NMR spectroscopic conformational analysis of 4‐methylene‐ cyclohexyl pivalate—the effect of sp2 hybridization

Article abstract of DOI:10.1002/mrc.4630

The conformational equilibrium of the axial/equatorial conformers of 4‐methylene ‐cyclohexyl pivalate is studied by dynamic NMR spectroscopy in a methylene chloride/freon mixture. At 153 K, the ring interconversion gets slow on the nuclear magnetic resonance timescale, the conformational equilibrium (?ΔG°) can be examined, and the barrier to ring interconversion (ΔG^#) can be determined. The structural influence of sp² hybridization on both ΔG° and ΔG^#of the cyclohexyl moiety can be quantified.

Full text of DOI:10.1002/mrc.4630

NMR spectroscopic conformational analysis of 4-
methylene-cyclohexyl pivalate – the effect of sp2
hybridization
Erich Kleinpeter,* Matthias Heydenreich, Andreas Koch, Angela
Krtitschka, Tobias Krüger, and Torsten Linker
Correspondence to: Erich Kleinpeter, Universität Potsdam, Institut für Chemie, Karl-
Liebknecht-Str. 24-25, D-14476 Potsdam (Golm), German. e-Mail ekleinp@uni-potsdam.de.
Universität Potsdam, Institut für Chemie, Potsdam (Golm), Germany
Abstract:
The conformational equilibrium of the axial/equatorial conformers of 4-methylene-
cyclohexyl pivalate is studied by dynamic NMR spectroscopy in a methylene chloride/freon
mixture. At 153 K the ring interconversion gets slow on the NMR time scale, the
conformational equilibrium (−ΔG°) can be examined and the barrier to ring interconversion
(ΔG#) can be determined. The structural influence of sp2 hybridization on both ΔG° and ΔG#
of the cyclohexyl moiety can be quantified.
Keywords:
4-Methylene-cyclohexyl pivalate; Conformational analysis; Dynamic NMR Spectroscopy;
Quantum chemical calculations; exo-Methylene conformational effect at cyclohexane.
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doi: 10.1002/mrc.4630
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Introduction
The conformational equilibria of 4-OR substituted cyclohexanones cannot be frozen
even at temperatures <100 K because the ring interconversion barrier (ΔG#/kcal mol-1) is too
low to be measured in solution due to the heavily flattened six-membered cyclohexanone ring
moiety. Only one example has been published [4-OR = −O−C(O)−CH2Br] where the 13C
signal of the carbonyl group starts to decoalesces at 103 K [barrier to ring interconversion < 6
kcal mol-1; the axial conformer is preferred].1 The extremely low barrier to ring
interconversion of the 4-substituted cyclohexanone moiety is not especially remarkable:
flattened ground states (GS) and the transition state (TS) − highest point on the reaction
coordinate) of this dynamic process approach and the barrier to ring interconversion as the
free energy differences between GS and TS get crucially smaller and, hereby, the coalescence
temperature Tc/K of the ring interconversion is decisively lowered. Actually, it is the large
preference of the 4-O−C(O)−CH2Br substituent for the axial conformation at 4-position of
cyclohexanone which is the more interesting result of this study,1 because substituents at
cyclohexane usually prefer the equatorial conformation.2
Several structural differences of cyclohexyl and 4-keto-cyclohexyl come into
consideration: (i) flattening of both GS and TS due to sp2 hybridization of C-4 and (b)
increasing polarity of the 4-oxocyclohexyl moiety due to carbonyl polarization. These
additional effects of the carbonyl group in 4-position can be of steric (by decreased
interaction of the axial −OR substituent and the axial protons in 1,3-positions − 1,3-diaxial
interactions)3 and/or electronic reasons (e.g. the stronger effect of hyperconjugation σC2−Hax
→ σ*C1−O7 compared with σC2−C3 → σ*C1−O7).4
There is one earlier manuscript dealing with 1,4-transannular effects in 4-substituted
cyclohexanol on the present conformational equilibrium (determined by line width
measurements of the R2C(OH)H proton signal in NMR spectra at room temperature);5 the
axial conformation of the OH substituent increases with the electron attracting ability of C-4
substitution.5 Steric destabilization of the axial conformer with increasing 1,3-diaxial
interactions has been observed in various aliphatic cyclohexyl esters (−OR = −O−COAlk),6
and the effect of hyperconjugation in 1,4-disubstituted cyclohexanes due to the polar effect of
the second −OR substituent in 4-position proved to be 0.5 − 0.7 kcal mol-1 (−OR = −Me, −Et,
−iso-Pr, −tert-Bu)6 and 0.3 − 0.5 kcal mol-1 (−OR = −OCOMe, −OCOEt, −OCOiso-Pr,
−OCOtert-Bu),3 respectively, preferring by this energy amount the axial conformation of the
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−OR substituent at cyclohexyl. Finally, the carbonyl group in position 4 too, increases the
axial orientation of the corresponding −OR substituents;1 quantitative information by low
temperature dynamic NMR spectroscopy, however, is hardly available because the barrier to
ring interconversion proved to be too low to be studied in solution.1
In the hope that the ring interconversion barrier of the 4-exo-methylene analogue 1 of
the 4-substituted cyclohexanones is higher than in the corresponding cyclohexanone
derivative and the conformational effect of C-4 sp2-hybridization can be determined (cf.
