Electronic Donation or Steric Contraction: A Spectroscopic and Structural Analysis of Medium-Sized Constrained Rings for Potential Long-Range Hyperconjugation

Article abstract of DOI:10.1021/acs.joc.9b00979

Herein, we report the ¹J_CH analyses, natural bond orbital analyses, and X-ray crystal structures of a number of C, O, and N constrained tricyclic cycles. These experiments provide access into the nature of the apparent Perlin effect previously reported in constrained tricyclic cycles, as well as evidence suggesting both steric contraction and long-range hyperconjugation account for the observed ¹J_CH perturbations. We report a true Perlin effect of 10.9 Hz in an azocane and large steric effect resulting in ?¹J_C-H = 10.9 Hz in a cyclooctane.

Full text of DOI:10.1021/acs.joc.9b00979

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Article
ELECTRONIC DONATION OR STERIC CONTRACTION: A SPECTROSCOPIC
AND STRUCTURAL ANALYSIS OF MEDIUM-SIZED CONSTRAINED
RINGS FOR POTENTIAL LONG- RANGE HYPERCONJUGATION
Robert Lee, Bryan Bashrum, Ethan C. Cagle, Jillian Walters, Jake Massey, Monica Zanghi,
Carolyn Birchfield, David French, Jessica Joy, Gabriel dos Passos Gomes, and Paul Andrew Wiget
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00979 • Publication Date (Web): 24 Jul 2019
Downloaded from pubs.acs.org on July 27, 2019
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ELECTRONIC DONATION OR STERIC CONTRACTION: A SPECTROSCOPIC AND STRUCTURAL ANALYSIS OF
MEDIUM-SIZED CONSTRAINED RINGS FOR POTENTIAL LONG-RANGE HYPERCONJUGATION
Robert Lee§, Bryan Bashrum§, Ethan C. Cagle, Jillian Walters§, Jake Massey≠, Monica Zanghi≠, Carolyn Birchfield≠, David
French, Jessica Joy≠, Gabriel dos Passos Gomes¥,a,Paul A. Wiget§*
§Department of Chemistry and Biochemistry, Samford University, 800 Lakeshore Blvd., Birmingham, Al 35229
≠Department of Biological and Environmental Sciences, Samford University, Birmingham, Al
¥Department of Chemistry & Biochemistry, Florida State University, Tallahassee, Fl
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aPresent address: Department of Chemistry, University of Toronto, Toronto, ON, Canada,
Department of Chemistry, The University of Alabama at Birmingham, Birmingham, Al
*pwiget@samford.edu
Keywords: Perlin effect, stereoelectronic effect, nmr, C-H coupling constant, conformational analysis
Abstract.
Herein we report the 1JCH analyses, Natural Bond Orbital analyses, and X-Ray crystal structures
of a number of C, O, and N constrained tricyclic cycles. These experiments provide access into
the nature of the apparent Perlin Effect previously reported in constrained tricyclic cycles, as well
as evidence suggesting both steric contraction and long-range hyperconjugation account for the
1
observed JCH perturbations. We report a true Perlin Effect of 10.9 Hz in an azocane and large
steric effect resulting in 1JC-H = 10.9 Hz in a cyclooctane.
Introduction.
Remote hyperconjugation is a well-established means of controlling stereo- and regioselectivity in
organic reactions, as well as having profound effects on reaction kinetics. These effects are
typically quantified experimentally by calculating G in dynamic systems from Keq, or evaluated
computationally via Natural Bond Orbital (NBO) analyses.1 We recently reported the appearance
of long-range hyperconjugation five bonds away from the donor atom as evaluated by NBO
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analysis in a semi-rigid oxocane system (1, Figure 1a) and postulated this donation was the source
of apparently anomalous experimental 1JC-H scalar couplings observed therein.2 The perturbation
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of the difference between geminal JC-H scalar couplings (1JC-H) due to remote electronic
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donations is known as a Perlin Effect (PE).3 Examples of PEs and the hyperconjugative donations
Figure 1. Examples of Perlin Effects.1-3 General
numbering scheme used throughout is provided
in a for 1.
associated with them are given in Figure 1.
Note, 1 appears to exhibit a combination of factors such as an anomeric-like donation (Figure 1,
b), and the chemical space between an cyclohexanone and a cyclohexane (Figure 1, c & d). Thus,
our prior report was of the discovery of the largest Perlin Effect at a non-anomeric position known
to-date. This claim was reevaluated by Salome and Tormena in this journal.4a Their computational
work suggested the perturbation of scalar couplings was due to steric contraction of the axial C-H
bond as opposed to electronic donation into the * of the remote equatorial C-H as proposed in
our work. Though this is not an uncommon perspective on such phenomena,4b we were surprised
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as we calculated and reported a 0.73 kcal/mol stabilization energy in that compound associated
with n(O)*(C5-Heq) NBO, with concomitant C5-Heq bond elongation and increase in p
character, supporting our claim at the time (see Figure 2, boxed).
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s *C—H
s *C—H
O
R
s *C—H
s *C—H
O
s *C—H
s *C—H
amines 4-6
N
O
n
1
r (Drdel)[Å]
%p
O
O
C-Heq
C-Hax
1.0940 (-0.00046) 78.2
ethers 1’, 2 & 3
orbital alignment
1.0878
77.3
electronegativty
and sterics
Estab (DEdel
)
0.73 (0.630)
[kcal/mol]
C
H
C
R1
s *C—H
s *C—H
R2
R2
S
H
s *C—H
s *C—H
s *C—H
C
R1
s *C—H
O
O
O
sulfide 1-S
size and polarization
cyclooctane 7
control group
alkene 8
bound electron donors
Figure 2. Proposed compounds for this study, and the stereoelectronic effects they target.
