH5′‑H6″ = 13.0
2JH1″‑H1′ = 12.6
3JH1″‑H2′ = 5.5
3JH1″‑H2″ = 11.5
2JH6″‑H6′ = 12.7
3JH6″‑H5′ = 11.2
3JH6″‑H5″ = 2.3
2JH6′‑H6″ = 12.7
3JH6′‑H5′ = 2.2
3JH6′‑H5″ = 5.5
3JH5″‑H4′ = 12.5
3JH5″‑H4′ = 1.5
3JH5″‑H4″ = 4.1
3JH5″‑H6′ = 5.5
3JH5″‑H6″ = 2.3
2JH5′‑H5″ = 12.5
3JH5′‑H4′ = 10.5
3JH5′‑H4″ = 3.0
3JH5′‑H6′ = 2.2
3JH5′‑H6″ = 11.2
2JH1″‑H1′ = 12.8
3JH1″‑H2′ = 14.3
3JH1″‑H2″ = 5.4
2JH6″‑H6′ = 11.8
3JH6″‑H5′ = 11.2
3JH6″‑H5″ = 5.1
2JH6′‑H6″ = 11.8
3JH6′‑H5′ = 5.3
3JH6′‑H5″ = 2.2
3JH5″‑H4′ = 12.1
3JH5″‑H4′ = 4.9
3JH5″‑H4″ = 11.4
3JH5″‑H6′ = 2.2
3JH5″‑H6″ = 5.1
2JH5′‑H5″ = 12.1
3JH5′‑H4′ = 2.1
3JH5′‑H4″ = 3.0
3JH5′‑H6′ = 5.3
3JH5′‑H6″ = 11.2
H5′
Additional validation of the BCa and BCb conformations
comes from the comparison of the differences between
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and 7.17−7.19 (m, 4H, H−Ar), 13C NMR (151 MHz, CDCl3), δ: 20.3
(C-12 and C-13), 26.9 (C-5), 34.2 (C-6), 35.6 (C-4), 47.0 (C-11),
48.9 (C-1), 126.6, 127.6, 128.7, 131.9 (C-7 − C10), 137.7 and 140.6
(C-6a and C-10a); MS m/z = 217 [M+]; HRMS (ESI-TOF) m/z calcd
for C14H20NO 218.1539; found: 218.1553 [M + H]+.
copy and the DFT computations. The calculated data of the
individual conformers and the Boltzmann-weighted averages of
the conformers were compared with the GIAO calculation of
the 1H and 13C NMR chemical shifts and homonulcear
coupling constants JH‑H. The excellent agreement between the
experimental and the predicted data allowed the establishment
of the ground-state conformations in solution for all
investigated compounds. The dynamic NMR was used to
determine the activation energy of the conformational
processes in the N-heterocyclic eight-membered ring.
Conformations of all of the compounds adopt the BC
structures similar to that seen in cis-cyclooctene. The
benzoannulation of the aliphatic ring and the localization of
the nitrogen atom in the core scaffold do not influence their
conformations. The conformation TC (conformer 4−6% of
population) was found for compound 1a. Such a local energy
minimum was not seen in cis-cyclooctene. The N-alkyl
substituent in hexahydrobenzazocine does not change the
geometry of the eight-membered ring.
3-Isopropyl-3,4,5,6-tetrahydro-1H-benzo[d]azocin-2-one (6).