Scheme 1), the latter compound 1 was synthesized and studied accordingly; the additional
polarity effect of 4-carbonyl on the present conformational equilibrium can be completely
separated hereby. Methylene-cyclohexane, 2- and 3-substituted analogues were studied by J.
B. Lamert;7 the higher barrier to ring interconversion (compared with the corresponding
cyclohexanones) and the remarkable influence of 2- and 3-substituents on the conformational
equilibrium was reported,7 however, the barrier of methylene-cyclohexane itself is unknown
yet and the corresponding effect of even polar substituents in position 4 was not studied yet
but expected to be negligibly small.7
Results and discussion
The exo-methylene pivalate 1 was synthesized starting from 1,4-dihydroxy-
cyclohexane. Thus, in analogy to literature,8 oxidation by 1 equiv. of NaBrO3 and catalytic
ammounts of CAN afforded 4-hydroxycyclohexanone as a labile intermediate, which was
directly esterified with pivaloyl chloride to the corresponding cyclohexanone ester 4a in 34%
yield in analytically pure form.9 The moderate yield is due to formation of cyclohexane
diketone as side-product in the first step. Subsequent Wittig reaction10 of the cyclohexanone
ester 4a afforded the desired 4-methylene-cyclohexyl pivalate 1 in 91% yield in analytically
pure form.11 Isolation of the product on neutral aluminum oxide was important, due to the
instability of the alkene and possible binding to silica gel.
For the NMR studies, the exo-methylene ester 1 was dissolved in the methylene
chloride/freon mixture (CD2Cl2 /CHFCl2/CHF2Cl = 1:1:3) which is still liquid at
temperatures down to 100K, and the solution was cooled down. At 165 K and at 170 K,
respectively, coalescence temperatures Tc/K of H-2/6 and H-1 protons, respectively, were
found (cf. Fig. 1). Together with the corresponding decoalesced chemical shift differences at
166 and 170 K, respectively, Δν/Hz (147 Hz and 270 Hz, respectively) of the corresponding
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protons (cf. Fig. 2) both rate constants kc = π Δν/√2 (600 and 370, respectively) and the ring
interconversion barrier [ΔGc# = 19.14 Tc (10.32 + log Tc/kc)] of 1 was calculated to be 7.6
kcal mol-1. At 153 K the dynamic process gets slow on the NMR time scale, the ratio of
nearly identically occurring axial (48 %) and equatorial conformer (52%) with the free
energy difference (−ΔG° = RTc ln K) of 0.020 kcal mol-1 was obtained.12 Thus at 153 K the
occurrence of the two participating conformers 1a and 1b proves to be nearly identical (cf.
Fig. 2).12 Compared (cf. Scheme 2) with the corresponding cyclohexyl derivatives 2a,b
(−ΔG° = 0.39 kcal mol-1) the content of the axial conformer 1ax proves to be higher (−ΔG° =
0.02 kcal mol-1), however, compared with the corresponding cyclohexanone ester 4a,b, on
the other hand, 4ax is still more preferred (−ΔG° = −0.46 kcal mol-1 and this by about the
same amount). And, compared with the di-ester 3a,b (−ΔG° = −0.03 kcal mol-1), cf. Scheme
2) the polarity effect of the second ester group in 4-position of the molecule (compared with
2a,b) proves to be about the same size as the effect of sp2 hybridization of C-4 on the present
conformational equilibrium.
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To better understand structural changes, the conformational equilibria of 1, 2 and 4 were
computed on the DFT level of theory (CDCl3 as the solvent).13 The computational results are
given in Table 1, the conformational equilibrium of the exo-methylene ester 1 is visualized in
Fig. 1 (GS
TS
GS).