We hypothesized that synthesizing a series of analogs whereby the donor functionality is modified
to affect the electronegativity, polorizability, orientation and/or conformation compared to the
donor/accepter system in 1, would provide greater insight into the interplay between the competing
theories presented on the origins of these Perlin Effects (see Figure 2). Herein we discuss the
synthesis, experimental NMR, conformational analysis and Natural Bond Order (NBO) analysis
of a number of synthesized constrained rings in order to probe the extent of donation. We also
1
compare our experimental JC-H values with the computational values provided by our afore-
mentioned colleagues.
Results and Discussion.
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We successfully synthesized the tricyclic analogs of 1 seen in TABLE 1 via [3+4] cycloaddition
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8
“boat-like”
“chair-like”
conformation
Y
conformation
Y
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n
O
O
n
Compound
Y
n
1
1'
2
3
4
5
O
O
O
1
1
0
2
1
1
O
NBoc
NCO2Et
6
7
8
NSO2Ph
CH2
1
1
1
CC(CH3)2
Table 1. [3+4]-cycloadducts synthesized
for this study.
reactions (see Experimental).
All protons and carbons were unambiguously assigned via H, 13C, HSQC, HMBC and NOESY
NMR for these compounds. The desmethyl analog of 1, compound 1’, was synthesized to compare
our data with the 1JC-H values obtained by Salome and to see if the steric bulk of the two methyl
1
1
groups on furan incorporated into the two prior publications affected the C5-H JC-H values.
Compounds 2 and 3 were synthesized to compare how orbital misalignment affected the data. In
order to compare N versus O donors, we synthesized compounds 4-6 anticipating a means of
deprotection affording the free amine. However, ring-opening appeared to be the major product
upon analyses of the acid-, base-, or nucleophile-mediated deprotection attempts of 4 and 5. This
process is under further investigation and will be reported in time. Recognizing sulfonamides do
not share the same resonance delocalization as amides, compound 6 provided access to a system
in which the lone pair on nitrogen was properly positioned for through-space donation, while
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maintaining the symmetry of the system not present in 4 and 5. However, concerns over the loss
of donation due to inductive or steric effects of the sulfonyl moiety, led us to reduce 5 with LiAlH4
(See Scheme 1). By controlling the equivalents, we were able to produce carboxyethyl
aminoalcohol 9 and free aminoalcohol 10 in 27% and 12% yield respectively in separate reactions.
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Scheme 1. Reduction of carboxyethyl azocane
Compounds 7 lacks a p-orbital donor and is thus a negative electronic control and a positive steric
control. Alkene 8 allows for a comparison of donations in protected azocanes 4 and 5 due to
their strong amide resonance contributions. Synthesis of alkene 8 thus provides possible electronic
or steric controls to explore the possibility of  donations into C5-Heq * or steric effects upon C5-
Hax. Our efforts to synthesize thiocane donors such as 1-S were unsuccessful. Attempts to use
thiophene (Figure 2, R1=R2=H) and 2,5-dimethyl thiophene (R1=Me, R2 = H) as the 4-
component in the cycloaddition reaction produced what appeared to be the electrophilic aromatic
substitution product, a competing process in such reactions.5 We sought to circumvent this process
by using 2,5-diphenylisobenzothiophene6 (R1=Ph, R2 = C4H4) and 2,3,4,5-tetramethylthiophene7
(R1=R2=Me) as 4- components, for they lack the  and  protons necessary for rearomatization.
The isobenzothiophene was unreactive and the tetramethylthiophene compound consistently
decomposed. Thus, only computational data will be discussed for 1-S (R1 = R2 = H) as our synthetic
efforts continue. All compounds synthesized are prone to rapid ring-opening via a Grob-like
fragmentation as we previously reported in the parent oxocane between the ketone  and 
carbons.8
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In our efforts, it became clear the specific pulse sequence utilized played a larger role in
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obtaining accurate JC-H values than the field strength. In our prior publication, we obtained our
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data using a standard HSQC pulse sequence with the decoupler turned off, on a 700 MHz
instrument; a more powerful magnet than used by our colleagues. This resulted in somewhat poor
spectral resolution (likely due to accidental isochrony) and the magnitude of the pseudoaxial 1JC-
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had to be extrapolated from the spectrum as discussed in the supporting information for that
H
1
publication. In order to obtain more accurate experimental JC-H values, we utilized the Perfect-
CLIP HSQC pulse sequence developed by Parella and performed the experiments on either a
500MHz, 600MHz, 700MHz or 850MHz instrument. This pulse sequence provides “pure in-phase
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cross peaks with respect to JCH and JHH, irrespective of the experiment delay optimization. In
addition, peak volumes are not attenuated by the influence of JHH, rendering practical issues such
as phase correction, multiplet analysis, and signal integration more appropriate.”9
Upon analysis of 1’ we obtained 1JC-H value of 9.0Hz; quite close to 7.8Hz in the methyl
analog 1. These values represent the largest 1JC-H values for a methylene remote to a donor atom
to our knowledge at the time. Table 2 provides a comparison of our experimental 1JC-H values and
those
calculated
for
analogous
compounds
by
Salome.
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Experimental
equitorial
1JC-H (Hz) 1JC-H (Hz)
Calculated4
equitorial
Compound
axial
axial
D 1J C-H
D 1J C-H
1JC-H (Hz) 1JC-H (Hz)
7
8
9
14.1
14.1
-
1
133.0
133.8
125.3
124.8
7.8
9.0
7.5
138.8
138.8
124.7
124.7
1'
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2a
140.4
132.9
-
-
3a
130.2
125.5
132.6
133.3
131.0
134.5
122.2
133.0
121.6
124.9
129.2
124.3
129.0
123.6
116.4
122.1
-
-
8.6
0.6
3.4
9.0
2.0
10.9
5.8
10.9
-
4
5
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8
9
10
134.2
134.2
134.2
128.9
-
126.6
126.6
126.6
128.4
-
7.6
7.6
7.6
0.5
-
-
-
-
7.3
133.7
126.4
Table 2. Comparison of experimental C5-H coupling constants and apparent Perlin Effects
(1JCH) and those calculated for analogous constrained 8-membered rings by Salome.4 aThe
protons of C4 on 2 and C6 on 3 are not aligned with the donor oxygen – axial here is defined as cis
to oxygen and equatorial is trans to oxygen.