Using 0.35 g (2.5 mmol, 1 equiv) 3,4,5,6-tetrahydro-1H-benzo[d]-
azocin-2-one, 0.45 g (8.0 mmol, 4 equiv) potassium hydroxide and
0.38 mL (4.0 mmol, 2.0 equiv) isopropyl bromide provided 3-
isopropyl-3,4,5,6-tetrahydro-1H-benzo[d]azocin-2-one (0.12 g, 28%)
as a colorless crystals; mp 113−114 °C (cyclohexane) Rf = 0.34
(SiO2//ethyl acetate/petroleum ether (40−60) 5:1); IR (ATR): 3062,
3018, 2974, 2937, 2859, 1620, 1488, 1455, 1419 cm−1; 1H NMR (600
MHz, CDCl2CDCl2, 360 K), δ: 1.00 (d, 6H, 3J = 6.8 Hz, H-12 and H-
3
13), 1.80 (br, 2H, H-5), 2.89 (dd, 2H, 3J = 6.2 Hz, J = 5.3 Hz, H-6),
3.45 (t, 2H, 3J = 5.1 Hz, H-4), 3.68 (br, 2H, H-1), 4.59 (septet, 1H, 3J
3
4
= 6.8 Hz, H-11), 7.07 (dd, 1H, J = 6.5 Hz, J = 2.4 Hz, H-7), 7.11−
7.15 (m, 2H, H-8 and H-9), 7.32 (dd, 1H, 3J = 6.5 Hz, 4J = 2.4 Hz, H-
10), 13C NMR (151 MHz, CDCl2CDCl2, 360 K), δ: 20.0 (C-12 and
C-13), 32.4 (C-5), 36.0 (C-6), 41.5 (C-1), 44.2 (C-4), 45.3 (C-11),
129.7 (C-7), 127.2 and 126.8 (C-8 and C-9), 130.1 (C-10), 136.2 and
140.1 (C-6a and C-10a), 172.2 (C-2); MS m/z = 217 [M+]; Anal.
calcd for C14H19NO: C, 77.38; H, 8.81; N, 6.45; Found: C, 77.30; H,
8.86; N, 6.62.
Only compound 1c does not show the spectral processes
related to the interconversion between two different BCa and
BCb conformers. The activation energy of the racemization of
the ground-state conformation are from 42 to 52 kJ mol−1, and
they are higher than for azacyclooctanes.5 The energy barrier
for the interconversion processes is in the range 42−43 kJ
mol−1.
General Method Synthesis of Benzazocines. To the
suspension of LiAlH4 (2 equiv) in dry ethyl ether lactam (1 equiv)
was added in portions at 0 °C. After the mixture was stirred at 0 °C for
30 min, the reaction was allowed to warm to room temperature and
then heated to reflux for 10 h. After this time, the mixture was cooled
in an ice-bath and quenched by the addition of water and 15% aqueous
NaOH. The inorganic solid was filtered off and washed with ethyl
ether. The ethereal filtrate was dried over potassium hydroxide and
evaporated. The residue was chromatographed on silica gel and
molecular distillated.
EXPERIMENTAL SECTION
■
General Procedures. TLC was carried out on SiO2 and was
visualized by UV light (254 nm) or iodine. Column chromatography
was performed on silica gel 60 (0.040−0.063 mm). Melting points
were uncorrected. IR spectra were recorded by ATR methods. Mass
spectral data were reported in m/z.
1,2,3,4,5,6-Hexahydrobenzo[b]azocine (1a). Using 0.78 g (4.6
mmol, 1 equiv) 3,4,5,6-tetrahydro-1H-benzo[b]azocin-2-one and 0.35
g (9.2 mmol, 2 equiv) LiAlH4 provided compound 1a (0.63 g, 88%) as
a colorless oil: bp 70−75 °C/0.05 mmHg (lit.15 bp 130−150 °C/15
mmHg); Rf = 0.42 (Al2O3//dichloromethane); IR (ATR): 3417, 3336,
Benzazocinones and their N-alkylated derivatives were prepared
according to reported procedures.7a,11
1
3050, 3011, 2926, 2848, 1603, 1493, 1453, 743 cm−1; H NMR (600
1-Isopropyl-3,4,5,6-tetrahydro-1H-benzo[b]azocin-2-one (4).