Structural changes in the six-membered ring moiety of 1, 2 and 4 are in complete
agreement with the experimental d-NMR measurements:
#
(i) Both experimental and calculated barriers to ring interconversion (ΔGc )
ΔGc#/kcal mol-1 (exp.): 2 [4-CH2 (10.2)] < 1 [4-C=CH2 (7.6)] < 4 [4-C=O (4.7 −5.1)];
ΔGc#/kcal mol-1 (calc.): 2 [4-CH2 (11.24)] < 1 [4-C=CH2 (8.87)] < 4 [4-C=O (4.34)],
and also free energy differences between equatorial and axial conformers (−ΔG°)
ΔG°/kcal mol-1 (exp.): 2 [4-CH2 (0.39)] < 1 [4-C=CH2 (0.02)] < 4 [4-C=O (−0.46)];
ΔG°/kcal mol-1 (calc.): 2 [4-CH2 (0.94)] < 1 [4-C=CH2 (0.47)] < 4 [4-C=O (0.07)]
excellently agree; the values are not completely the same but in relative sequence and size.
(ii) Barriers to six-membered ring interconversion ΔGc# of the exo-methylene
compound 1, due to the completely flat C(3)C(5)C(4)=CH2 moiety, prove to be 2.5 kcal mol-1
lower compared with the barrier in 2 and 3 with 4-sp3 moiety. This is quantitatively the effect
of 4-sp2 hybridization on ΔG# of the cyclohexyl ring structure.
(iii) The barrier to ring interconversion of the cyclohexanone derivate 4 proves to be
another 2.5 kcal mol-1 lower as in the corresponding exo-methylene compound 1. This is
quantitatively the effect of the polarity 4-C=O on ΔG# of the cyclohexyl ring structure.
(iv) The effect of the flat 4-C=CH2 moiety on the conformational equilibrium of the
exo-methylene compound 1, compared with ΔG° of cyclohexyl in 2, proves to be 0.42 kcal
mol-1; the portion of the axial conformer increases to ca. 50 %. This is quantitatively the
effect of the flat 4-C=CH2 moiety in the exo-methylene compound on ΔG° of the cyclohexyl
ring structure.
(v) The effect of 4-C=O on ΔG° in the corresponding ketone 4, compared with the
exo-methylene analogue 1 decreases to −0.46 kcal mol-1; the portion of the axial conformer
increases to ca. 70 %. This is quantitatively the effect of the polarity 4-C=O on ΔG° of the
cyclohexyl ring structure.
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(vi) The effect of the flat 4-C=CH2 moiety in the exo-methylene compound 1 is about
the same as the corresponding effect of the second 4-ester substituent in the di-ester 3 (cf.
Scheme 2).
(vii) The steric contribution to (i) to (vi) is proved by the structural variations as
collected in Table 1 [especially, the lowering of steric strain dH(1)eq...O=C/Å and dH(3,5)ax...O(7)/
Å
in axial conformers of 2 (4-CH2) < 1 (4-C=CH2)] < 4 (4-C=O)]. The corresponding
electronic contribution to the conformational effects in ΔG° and ΔG# of 1 to 4 quantitatively
complement one another.
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References
[1]
[2]
Kleinpeter, E.; Heydenreich, M.; Koch, A.; Linker, T. Tetrahedron 2012, 68, 2363.
Kleinpeter, E. Adv. Heterocycl. Chem. 2004, 86, 41 − Conformational analysis of
Saturated Heterocyclic Six-Membered Rings.
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Kleinpeter, E.; Rolla, N.; Koch, A.; Taddei, F. J. Org. Chem. 2006, 71, 4393.
Kleinpeter, E.; Taddei, F.; Wacker, Ph. Chem., A Eur. J. 2003, 9, 1360.
Stolow, R. D.; Groom, Th. Tetrahedron Letters 1968, 5781.
Kleinpeter, E.; Thielemann, J. Tetrahedron 2007, 63, 9071.
J. B. Lambert, Conformational Analysis of Six-Membered Carbocyclic Rings with
exocyclic Double Bonds, Chapter 2 of Conformational Analysis of Cyclohexenes,
Cyclohexadienes, and Related Hydroaromatic Compounds, ed. by P. W. Rabideau,
Methods in stereochemical Analysis, ed. by A. P. Marchand, VCH Publishers, Inc.
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(a) Ayres, F. D.; Khan, S. I.; Chapman, O. L.; Kaganove, S. N. Tetrahedron Lett.
1994, 35, 7151; (b) Wessig, P.; Möllnitz, K.; Eiserbeck, C. Chem. Eur. J. 2007, 13,
4859.