Our data suggests the axial proton in proximity to the donor (C5-Hax) is compressed due to the
larger 1JC-H values in all substrates supporting much of Salome’s claim. The PEs of 4 and 5 more
closely resemble methylene 7 suggesting the C5 protons are sufficiently removed from both steric
compression or long-range donation. Alkene 8 shows a large  1JC-H of 10.9 Hz suggesting a large
degree of steric constriction in the C5 axial proton to 1.869 Å with concomitant C5-Heq bond
elongation of 1.0964 Å (vida infra). These bond lengths suggest a slightly greater influence of
steric strain than plausible donation comparative to 1’. Observing sulfonamide 6 the equatorial C-
H bond is longer (1JC-Heq = 124.3 Hz) than calculated in either the N-phenyl analog (1JC-Heq = 126.6
Hz) or the unsubstituted azocane (1JC-Heq = 126.4 Hz), presumably due to remote hyperconjugation
(vida infra). Additionally, when comparing synthesized aminoalcohol 10 with the azocane
calculations, both the degree of C5-Hax compression and C5-Heq elongation are not well modeled
when compared with the experimental values of 1JC-H. Concerns over comparing the aminoketone
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6 to aminoalcohol 10 led us to obtain 1JC-H values for cyclohexanol and cyclohexanone (See
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8
C5-Hax
129.6
C5-Heq
129.8
compound
C6H11OH
C6H10O
129.8
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Table 3. Comparison of cyclohexanol
(C6H11OH) and cyclohexanone (C6H10O)
in CD2Cl2 @ 298K.
Table 3).
The similarity between cyclohexanol and cyclohexanone at C5 suggests this modification
has little impact on the PEs at this position, affording additional confidence in this interpretation
of the data for 6 and 10. Compound 7 shows little PE at all, and exhibits 1JC-H values dissimilar to
cyclohexanone or any other 8-membered cycle we synthesized, save carboxyethyl azocane 5. The
similarity between 5 and 7 implies a similar electronic environment surrounding the methylenes
in both compounds. Alkene 8 exhibits the largest 1JC-Hax (134.5 Hz) of all the 8-membered cycles
suggesting a large degree of compression. As we are seeking to ascertain the cause of the PEs we
plotted 1JC-Heq versus 1JC-Hax (Figure SI-90) and found that 1, 1’, 6, 8, and 10 were highly similar
in coupling constants. Of the calculated coupling constants, only the NH and NPh analogs were
similar to experimental values for 1, 1’ and 6, and calculations for 7 were similar to those
determined experimentally. Compound 1 varied significantly from the experimental 1JC-Hax value.
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The syntheses of oxopane 2 and oxonane 3 were carried out to evaluate field effects the
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donor oxygen would have when donor and acceptor orbitals are misaligned compared to oxocane
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Figure 3: Side-view of 1’, 2, and 3 with
"equatorial" proton emphasized for reference.
(top). Top-down view of the cyclic ether
portion of 1, 2, and 3 with * orbitals
emphasized for reference.
1’ (see Figure 3).
The protons of interest in oxopane 2 both have larger coupling constants than either 1’, or
3, consistent with their proximity to oxygen. Their Perlin Effect,  1JC-H = 7.5 Hz, is still quite
large for a non-anomeric methylene. In oxonane 3, the methylenes are considerably further away
from the donor oxygen yet experience a comparable apparent PE of 8.6 Hz. This is intriguing as
this compound likely isn’t in the conformation for donation. These results suggest either orbital
alignment is not as necessary for donation hypothesized, or the proximity to the donor is all that is
necessary to convolute 1JC-H interpretation.
Varying the solvent had minimal effect on the coupling constants for 1’ when experiments
were
performed
at
the
same
temperature
(See
Table
4).
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CD2Cl2
toluene-d 8
5
6
7
8
signal
298 K
283 K
134.1
127.7
298 K
283 K
277 K
C5-Hax
134.2
124.0
10.2
133.7
122.8
10.9
-
-
-
-
C5-Heq
1'
9
1
D JCH
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6.4
132.8
129.8
3.0
-
-
C5-Hax
129.6
129.8
0.2
126.9
123.3
3.6
122.7
123.0
0.3
127.6
129.8
2.2
C5-Heq
C6H11OH
C6H10O
1
D JCH
C5-H
129.8
123.6
127.8
121.2
-
Table 4. Evaluation of solvent and temperature effects between 1', cyclohexanol and
cyclohexanone.
The CH coupling constants were however fairly different at different temperatures presumably due
to the changes in Boltzmann distribution of conformers. No discernable trend was observed
between 1’, cyclohexanone and cyclohexanol. These interesting data warrant further investigation
which will be presented in future works. Unfortunately we have not been able to obtain nmr data
below the temperature necessary to slow conformational changes at this time.
We solved crystal structures for compounds 1, 1’, 2, 6 and 7 (Figure 3).
Figure 4. Top: ChemDraw structures of compounds 1’, 1, 2, 6, and 7 depicting conformations and
donor-acceptor intramolecular bond distances. Bottom: X-Ray crystal structures and pertinent bond
distances and dihedral angles. Atomic displacement ellipsoids generated at 50% probability.