Using 0.70 g (4.0 mmol, 1 equiv) 3,4,5,6-tetrahydro-1H-benzo[b]-
azocin-2-one, 0.20 g (5.2 mmol, 1,3 equiv) NaH and 0.75 mL (8.0
mmol, 2.0 equiv) isopropyl bromide provided 1-isopropyl-3,4,5,6-
tetrahydro-1H-benzo[b]azocin-2-one (0.66 g, 76%) as a colorless
crystals: mp 73−74 °C (hexane); Rf = 0.43 (SiO2//ethyl acetate); IR
(ATR): 2981, 2962, 2943, 1861, 1637, 1489, 1447, 1394, 1362, 1362,
1342, 1303, 1260, 1126, 1039, 767 cm−1; 1H NMR (600 MHz,
MHz, CD2Cl2), δ: 1.49−1.55 (m, 4H, H-3, H-4), 1.70−1.74 (m, H-5),
2.85 (t, 2H, 3J = 6.4 Hz, H-6), 3.21 (t, 2H, 3J = 5.5 Hz, H-2), 3.79 (br,
3
4
1H, H-1 (NH)), 6.85 (dd, 1H, J = 7.5 Hz; J = 1.3 Hz, H-10), 6.88
(td, 1H, 3J = 7.5 Hz; 4J = 1.3 Hz, H-8), 7.03 (dd, 1H, 3J = 7.5 Hz; 4J =
3
1.6 Hz, H-7), 7.06 (td, 1H, J = 7.5 Hz; 4J = 1.6 Hz, H-9); 13C NMR
(151 MHz, CD2Cl2), δ: 25.4 (C-4), 29.3 (C-3), 3.6 (C-5), 32.2 (C-6),
51.3 (C-2), 122.6 (C-8 and C-10), 127.4 (C-9), 130.9 (C-7), 134.8
(C-6a), 148.2 (C-10a); MS m/z = 161 [M+]; Anal. calcd for C11H15N:
C, 81.94; H, 9.38; N, 8.69; Found: C, 81.99; H, 9.33; N, 8.88.
1-Methyl-1,2,3,4,5,6-hexahydrobenzo[b]azocine (1b). Using 0.47
g (2.5 mmol, 1 equiv) 1-methyl-3,4,5,6-tetrahydro-1H-benzo[b]-
azocin-2-one and 0.19 g (5.0 mmol, 2 equiv) LiAlH4 provided
compound 1b (0.37 g, 86%) as a colorless oil: bp 66 °C/0.05 mmHg
(lit.14 bp 135−145 °C/14 mmHg); Rf = 0.86 (Al2O3//dichloro-
methane); IR (ATR): 3059, 3019, 2919, 2846, 2791, 1492, 1445, 1288,
3
CDCl3), δ: 0.91 (d, 3H, J = 6.8 Hz, H12), 1.33−1.38 (m, 1H, H5′),
3
1.35 (d, 3H, J = 6.8 Hz, H-13), 1.75−1.83 (m, 1H, H4′), 1.82−1.89
(m, 1H, H4″), 1.91 (td, 1H, 3J = 12.1 Hz, 3J = 1.5 Hz, H3′), 2.08−2.13
3
3
3
(m, 1H, H5″), 2.22 (ddd, 1H, J = 12.1 Hz, J = 7.9 Hz, J = 1.2 Hz,
H3″), 2.45 (td, 1H, 3J = 13.3 3J = 1.2 Hz, H6′), 2.73 (dd, 1H, 3J = 13.3
3J = 7.1 Hz, H6″), 4,99 (septet, 1H, 3J = 6.8 Hz, H11), 7.14 (d, 1H, 3J
3
4
= 7.8 Hz, H10), 7.19−7.24 (m, 1H, J = 5.5 Hz; J = 3.1 Hz, H9),
7.27−7.31 (m, 2H, H7/9); 13C NMR (151 MHz, CDCl3), δ: 19.4
(C12), 22.6 (C13), 25.7 (C4), 29.9 (C5), 31.0 (C6), 34.0 (C3), 47.4
(C11), 126.5 (C9), 127.2 (C10), 128.4 (C8), 130.5 (C7), 138.5
(C10a), 142.6 (C6a), 174.3 (C2); MS m/z = 217 [M+]; Anal. calcd for
C14H19NO: C, 77.38; H, 8.81; N, 6.45; Found: C, 77.17; H, 8.80; N,
6.61.