4-Oxocyclohexyl pivalate 4a: m.p. 47–48 °C; Rf = 0.55 (pentane/ethyl acetate 1:1); 1H
NMR (600 MHz, CDCl3 ppm) δ = 5.10 (sept, 1H, 4-H), 2.47–2.52 (m, 2H, 2-H, 6-H),
2.30–2.34 (m, 2H, 2-H, 6-H), 2.04–2.09 (m, 2H, 3-H, 5-H), 1.96–2.02 (m, 2H, 3-H, 5-
H), 1.18 (s, 9H, C(CH3)3); 13C NMR (150 MHz, CDCl3, ppm) δ = 210.0 (C-1), 177.7
(CO), 68.0 (C-4), 39.0 (C(CH3)3), 37.2 (C-2, C-6), 30.4 (C-3, C-5), 27.1 (C(CH3)3). IR
(KBr):  = 2968, 1713, 1475, 1281, 1157, 1087, 888 cm. elemental analysis
calculated (%) for C11H18O3 (198.26): C 66.64, H 9.15; found: C 66.69, H 9.40.
[10] Wittig, G.; Schoellkopf, U. Organic Syntheses, Coll. Vol. 5 1973, 751.
[11] 4-Methylene-cyclohexyl pivalate 1: colorless liquid, Rf = 0.46 on aluminum oxide
1
(pentane); H NMR (600 MHz, CDCl3 ppm) δ = 4.91 (sept, 1H, 4-H), 4.65 (s, 2H, 7-
H), 2.29–2.34 (m, 2H, 2-H, 6-H), 2.10–2.14 (m, 2H, 2-H, 6-H), 1.76–1.81 (m, 2H, 3-
13
H, 5-H), 1.63–1.68 (m, 2H, 3-H, 5-H), 1.18 (s, 9H, C(CH3)3); C NMR (150 MHz,
CDCl3, ppm) δ = 178.0 (CO), 147.5 (C-1), 108.0 (C-7), 70.6 (C-4), 38.9 (C(CH3)3),
32.1 (C-2, C-6), 31.2 (C-3, C-5), 27.3 (C(CH3)3). IR (film):  = 3073, 2942, 2871,
1724, 1282, 1155, 891 cm; elemental analysis calculated (%) for C12H20O2 (196.29):
C 73.43, H 10.21; found: C 73.34, H 10.49.
[12] About the same quantity of axial and equatorial conformer in the exo-methylene
cyclohexyl moiety 1 was obtained at room temperature employing the line width
method:2 T = 273 K; Δν = 21.8 Hz; K = (30 Hz − 21.8 Hz)/(21.8 Hz − 16 Hz) = 1.4;
−ΔG° = RT ln K = 0.02 kcal mol-1. Further, the resolved 1H NMR spectrum at room
temperature was examined by PERCH simulation20 and conformationally useful and
analyzable H,H coupling constants [3J(1,2ax), 3J(1,2eq), 3J(2ax,3ax), 3J(2ax,3eq),
3J(2eq,3ax) and 3J(2eq,3eq)] could be extracted and evaluated (with the reference
values in 1a and 1b, respectively, given in ref. 1); the same result (−ΔG° = 0.02 kcal
mol-1) was obtained. Actually, the same result was obtained when employing the
ALTONA equation.21
[13] The geometries of both ground and transition states (GS, TS) of the ring
interconversion of 4-methylene-cyclohexyl pivalate 1 were fully optimized using the
Gaussian0914 program employing ab initio calculations at the B3LYP/6-311G* level
of theory.15 The QST2 (quadratic synchronous transition approach) methods were
used for locating the transition state structures16,17 characterized by their vibrational
frequencies which are −125.98 (for 1), −104.98 (for the carbonyl analogue 4) and
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−181.18 (for the cyclohexane analogue 2); structures of TS of 1 is involved in Fig. 3
and TS of 2 and 4 are given in Fig. 4. The SCRF PCM method18 was used to consider
the solvent chloroform. The 3D structures were visualized using the SYBYL-X 2.1.1
molecular modelling software.19
[14] Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.;
Nakatsuji, 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, T. A.; Peralta, Jr. J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.;
Brothers,
Raghavachari,
Rega, N.;
E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
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.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas,
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.02,
Gaussian, Inc., Wallingford CT, 2009.
O.;
[15] (a) Hehre, J. W.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio Molecular
Orbital Theory; Wiley & Sons: New York, NY, 1986; (b) Becke, A. D. J. Chem. Phys.
1993, 98, 1372; (c) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. 1988, B 37, 785.