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These structures show how the increase in size of the donor atom or group affect the overall
conformation of the ring system in the solid phase. In the two oxocanes 1 and 1’ the oxygen atom
is slightly closer to C5 than it is in the nitrogen analog 6. The C4-C5 dihedral angle is also
compressed by ~4o in the azocane system. These features support the claim steric or Lewis
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1
interactions are strongly contributing to the difference in observed JC-H . However, the Perlin
Effects in both 1’ and 6 are identical. This could suggest the increased distance between the donor
and acceptor are perhaps increasing the ability of through space hyperconjugation via better orbital
alignment. Compound 10, which incorporates a methyl substituent in place of the sulfonylphenyl
moiety, shows near identical 1JC5-Hax values to6 but a smaller 1JC5-Heq value, resulting in an apparent
Perlin Effect of 10.9 Hz. This represents the largest Perlin Effect to date in a non-anomeric
methylene. If one considers the larger van der Waal radius of the sulfonylphenyl group (A = 2.94
kcal/mol) compared to that of a methyl group (A = 1.74 kcal/mol)10 this result is surprising, as the
1
compression of C5-Hax should be greater (as evidenced by a larger JC5-Hax) with the larger
substituent in close proximity, thus increasing the PE compared to 10. Oxopane 2 shows a donor
oxygen ~0.3Å further away due to the inherent conformational constraints in the smaller ring. In
the methylene “donor” compound 7, the steric bulk has increased to such a degree that the Lewis
interactions have forced a conformational change in the structure to the chair-like cyclooctane.
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Y
Y
H
H
O
O
H
H
boat-like
donation possible
chair-like
donation impossible
Figure 5. Conformational requirements for donation
As seen in Figure 5,
the molecules
must adopt the proper conformation in solution in order to achieve long-range orbital overlap to
be possible. In the chair-like conformation, the donor and acceptor are too far from one another to
achieve orbital overlap. Thus, a conformational analysis of the synthesized compounds is needed
to determine to what extent the compounds are in the boat-like conformation necessary for
donation. Table 5 provides G, Keq and the percent of each compound in the boat-like
conformation for all compounds.
% boat-
Compound
Keq
G
like
99
1'
1
2
3
4
5
6
2.5 68.3
1.7 17.7
95
single conformer
-0.7 0.3
23
87
87
42
1.1 6.4
1.1 6.4
-0.2 0.7
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-0.5 0.4
0.6 2.8
-0.2 0.7
30
73
42
50
10
0
1.0
9
S-1
2.4 57.7
98
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Table 5. Calculated G values (boat-like  chair-like, kcal/mol) for each compound and their
associated Boltzmann Distributions @ 298K.
Conformer estimates for compounds 3 and 7 suggest the wrong conformer (chair-like
conformation) for remote donation dominates the equilibrium providing controls. Compound 8 is
thought to hold the proper conformation and utilize -electrons for donation instead of a lone pair.
Compounds 1, 1’, 4, 5, 8, and S-1 heavily favor the boat-like conformation. Compounds 6, 9, and
10 have essentially equal proportions of each conformer.
All compounds show only one set of signals in their 1H NMR, thus the observed signals (and 1JC-
values) represent weighted averages of the conformations present (suggesting a low energy
H
barrier for interconversion). The conformation of 10 was unambiguously determined via NOESY
NMR (see Figure SI-77), with the only in-phase signal being that of the OH. Compounds 4 and
5 theoretically provide examples of -donation electronically similar to alkene 8 due to resonance
delocalization. Unfortunately, the strong amide resonance contribution renders the constrained
rings asymmetrical, complicating J-analysis. Compound 9 showed an out-of-phase signal in the
NOESY, however this signal could be either C5-Hax or O-H as these signals are isochronous.
Comparing the NMR predictions for the two conformations of 4, 5, 8 and 10 and the experimental
NMR of these compounds, suggests they exist predominantly in the boat-like 8-membered ring
conformation necessary for remote donation. 4 also appears to have adopted a stable half-chair-
like conformation, with a C4-Heq-C5-Hax dihedral angle of -20o. Compound 5 showed an out-of-
phase signal in the NOE between C5-Hax and one of the C2 protons. This suggests the
cyclohexanone is involved in a rapid equilibrium between the chair-like oxocane and a twist-boat-
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like conformer. These differences are presumably due to reduced steric strain in the carboxyethyl
substituent compared with the Boc group. J-analysis of compound 6 suggests it is in a half-chair
conformation with C4-H coupling constants of 7.3Hz and 2.0Hz representing a near-eclipsed
synperiplanar and anticlinal relationship to the C5 protons. The crystal structure also strongly
supports this conformation, though the lattice energy may overcome the solution-phase preference
for the chair-like conformer.
10
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We then turned to NBO analysis to estimate the stabilization (and deletion) energies, C5-H
bond lengths, and p-orbital contribution in the plausible conformations of these compounds.