1
1181, 1109, 748 cm−1; H NMR (600 MHz, CD2Cl2), δ: 1.18−1.21
(m, 2H, H-3), 1.60−1.67 (m, 4H, H-4, H-5), 2.74−2.76 (m, 5H, H-2,
3
H-11), 2.75 (t, 2H, J = 5.5 Hz, H-6), 7.02−7.04 and 7.16−7.19 (td,
1H, 3J = 7.6 Hz, 4J = 2.5 Hz and m, 2H; H-8, H-9, H-10), 7.13 (d, 1H,
3J = 7.4 Hz, H-7); 13C NMR (151 MHz, CD2Cl2), δ: 27.5 (C-3), 28.8
(C-4), 32.9 (C-6), 33.0 (C-5), 44.3 (C-11), 62.6 (C-2), 121.7 (C-10),
125.0 and 127.2 (C-8 and C-9), 129.8 (C-7), 142.7 (C-6a), 151.2 (C-
10a); MS m/z = 175 [M+]; HRMS (ESI-TOF) m/z calcd for C12H18N
176.1439; Found: 176.1451 [M + H]+.
2-Isopropyl-1,4,5,6-tetrahydro-2H-benzo[c]azocin-3-one (5).
Using 0.29 g (1.7 mmol, 1 equiv) 1,4,5,6-tetrahydro-2H-benzo[c]-
azocin-3-one, 0.28 g (6.8 mmol, 4 equiv) potassium hydroxide and
0.32 mL (3.4 mmol, 2.0 equiv) isopropyl bromide provided 2-
isopropyl-1,4,5,6-tetrahydro-2H-benzo[c]azocin-3-one (0.11 g, 31%)
as a colorless oil; Rf = 0.34 (SiO2//ethyl acetate); IR (ATR): 3062,
1-Isopropyl-1,2,3,4,5,6-hexahydrobenzo[b]azocine (1c). Using
0.57 g (2.6 mmol, 1 equiv) 1-isopropyl-3,4,5,6-tetrahydro-1H-benzo-
[b]azocin-2-one (4) and 0.20 g (5.2 mmol, 2 equiv) LiAlH4 provided
compound 1c (0.50 g, 94%) as a colorless oil: bp 70−76 °C/0.05
mmHg; Rf = 0.82 (Al2O3//dichloromethane); IR (ATR): 3059, 3019,
1
2969, 2932, 2868, 1631, 1451, 1420, 1363, 1215, 747 cm−1; H NMR
3
(600 MHz, CDCl3), δ: 1.13−1.14 (d, 6H, J = 6.9 Hz, H-12 and H-
13), 2.03 (br, 2H, H-5), 2.66 (t, 2H, 3J = 6.6 Hz, H-4), 2.88 (t, 2H, 3J
= 5.9 Hz, H-6), 4,53 (br s, 2H, H-1), 4,63 (br, 1H, H-11), 7.11−7.12
1
2965, 2917, 2847, 2796, 1491, 1447, 1178, 747, 563 cm−1; H NMR
G
DOI: 10.1021/acs.joc.5b01687
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3
(600 MHz, CD2Cl2), δ: 1.05−1.06 (d, 6H, J = 6.2 Hz, H-12 and H-
13), 1.08−1.11 (m, H-3), 1.58−1.64 (m, 4H, H-4, H-5), 2.79−2.82
(m, 4H, H-2, H-6), 3.28 (septet, 1H, 3J = 6.2 Hz, H-11), 7.06 (td, 1H,
3-Methyl-1,2,3,4,5,6-hexahydrobenzo[d]azocine (3b). Using 0.13
g (0.7 mmol, 1 equiv) 3-methyl-3,4,5,6-tetrahydro-1H-benzo[d]-
azocin-2-one and 0.06 g (1.4 mmol, 2 equiv) LiAlH4 provided
compound 3b (0.09 g, 72%) as a colorless oil: bp 64−66 °C/0.05
mmHg; (lit.17 bp 80−60−62 °C/0.1 mmHg Rf = 0.21 (Al2O3//
petroleum ether (40−50)/ethyl acetate 11:1); IR (ATR): 3060, 3014,
3J = 7.0 Hz, J = 1.6 Hz, H-8), 7.15 (d, 1H, J = 6.3 Hz, H7), 7.16−
7.19 (m, 2H, H8 and H10); 13C NMR (151 MHz, CD2Cl2), δ: 22.6
(C-12 and C-13), 27.2 (C-3), 28.9 (C-4), 33.2 (C-6), 33.5 (C-5), 52.7
(C-11), 56.0 (C-2), 125.0 (C-10), 125.4 (C-8), 127.1 (C-9), 129.4 (C-
7), 145.2 (C-6a), 149.9 (C-10a); MS m/z = 203 [M+]; HRMS (ESI-
TOF) m/z calcd for C14H22N 204.1752; Found: 204.1749 [M + H]+.