[16] Peng, C.; Schlegel, H. B. Israel J. Chem. 1993, 33, 449.
[17] Peng, C.; Ayala, P. Y.; Schlegel, H. B.; Frisch, M. J. J. Comp. Chem. 1996, 17, 49.
[18] Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev. 2005, 105, 2999.
[19] SYBYL-X 2.1.1 Centara Inc. 1699 South Hanley Road, St. Louis, Missouri 63144,
USA, 2013.
[20] Laatikainen, R.; Niemetz, M.; Malaisse, W. J.; Biesemans, M.; Willem, R. Magn.
Reson. Chem.1996, 36, 359.
[21] Altona, C. in Encyclopedia of NMR: Grant, D. M.; Morris, R., Eds.; Wiley, New York
1996, pp 4909−4929.
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Table 1. Conformational equilibria of the pivalic acid esters of cyclohexanol 2, of 4-hydroxy-
cyclohexanone 4 and the corresponding exo-methylene ester 1 (DFT computed at B3LYP/6-
311G* level of theory, CDCl3 as solvent),13 and steric interactions (dH...H and dH...O=C
distances) within the certain geometries .
__________________________________________________________________________
Compound ΔG#/kcal mol-1
ΔG°/kcal mol-1
[ax]/%
[eq]/%
__________________________________________________________________________
2 (4-CH2)
1 (4-C=CH2) 8.87
4 (4-C=O) 4.34
11.24
0.94
0.47
0.07
17
31
53
83
69
47
___________________________________________________________________________
Compound axial conformer
dH(1)eq...O=C/Å
2.357
1 (4-C=CH2) 2.366
4 (4-C=O) 2.368
dH(3,5)ax...O(7)/
2.760
2.753
Å
dH(2,6)eq...O(7)/Å ϴC(1)-O-C=O/dgr.
2 (4-CH2)
2.630
2.629
2.616
31.5
32.8
33.2
2.735
___________________________________________________________________________
Compound equatorial conformer
dH(1)ax...O=C/Å
dH(2,6)ax...O(7)/
Å
dH(2,6)eq...O(7)/Å ϴC(1)-O-C=O/dgr.
___________________________________________________________________________
2 (4-CH2)
1 (4-C=CH2) 2.357
4 (4-C=O) 2.362
2.360
2.612
2.616
2.613
2.681
2.683
2.677
31.6
31.5
32.8
___________________________________________________________________________
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Figure 1 1H NMR spectra of 4-methylene-cyclohexyl pivalate 1 at various temperatures.
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Figure 2. 1H NMR spectrum of 4-methylene-cyclohexyl pivalate 1 at 153 K.
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(a)
(b)
(c)
Figure 3. Computed structures of 4-methylene-cyclohexyl pivalate 1 − (a) and (c) ground states (GS), (b)
transition state (TS) of the ring interconversion of the exo-methylene cyclohexyl moiety.
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Figure 4. Computed structures of the transition state structures of the carbonyl (4, right) and of the cyclohexyl
analogue (2, left) of 4-methylene-cyclohexyl pivalate 1.
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Scheme 1. Conformational equilibrium of 4-methylene-cyclohexyl pivalate.
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ΔG° = 0.39 kcal mol-1
(at 183 K);
ΔG# ca. 10 kcal mol-1
ΔG° = −0.03 kcal mol-1
(at 183 K);
ΔG# ca. 10 kcal mol-1
ΔG° = −0.46 kcal mol-1
(at 298 K);
ΔG# = 4.7−5.1kcal mol-1
ΔG° = 0.02 kcal mol-1
(at 153 K);
ΔG# = 7.6 kcal mol-1
Scheme 2. Conformational equilibria of pivalic acid esters 1, 2, 4 and the diester 3.
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Graphical Abstract:
The conformational equilibrium of the axial/equatorial conformers
cyclohexyl
of 4-methylene-cyclohexyl pivalate is studied by dynamic NMR
NMR spectroscopic conformational analysis of 4-methylene-
pivalate – the effect of sp2 hybridization
... − ...
spectroscopy in a methylene chloride/freon mixture. At 153 K the
ring interconversion gets slow on the NMR time scale, the
conformational equilibrium (−ΔG°) can be examined and the barrier
to ring interconversion (ΔG#) can be determined. The structural
influence of sp2 hybridization on both ΔG° and ΔG# of the cyclohexyl
moiety can be quantified.
Erich Kleinpeter,* Matthias Heydenreich, Andreas Koch, Angela Krtitschka, Tobias
Krüger and Torsten Linker
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