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1
r (Drdel)[Å]
%p
1'
r (Drdel)[Å]
%p
2
r (Drdel)[Å]
%p
10
11
12
13
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C-Heq
C-Hax
1.0940 (-0.00046) 78.2
C-Heq
C-Hax
1.0937 (-0.00091)
1.0873
78.2
77.3
C-Heq
C-Hax
1.0947 (-0.00091) 77.0
1.0878
77.3
1.0864
76.4
Estab (DEdel
)
Estab (DEdel
)
Estab (DEdel)
0.73 (0.630)
0.77 (0.642)
0.77 (0.7105)
[kcal/mol]
[kcal/mol]
[kcal/mol]
3
r (Drdel)[Å]
%p
4
r (Drdel)[Å]
%p
5
r (Drdel)[Å]
%p
C-Heq
C-Hax
1.094 (-0.00007)
1.0913
78.8
78.2
C-Heq
C-Hax
1.0935 (-0.00115)
1.0883
78.4
77.3
C-Heq
C-Hax
1.0936 (-0.00133) 78.3
1.0882
77.4
Estab (DEdel
)
Estab (DEdel
)
Estab (DEdel)
0.59 (0.4915)
0.77 (0.908)
0.93 (0.902)
[kcal/mol]
[kcal/mol]
[kcal/mol]
<0.5
kcal/mol
s *C—H
s *C—H
O
6
r (Drdel)[Å]
%p
7
r (Drdel)[Å]
%p
8
r (Drdel)[Å]
%p
C-Heq
C-Hax
1.0935 (0.00138) 78.2
C-Heq
C-Hax
1.0928 (-0.00018)
1.0885
78.4
77.3
C-Heq
C-Hax
1.0934
1.0869
78.3
76.7
1.0868
77.2
Estab (DEdel
)
Estab (DEdel
)
Estab (DEdel)
1.16 (0.945)
0.53 (0.580)
-
[kcal/mol]
[kcal/mol]
[kcal/mol]
9
r (Drdel)[Å]
%p
10
r (Drdel)[Å]
%p
1-S
r (Drdel)[Å]
%p
C-Heq
C-Hax
1.0938 (-0.00148) 78.4
C-Heq
C-Hax
1.0947 (-0.00205)
1.0864
78.4
77.6
C-Heq
C-Hax
1.0937 (-0.00221) 77.8
1.0885
77.7
1.0855
76.7
Estab (DEdel
)
Estab (DEdel
)
Estab (DEdel)
1.14 (1.057)
1.44 (1.278)
1.42 (1.413)
[kcal/mol]
[kcal/mol]
[kcal/mol]
Figure 6. Natural Bond Orbital Results for compounds 1-10 and 1-S ((SMD=C6H6)/M06-
2X(D3)/6-311++G(d,p)). Edel and rdel are the change in energy and bond length, respectively,
when the specific NBO donation is deleted.
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As seen in Figure 6, the long-range stabilization energy in 1, 1’ and 2 are comparable to 4, which
is intriguing given the primary means of delocalization in compound 4 is the expected resonance
delocalization into the carbamate (Estab = 82.5 kcal/mol). Oxonane 3 and cyclooctane 7 show near
identical donations, though the donor in 7 is the C1-H  bond! Protected amine 5 and amino alcohol
9 show subtle structural features can dramatically change the estimated donations. Amine 10 and
sulfonamide 6 show significant increases in long-range hyperconjugation stabilization energy
compared to any of the other compounds with a lone pair donor. Surprisingly, the more polarizable
compound S-1 exhibits a slightly lower donation than 10. Compound 8 provided the greatest PE
but no donations were found. Surprising though it may be, the calculated structure of 8 shows
how are sterically bulky group can push the distal carbon away from C1, but not always into a
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7
8
Figure 7. Comparison of 7 and 8
C1-C5 calculated intramolecular
distance.
chair-like conformation. Figure
7
compares the
intramolecular distance between donor and acceptor in 7 and 8. This data suggests that a minor
difference in conformation and intramolecular atomic distance can account for a lack in
hyperconjugation. This also allows for the apparent PEs in compound 8 to be considered solely
due to steric contraction axial CH bond.
The data shows a complex interplay between steric contraction of the C5-Hax and possible
C5-Heq bond lengths elongation due to hyperconjugation. When comparing stabilization energy
and Perlin Effect, there is no direct correlation across the complete set of compounds. There is no
observable correlation between stabilization energy and either C5-Hax or C5-Heq bond lengths for
the complete set of compounds. Though increased p-orbital contribution in C5-H hybridization is
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also observed in all synthesized compounds, it provides no specific correlation to stabilization
energy across the set.
7
8
9
Cyclic ethers 1-3 show sheer proximity to the donor is enough to have highly similar
estimated stabilization energies. However, NBO calculations were only performed on
conformations in the boat-like 8-membered ring and thus not comparable in compounds 3 and 7.
Through-bond proximity to oxygen does appear to perturb the 1JC-H scalar couplings, regardless of
orbital alignment as evident in 3. This is interesting because the steric influence on each of the C5-
Hax is presumably quite different. Fulvene-derived alkene 8 shows a large apparent PE of 10.9 Hz
10
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1
but lacks any NBO stabilization energy. Coupled with having the largest JC5-Hax, this compound
provides an extreme example of the steric influence on the appearance of a perceived Perlin Effect
which is actually due to steric contraction of a C-H bond. The amide -donors 4, 5, and 9 exhibit
a strong steric repulsion of C5, perturbing their conformations and thus complicating their
analyses. Aminoalcohol 10 shows the largest PE and the largest stabilization energy amongst the
series. Compared to that of 10, sulfonamide 6 shows greater extent of steric contraction in C5-Hax,
but a shorter C5-Heq bond length. This strongly suggests the nature of the PE in 10 is predominantly
due to long-range hyperconjugation. At this time we have observed a sterically-driven apparent
PE in cyclooctane 8 and an electronically-driven apparent PE in 10 with all other compounds
studied falling within those bounds.
When only those compounds whose conformation has been determined to be proper for
1
donation, and those which are have similar JC-H scalar couplings (1, 1’, 6, and 10), correlations
amongst
1JCHeq
,
JCH,
Edel
and
rdel
emerge.