1,2,3,4,5,6-Hexahydrobenzo[c]azocine (2a). Using 0.20 g (1.1
mmol, 1 equiv) 1,4,5,6-tetrahydro-2H-benzo[c]azocin-3-one and 0.09
g (2.2 mmol, 2 equiv) LiAlH4 provided compound 2a (0.14 g, 77%) as
a colorless oil: bp 62−64 °C/0.05 mmHg (lit.14 bp 123 °C/15
mmHg); Rf = 0.29 (Al2O3//chloroform/methanol 13:1); IR (ATR):
3409, 3014, 2925, 2850, 2799, 2756, 1597, 1472, 1449, 1351, 762
4
3
1
2926, 2839, 2791, 1491, 1464, 1375, 1310, 1117, 759 cm−1; H NMR
3
(600 MHz, CDCl3), δ: 1.71−1.75 (m, 2H, H-5), 2.32 (t, 2H, J = 5.6
3
3
Hz, H-4), 2.41 (s, 3H, H-11), 2.76 (dd, 2H, J = 6.7 Hz, J = 4.1 Hz,
3
3
H-2), 2.83 (t, 2H, J = 6.5 Hz, H-6), 2.87 (t, 2H, J = 5.3 Hz, H-1),
7.09−7.12 (m, 2H, H-7 and H-10), 7.14−7.18 (m, 2H, H-8 and H-9);
13C NMR (151 MHz, CDCl3), δ: 31.0 (C-6), 31.6 (C-5), 34.7 (C-1),
47.2 (C-11), 54.4 (C-4), 61.4 (C-2), 126.4 and 126.8 (C-8 and C-9),
128.9 (C-7), 129.2 (C-10), 140.4 (C-10a), 140.5 (C-6a); MS m/z =
175 [M+]; HRMS (ESI-TOF) m/z calcd for C12H18N 176.1439;
Found: 176.1449 [M + H]+.
cm−1; H NMR (600 MHz, CD2Cl2), δ: 1.50−1.54 (m, 2H, H-4),
1
1.67−1.71 (m, 2H, H-5), 2.30 (br s, 1H, H-2 (NH)), 2.66 (t, 3J = 4.8
3-Isopropyl-1,2,3,4,5,6-hexahydrobenzo[d]azocine (3c). Using
0.11 g (0.5 mmol, 1 equiv) 3-isopropyl-3,4,5,6-tetrahydro-1H-benzo-
[d]azocin-2-one (6) and 0.04 g (1.0 mmol, 2 equiv) LiAlH4 provided
compound 3c (0.07 g, 70%) as a colorless oil: bp 70−72 °C/0.05
mmHg; Rf = 0.73 (Al2O3//petroleum ether (40−50)/ethyl acetate
5:1); IR (ATR): 3060, 3014, 2960, 2927, 2865, 2841, 2804, 1490,
1381, 1359, 1166, 757 cm−1; 1H NMR (600 MHz, CDCl3), δ: 0.94 (d,
3
Hz, H-3), 2.85 (t, 2H, J = 6.3 Hz, H-6), 3.87 (s, 2H, H-1), 7,11 (dd,
3
4
1H, J = 6.7 Hz; J = 1.4 Hz, H-7), 7.16−7.20 (m, 3H, H-8, H-9, H-
10); 13C NMR (151 MHz, CD2Cl2), δ: 29.1 (C-4), 31.3 (C-5), 32.4
(C-6), 46.7 (C-3), 49.7 (C-1), 126.9 and 127.9 (C-8 and C-9), 129.6
and 129.9 (C7 and C10), 139.6 (C-6a), 142.0 (C-10a); MS m/z = 161
[M+]; HRMS (ESI-TOF) m/z calcd for C11H16N 162.1283; Found:
162.1296 [M + H]+.
3
3
6H, J = 6.6 Hz, H-12 and H-13), 1.53 (br q, 2H, J = 5.5 Hz, H-5),
3
3
2.15 (t, 2H, J = 5.0 Hz, H-4), 2.71 (t, 2H, J = 4.7 Hz, H-2), 2.81−
2-Methyl-1,2,3,4,5,6-hexahydrobenzo[c]azocine (2b). Using 0.17
g (0.9 mmol, 1 equiv) 2-methyl-1,4,5,6-tetrahydro-2H-benzo[c]azocin-
3-one and 0.07 g (1.8 mmol, 2 equiv) LiAlH4 provided compound 2b
(0.13 g, 81%) as a colorless oil: bp 66 °C/0.05 mmHg (lit.16 bp 114−
116.5 °C/4.5−5.4 mmHg); Rf = 0.25 (Al2O3//chloroform); IR
(ATR): 3060, 2922, 2848, 2790, 1472, 1446, 1043, 751, 717 cm−1; 1H
NMR (600 MHz, CD2Cl2), δ: 1.54−1.58 (m, 2H, H-4), 1.65−1.69 (m,
H-5), 2.32 (s, 3H, H-11), 2.41 (t, 2H, 3J = 5.0 Hz, H-3), 2.83 (t, 2H, 3J
= 6.2 Hz, H-6), 3.73 (s, 2H, H-1), 7.12−7.13 (m, 2H, H-7 and H-10),
7.16 (td, 1H, 3J = 7.2 Hz, 4J = 1.5 Hz, H-9), 7.19 (td, 1H, 3J = 7.2 Hz,
4J = 1.8 Hz, H-8); 13C NMR (151 MHz, CD2Cl2), δ: 23.9 (C-4), 31.3
(C-5), 33.3 (C-6), 43.7 (C-11), 54.5 (C-3), 56.3 (C-1), 126.1 (C-9),
128.0 (C-9), 129.9 and 131.2 (C-7 and C-10), 135.2 (C-10a), 142.6
(C-6a); MS m/z = 175 [M+]; HRMS (ESI-TOF) m/z calcd for
C12H18N 176.1439; Found: 176.1449 [M + H]+.
3
4
2.88 (m, 5H, H1, H-6 and H-11), 7.06 (dd, 1H, J = 6.7 Hz, J = 2.3
Hz, H-10), 7.09 (dd, 1H, 3J = 6.5 Hz, 4J = 2.5 Hz, H-7), 7.11−7.15 (m,
2H, H-8 and H-9); 13C NMR (151 MHz, CDCl3), δ: 18.6 (C-12 and
C-13), 30.6 (C-6), 33.5 (C-5), 36.6 (C-1), 47.1 (C-4), 56.0 (C-2 and
C-11), 126.0 and 126.4 (C-8 and C-9), 128.8 (C-7), 129.1 (C-10),
141.1 and 141.2 (C-6a and C-10a); MS m/z = 203 [M+]; HRMS (ESI-
TOF) m/z calcd for C14H22N 204.1752; Found: 204.1750 [M + H]+.
1
NMR Measurements. H and 13C NMR spectra were recorded at
600.26/150.94 MHz for 5 mg/mL solutions in CD2Cl2 for low-
temperature measurements. The 1H and 13C chemical shifts were
referenced to TMS as the internal standard. Temperature calibrations
were performed using the temperature dependency of the observed
chemical-shift separation between the OH resonances and CHn
resonances in methanol for low temperature. The uncertainty in the
temperatures was estimated from the calibration curve to be 1 K.