Figure
8
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1
1
D JCH vs. Drdel
D JCH vs. DEdel
12.0
11.0
10.0
9.0
12.0
11.0
10.0
9.0
R² = 0.9169
R² = 0.8106
10
10
6
1'
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9
8.0
8.0
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1
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7.0
7.0
6.0
6.0
-0.0025
-0.002
-0.0015
-0.001
-0.0005
0
0.4
0.6
0.8
1
1.2
1.4
Drdel (Ȧ)
DEdel (kcal/mol)
1JCH vs. Drdel
1JCH vs. DEdel
128.0
126.0
124.0
122.0
120.0
118.0
116.0
114.0
128.0
126.0
124.0
122.0
120.0
118.0
116.0
114.0
R² = 0.7798
R² = 0.8392
1
1
1'
6
6
1'
10
10
-0.0025
-0.002
-0.0015
-0.001
-0.0005
0
0.4
0.6
0.8
1
1.2
1.4
Drdel (Ȧ)
DEdel (kcal/mol)
Figure 8. Plots showing linear correlations between computed and experimental properties.
provides the correlations between computed and experimental properties of this subset of
compounds. When either 1JCHeq or JCH are plotted against Edel or rdel, a linear trend with an r2
factor greater than 0.77 arises. The best correlation (r2 =0.9169) exists between JCH vs rdel.
Conclusions.
We synthesized a number of constrained rings via [3+4] cycloaddition. The conformations
of the cycles were unambiguously determined via NOE or/and 3JH-H analyses. Perlin Effects were
1
estimated via JC-H scalar couplings differences between the axial and equatorial protons on C5.
Crystal structures for 1’, 1, 2, 6, and 7 were solved. Conformational analyses were performed and
the Boltzmann distributions of minimized structures were estimated. Natural Bond Orbital
analyses were performed on all compounds to estimate the stabilization energy, C5-H bond lengths,
and p-orbital contribution. Cyclooctane 8 exhibits a sterically driven apparent PE, and compounds
1, 1’, 6, and 10 exhibit a strong correlation between JCH vs rdel, maximized in 10. All other
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compounds show some degree of both steric and electronic contribution to the apparent PEs. These
observations suggest that once conformational distribution is accounted for, long-range
hyperconjugation can be inferred via JCH, also known as Perlin Effects.
10
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Future research efforts will focus on acquiring low-temperature NMR data in order to
freeze out conformational changes and attenuate specific CH scalar couplings. Additionally, the
syntheses of analogs of 1’ when a leaving group such as a carboxylate will be incorporated into
the equatorial position of C5 to explore the electronic demand for the oxocane lone pair. Finally,
kinetic studies will be used to create a Swain-Scott plot to determine the degree of donation in the
transition state of substitution reactions, and thus the degree of hyperconjugation in these systems.
Experimental Section.
General. All chemicals were used as purchased. Reactions were performed under a static argon
atmosphere in a fume hood. Infrared spectra were obtained using a spectrometer equipped with a
SMART iTR sampling accessory. NMR data were obtained using an 850MHz, 700MHz, 600MHz,
500MHz nuclear magnetic resonance spectrometers equipped with a cryoprobe and 13C cold
preamp. Samples were prepared in benzene-d6 (5, 7) chloroform-d (1’, 2, 3, 4, 6, 8, 9, 10). High-
resolution mass spectra were acquired on an Agilent Technologies 6530 Accurate-Mass Q-TOF
LC/MS (ESI source G1958-65138). Preliminary density functional theory (DFT) calculations at
the B3LYP/6-31G* level of theory were performed using Spartan Student v6.1.9. Calculations
were performed on both confirmations. All remaining calculations were carried with the Gaussian
09 software package,11 using the M06-2X functional12 with the D3 version of Grimme’s
13
27
dispersion and the 6-311++G(d,p) basis set. The self-consistent reaction field (SCRF) correction
was applied through the SMD14 solvent model for benzene to evaluate solvent effects. Delocalizing
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interactions were evaluated from M06-2X data with NBO method, using NBO 6.0 software.15
NBO analysis transforms the canonical delocalized molecular orbitals from DFT calculations into
localized orbitals that are closely tied to the chemical bonding concepts. Each of the localized NBO
sets is complete and orthonormal. The filled NBOs describe the hypothetical, strictly localized
Lewis structure. The interactions between filled and antibonding orbitals represent the deviation
from the Lewis structure and can be used to measure delocalization. For example, delocalizing
interaction can be treated via the 2nd order perturbation energy approach as, where ni is the
population of a donor orbitals, Fij is the Fock matrix element for the interacting orbitals i and j, and
is the energy gap between these orbitals. Chemcraft 1.716 were used to render the molecules and
orbitals.
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X-Ray Data Collection and Solution. Compound 1’, 2, 6, 7 were recrystallized according to the
methods outlined in the experimental section. A suitable single crystal was mounted on a
MicroLoop after coating in Paratone-N oil. Data were collected at the specified temperature with
a CCD diffractometer (SMART APEX2) fitted with a low-temperature device. The diffractometer
used graphite-monochromated Cu Kα (λ = 1.54178 Å) radiation with a detector distance of 5 cm.
The program SAINT was used to collect and reduce the data.17 Unit cell constants are based upon
refinement of the XYZ centroids found using a standard indexing routine (APEX2).18 The details
of the data collection are given in the Supplemental Information. All data were corrected for
Lorentz and polarization effects and were scaled using the numerical method SADABS.19 The
structures were solved and refined using the Bruker SHELXTL software package.20 Some of the
heavy atoms were found using direct methods, and the remainder were located in difference
Fourier maps. Hydrogen atoms were placed in calculated positions with the appropriate molecular
geometry δ (C−H = 0.96 Å). The isotropic thermal parameter associated with each hydrogen atom
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was fixed equal to 1.2 times the Ueq value of the atom to which it is bound. Full-matrix least-
squares refinement on F2 was performed on positional and anisotropic parameters for these atoms.