The COSY, HSQC, and HMBC spectra were recorded using standard
procedures and were used to confirm the NMR peak assignments.
Calculation of Energy Barriers. For the estimation of the energy
barrier for the inversion process, line shape simulation has been
performed using the dynamic 1H NMR (DNMR) program of the
TopSpin package,14 which allowed the calculation of rate constants.
Using the Eyring equation, the free enthalpy of activation (ΔG⧧) was
calculated (Supporting Information Figures S45−S52). Based on the
2-Isopropyl-1,2,3,4,5,6-hexahydrobenzo[c]azocine (2c). Using 90
mg (0.4 mmol, 1 equiv) 2-isopropyl-1,4,5,6-tetrahydro-2H-benzo[c]-
azocin-3-one (5) and 0.30 mg (0.8 mmol, 2 equiv) LiAlH4 provided
compound 2c (50 mg, 60%) as a colorless oil: bp 72−74 °C/0.1
mmHg; Rf = 0.64 (Al2O3//ethyl acetate); IR (ATR): 3060, 3016,
2920, 2849, 2803, 1493, 1448, 1360, 1186, 1161, 752, 725 cm−1; H
1
3
NMR (600 MHz, CD2Cl2), δ: 1.11−1.12 (d, 6H, J = 6.5 Hz, H-12
3
and H-13), 1.41−1.45 (m, 2H, H-4), 1.66 (q, 2H, J = 6.3 Hz, H-5),
2.67 (t, 2H, 3J = 5.2 Hz, H-3), 2.92−2.98 (m, 3H, H-6 and H-11), 3.75
equations described by Strondstom,18 the energetic barrier of
̈
(s, 2H, H-1), 7.06 (dd, 1H, 3J = 7.0 Hz, J = 2.0 Hz, H-7), 7.12−7.16
4
interconversion process between two different conformers were
calculated.
(m, 3H, H-8, H-9, H-10); 13C NMR (151 MHz, CD2Cl2), δ: 19.8 (C-
12 and C-13), 25.0 (C-4), 30.7 (C-5), 32.1 (C-6), 51.0 (C-3), 53.5 (C-
1), 55.0 (C-11), 126.3 and 127.5 (C-9 and C-10), 130.0 and 130.3 (C-
7 and C-10), 139.0 (C-10a), 141.7 (C-6a); MS m/z = 203 [M+];
HRMS (ESI-TOF) m/z calcd for C14H22N 204.1752; Found:
204.1746 [M + H]+.
Computational Methods. The conformational search of
compounds 1−3 was explored using the molecular mechanics MM
+.19 For the found energy minima, further geometry optimization with
the Gaussian 09 program20 using DFT with the hybrid B3LYP
functional and 6-311G++(d,p) basis set was performed. Energy
minima were confirmed by vibrational analysis, which did not show
imaginary frequencies and were not scaled. The same combination of
functional and basis set was used for 1H and 13C shielding and
coupling constants calculation, which were done with GIAO methods
and IEF-PCM model solvent (dichloromethane).21 The isotropic
shielding constants were scaled into chemical shifts using the equation
δcalcd = (σcalcd − b)/a from the linear regression of the calculated
isotropic shielding (σcalcd) against the experimental chemical shift
values (δexptl).22 The calculated GIAO isotropic chemical shifts and
experimental data for proton and carbon nuclei are presented in
Supporting Information Tables S11−S27. The δ values obtained from
proton and carbon spectra were compared with calculated chemical
shifts. Agreement between the calculated and experimental chemical
shifts was evaluated on the basis of the following parameters: the
1,2,3,4,5,6-Hexahydrobenzo[d]azocine (3a). Using 0.25 g (1.4
mmol, 1 equiv) 3,4,5,6-tetrahydro-1H-benzo[d]azocin-2-one and 0.11
g (2.8 mmol, 2 equiv) LiAlH4 provided compound 3a (0.11 g, 48%) as