(1R,2R,5S,6S)-11-oxatricyclo[4.3.1.12,5]undec-3-en-10-one (1’), tert-butyl (1R,2R,5S,6S)-
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10-oxo-11-azatricyclo[4.3.1.12,5]undec-3-ene-11-carboxylate
(4),
(1R,2R,5S,6S)-
tricyclo[4.3.1.12,5]undec-3-en-10-one (7), were synthesized according to the procedures
outlined by Cha.21 Data was consistent with known literature. 1’ was recrystallized from boiling
hexane for crystallography analysis. (1R,2R,5S,6S)-9-oxatricyclo[4.2.1.12,5]dec-7-en-10-one
(2) was synthesized according to procedures outlined by Fölisch.22 Data was consistent with
known literature. 8 was recrystallized from boiling hexane for crystallography analysis.
(1R,2R,5S,6S)-11-(propan-2-ylidene)tricyclo[4.3.1.12,5]undec-3-en-10-one
(8)
was
synthesized according to procedures outlined by Tombo.23 Data was consistent with known
literature. 2 was crystalized upon purification via flash chromatography in silica gel in 2:1
hexane:EtOAc for crystallography analysis.
(1R,2R,5S,6S)-12-oxatricyclo[4.4.1.12,5]dodec-3-en-11-one (3). Procedures relating to the
synthesis of 2,7-dibromocycloheptanone were followed according to those outlined by Noyori.24
Dissolved 1.80g (6.67 mmol) of 2,7-dibromocycloheptanone in 7.5mL toluene followed by
addition of 7.5mL (118 mmol) of furan. The flask was charged under inert atmosphere and cooled
to 0°C. To this was added 11.5 mL (12.65 mmol) of 15 w% diethyl zinc in toluene. The reaction
was stirred overnight. It was subsequently sufficiently quenched with saturated ammonium
chloride, extracted with diethyl ether, washed with brine, and dried over MgSO4. The collected
organic was brought to dryness in vacuo to yield crude 3. The product was purified via flash
chromatography in silica gel (3:1 hexane: EtOAc, rf 0.45) to yield 91.0 mg (7.66% yield) of 3 as
a solid. Confirmed by comparison with literature data outlined by Noyori.25
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ethyl
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(5):
5
6
7
8
(General Procedure) Dissolved 3.00g (22.6 mmol) of 2-chlorocylcohexanone in 37.5 mL
anhydrous cyclohexanone with 11.71 g (97.3 mmol, excess) MgSO4. To these 9.75 mL (158 mmol,
excess) pyrrolidine were added, the reaction was covered and stirred overnight. The reaction
mixture was filtered through diatomaceous earth and washed with hexanes. The resulting organic
was brought to dryness in vacuo to yield crude 6-Chloro-1-pyrrolidinocyclohexene which was
dissolved in dry DCM to a final concentration of 0.790 M.
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1.520 g (7.808 mmol) silver tetrafluoroborate in a dark environment was added to a flask
and charged under inert atmosphere. To this 1.701 g (12.22 mmol) ethyl 1H-pyrrole-1-carboxylate
dissolved in 20 mL dry DCM. This was cooled to -78°C to which 7.8 mL of 0.790 M solution of
6-Chloro-1-pyrrolidinocyclohexene was added slowly over the course of thirty minutes. The
reaction mixture was slowly warmed to room temperature and stirred overnight. Subsequently the
reaction was filtered through diatomaceous earth and washed with DCM. The organic was
collected and brought to dryness in vacuo. The work up material was dissolved in 1:2 MeOH:H2O
(20mL:40mL) with 1.1578 g (28.967 mmol, excess) NaOH and stirred overnight. The product was
extracted 4 times with diethyl ether, dried over Na2SO4 and brought to dryness in vacuo to yield a
crude 5 which was purified via flash chromatography in silica gel (1:3 EtOAc:hexane, rf 0.3) to
yield 352.0 mg (24.3% yield) of 5 as an oil; 1H NMR (700 MHz, Chloroform-d) δ 5.84 (d, J = 6.0
Hz, 1H), 5.78 (d, J = 6.1 Hz, 1H), 4.85 (s, 1H), 4.51 (s, 1H), 4.08 (dd, J = 10.0, 6.3 Hz, 1H), 4.03
– 3.93 (m, 1H), 2.18 (d, J = 21.5 Hz, 2H), 2.09 – 1.95 (m, 1H), 1.95 – 1.83 (m, 1H), 1.77 (tdd, J =
11.5, 7.4, 5.4 Hz, 3H), 1.26 – 1.14 (m, 1H), 0.99 (t, J = 7.1 Hz, 3H);13C{H} NMR (176 MHz,
CDCl3) δ 212.1, 154.1, 137.1, 135.9, 62.7, 61.4, 51.0, 29.3, 19.9, 14.8; IR (cm-1) 2926, 2855, 1734,
1697; HRMS (ESI+QTOF) m/z: [M+H]+ Calcd for C13H18NO3 236.1281, found 236.1283.