a colorless oil: bp 68 °C/0.1 mmHg (lit.14 bp 80−84 °C/1 mmHg); Rf
= 0.44 (Al2O3//dichloromethane/methanol 11:1); IR (ATR): 3400,
3059, 3015, 2934, 2784, 2727, 2692, 2494, 1583, 1475, 774, 762 cm−1;
1H NMR (600 MHz, CD2Cl2), δ: 1.66−1.70 (m, 2H, H-5), 1.79 (br s,
1H, H-3 (NH)), 2.58 (t, 2H, 3J = 5.7 Hz, H-4), 2.77−2.81 (m, 4H, H-
3
1 and H-2), 2.91 (t, 2H, J = 5.5 Hz, H-2), 7.06−7.09 (m, 1H, H-7),
7.10−7.14 (m, 3H, H-8, H-9 and H-10); 13C NMR (151 MHz,
CD2Cl2), δ: 31.7 (C-6), 34.8 (C-5), 36.0 (C-1), 47.6 (C-4), 52.5 (C-
2), 126.6 and 126.8 (C-8 and C-9), 129.4 and 129.5 (C-7 and C-10),
140.6 (C-10a), 142.0 (C-6a); MS m/z = 161 [M+]; HRMS (ESI-TOF)
m/z calcd for C11H16N 162.1283; Found: 162.1303 [M + H]+.
H
DOI: 10.1021/acs.joc.5b01687
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The Journal of Organic Chemistry
Article
maximum (|Δδ|max) and average (|Δδ|avg) value of the modules of
chemical shifts difference and correlation coefficient r2.
(6) (a) Lambert, J. B.; Khan, S. A. J. Org. Chem. 1975, 40, 369−374.
(b) Cameron, S. T.; Scheeren, H. W. J. Chem. Soc., Chem. Commun.
1977, 939−941.
́ ́
(7) (a) Witosinska, A.; Musielak, B.; Serda, P.; Owinska, M.; Rys, B. J.
ASSOCIATED CONTENT
■
Org. Chem. 2012, 77, 9784−9794. (b) King, F. D.; Aliev, A. E.;
Caddick, S.; Tocher, D. A.; Courtier-Murias, D. Org. Biomol. Chem.
2009, 7, 167−177. (c) Hassner, A.; Amit, B.; Marks, V.; Gottlieb, H. E.
Eur. J. Org. Chem. 2006, 2006, 1256−1261.
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01687.
(8) Qadir, M.; Cobb, J.; Sheldrake, P. W.; Whittall, N.; White, A. J.
P.; Hii, K. K.; Horton, P. N.; Hursthouse, M. B. J. Org. Chem. 2005, 70,
1552−1557.
1H and 13C NMR spectra of compounds 1−6 at 300 K,
VT-NMR spectra (Figures S25−S42). HSQC spectrum
of molecules 3a and 3b (Figures S43 and S44). Fitted
line shapes of the protons, the calculated rate constants
from the DNMR (Figures S45−S52). The computed
structures of 2a−c and 3a−c (Figures S53−S58). The
values of torsion angles of conformers of cis-cyclooctene
(Table S1). Electronic energies, enthalpies, free energies,
torsion angles of investigated compounds (Tables S2−
S10). Comparison of experimental and calculated 1H and
13C chemical shifts (Tables S11−S27). Total electronic
energies, and atomic coordinates from DFT calculations
(Tables S28−S69) (PDF)
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: rys@chemia.uj.edu.pl.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(18) Sandstrom, J. Dynamic NMR Spectroscopy; Academic Press,
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■
London, 1982.
This study was supported by the Funds for the Statutory
Activity of the Faculty of Chemistry of the Jagiellonian
University and in part by the PL-Grid Infrastructure. The
research was carried out with the equipment purchased thanks
to the financial support of the European Regional Development
Fund within the framework of the Polish Innovation Economy
Operational Program (contract no. POIG.02.01.00-12-023/08).
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DOI: 10.1021/acs.joc.5b01687
J. Org. Chem. XXXX, XXX, XXX−XXX