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(1R,2R,5S,6S)-11-(phenylsulfonyl)-11-azatricyclo[4.3.1.12,5]undec-3-en-10-one
(6):
5
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8
According to general procedure,21 dissolved 2.1350g (16.102 mmol) of 2-chlorocylcohexanone in
25 mL anhydrous cyclohexanone with 7.9060g (65.683 mmol, excess) MgSO4 and 6.5 mL
pyrrolidine (105.53 mmol). Dissolved in DCM to produce a 0.790M solution. 3.1 mL of this was
added to 0.6330g (3.252 mmol) silver tetrafluoroborate, 1.0610g (5.119 mmol) 1-
(phenylsulfonyl)-1H-pyrrole dissolved in 8 mL dry DCM. After workup, the resulting product was
dissolved in 8 mL MeOH:16 mL water with 1.4606g (36.518 mmol) NaOH. The extracted organic
was purified via flash chromatography in silica gel (1:1 EtOAc:hexane, rf 0.5) to yield 79.4 mg
(10.7% yield) of 6 as a crystalline solid. This was recrystallized by slow evaporation from diethyl
ether for crystallographic analysis; 1H NMR (850 MHz, Chloroform-d) δ 7.69 (d, J = 8.4 Hz, 2H),
7.52 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 5.75 (s, 2H), 4.67 (s, 2H), 2.49 – 2.46 (m, 2H),
2.40 (dt, J = 14.0, 7.1 Hz, 2H), 2.32 (dp, J = 13.5, 6.7 Hz, 1H), 2.09 (dt, J = 14.2, 7.2 Hz, 2H),
1.46 (dp, J = 14.8, 7.4 Hz, 1H);13C{H} NMR (214 MHz, CDCl3) δ 214.2, 138.6, 134.2, 133.0,
129.2, 127.7, 65.8, 51.4, 29.4, 19.8; IR (cm-1) 3092, 2991, 2932, 2855, 1723, 1705, 1476, 1450,
1334, 916; (ESI+QTOF) m/z: [M+H]+ Calcd for C16H18NO3S 304.1002, found 304.1004; MP:
174.2-175.9 °C.
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ethyl (1R,2R,5S,6S)-10-hydroxy-11-azatricyclo[4.3.1.12,5]undec-3-ene-11-carboxylate
(9): 145 mg (0.616 mmol) of 5 was dissolved in 15 mL dry THF, cooled to 0°C and charged under
inert atmosphere. 490 mg (12.9 mmol) LAH was added slowly portion-wise. The reaction was
brought to gentle reflux overnight. The organic was cooled to 0°C, sufficiently quenched with 1M
KOH, filtered, dried over MgSO4 and brought to dryness in vacuo to yield crude 9. It was purified
via flash chromatography in silica gel in 1:1 hexane:EtOAc (rf 0.3) to produce 37.0 mg (27.2%
yield) of 9 as a solid; 1H NMR (600 MHz, Benzene-d6) δ 5.96 (dd, J = 6.0, 2.3 Hz, 1H), 5.89 (dd,
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J = 5.9, 2.2 Hz, 1H), 4.87 (t, J = 2.9 Hz, 1H), 4.56 (t, J = 2.8 Hz, 1H), 4.15 – 4.04 (m, 1H), 4.04 –
3.91 (m, 1H), 3.53 (d, J = 6.9 Hz, 1H), 2.10 (dtt, J = 14.0, 10.5, 8.9 Hz, 2H), 1.87 (dd, J = 14.0,
9.0 Hz, 1H), 1.83 – 1.77 (m, 2H), 1.75 (dd, J = 14.1, 9.1 Hz, 1H), 1.59 (dh, J = 14.9, 5.6, 5.0 Hz,
2H), 1.32 (dtt, J = 14.0, 9.1, 1.4 Hz, 1H), 0.98 (t, J = 7.1 Hz, 3H);13C{H} NMR (151 MHz, C6D6)
δ 153.9, 139.1, 137.7, 75.4, 63.0, 62.7, 61.0, 40.4, 40.4, 29.3, 29.2, 19.0, 15.0; IR (cm-1) 3427,
2976, 2916, 2882, 1668, 1583; (ESI+QTOF) m/z: [M+H]+ Calcd for C13H20NO3 238.1438,
found 238.1443.
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(1R,2R,5S,6S)-11-methyl-11-azatricyclo[4.3.1.12,5]undec-3-en-10-one (10): 423.2 mg (1.799
mmol) 5 was dissolved in 100mL dry THF, cooled to 0°C and charged under inert atmosphere. To
this 718.5 mg (18.93 mmol) of LAH is added slowly portion-wise.26 The reaction was brought to
gentle reflux overnight. The organic is cooled to 0°C, sufficiently quenched with 1M KOH,
filtered, dried over MgSO4 and brought to dryness in vacuo to yield crude 10. It was purified via
flash chromatography in silica gel in 95:5 DCM:MeOH (rf 0.35) to yield 85.8mg (12.13% yield)
of 10 as an oil; 1H NMR (850 MHz, Chloroform-d) δ 6.39 (s, 1H), 3.53 (d, J = 11.1 Hz, 1H), 3.47
(d, J = 4.1 Hz, 2H), 2.79 (d, J = 11.8 Hz, 1H), 2.66 (dddd, J = 19.1, 12.9, 10.1, 9.0 Hz, 1H), 2.09
(s, 3H), 2.00 (tt, J = 4.0, 2.0 Hz, 2H), 1.87 – 1.75 (m, 4H), 1.43 (dtt, J = 14.8, 8.4, 1.8 Hz, 2H);
13C{H} NMR (214 MHz, CDCl3) δ 136.4, 75.6, 72.6, 41.6, 41.2, 30.7, 29.9, 20.4; IR (cm-1) 3397,
2921, 2850, 2787, 1674, 1444; (ESI+QTOF) m/z: [M+H]+ Calcd for 180.1383, found 180.1387.
Acknowledgments.
This work was funded in part by an Arts and Sciences Program for Independent Research
(ASPIRE) grant provided by the Howard College of Arts and Sciences at Samford University, and
the Department of Chemistry and Biochemistry at Samford University. The NMR experiments
were performed at the UAB Cancer Center High-Field NMR Facility supported by the NIH grants
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1P30 CA-13148 and 1S10 RR022994. We appreciate the help of Dr. Steve Sorey at the University
of Texas at Austin for his assistance with NOESY processing. We appreciate the assistance of Dr.
Igor Alabugin for allowing us to work with Gabriel dos Passos Gomes.
Supporting Information.
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All spectral, computational and crystal data is available online at pubs.acs.org.
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