Anthony R.
Izzotti
and
James L.
Gleason
*
Department of Chemistry, McGill University, 801 SherbrookeW., H3A 0B8, Montreal, QC, Canada. E-mail: jim.gleason@mcgill.ca
First published on 8th October 2024
The presence of a small spirocyclic ring at an adjacent position alters the conformational preference for equatorial substitution in six-membered rings. DFT calculations and low-temperature 1H NMR experiments demonstrate that alkyl groups larger than methyl possess negative A-values when geminal to a spirocyclopropane, with larger groups such as isopropyl and tert-butyl being exclusively axial at −78 °C. Similar effects are found for heteroatoms, including halogens, and for a range of other electron-withdrawing substituents. Similar effects are observed for other strained rings (epoxide, cyclobutane, oxetane) and the concepts extend to acyclic models as well as heterocycles such as piperidines and piperazines. The origin of the effect is traced to an increase in torsional strain in combination with hyperconjugative effects in the case of electron-poor groups.
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Fig. 1 Conformational elements in cyclohexanes and examples of cyclopropane-containing relevant molecules. |
The quintessential example of conformational analysis in organic chemistry is the understanding of structure in cyclohexanes (Fig. 1a), where the chair form is preferred over the twist-boat and substituents prefer equatorial positions over axial to minimize gauche interactions with C3 and C5. The equatorial preference is quantified in the form of A-values and in general, larger groups possess larger A-values.11 Known exceptions to the preference for equatorial substitution do exist, with the most common examples resulting from stereoelectronic effects, including anomeric effects in carbohydrates and related acetals, hyperconjugative stabilization observed in 1,3,5-triazinanes,12,13 vinylogous anomeric effects in 2-chlorocyclohexanone oximes,14 and dipole minimization in α-halo-cyclohexanones,15 as well as cases where hydrogen bonding stabilizes axial substitution.16–18
In the context of examining an organocatalytic Cope rearrangement,19 we observed anomalous preference for axial orientation of alkyl groups adjacent to a cyclopropane in chair-like transition states (Fig. 2).20 Modest preference for axial disposition of α-ethers and acetates adjacent to spirocyclopropanes had previously been noted and had been attributed mainly to stereoelectronic effects.6,21 In addition, a spiro-oxetane was previously found to induce an N-alkyl group to adopt an axial conformation in a heterocycle in the solid state.22 As our studies here will show, the effect is in fact broadly applicable to a range of groups and is more significant for large alkyl groups, such that isopropyl and tert-butyl are exclusively axial. In addition, we show that the effect is not limited to cyclopropanes, but is operative with other three- and four-membered rings and the effects can be generalized into heterocycles and acyclic systems. These conformational effects have potential for application in molecular design of catalysts and rational design in medicinal chemistry.
The effect of a spirocyclopropane on the A-value of a simple methyl group was significant (Table 1). While a geminal dimethyl group adjacent had, as previously observed,28,29 little effect on the A-value, an adjacent cyclopropane resulted in a computed A-value of −0.09 kcal mol−1, a change of −2.04 kcal mol−1vs. the computed value for methylcyclohexane. Even more striking were the effects on groups larger than methyl. While the presence of a geminal dimethyl group generally had minimal effect, the A-values for groups adjacent to a spirocyclopropane were uniformly negative and generally shifted by −3 kcal mol−1 or greater. For instance, an ethyl group was predicted to have an A-value of −0.89 kcal mol−1, indicating a clear preference for axial substitution and a change of −2.95 kcal mol−1 relative to ethylcyclohexane. Larger groups such as isopropyl and tert-butyl were predicted to have even larger preferences for the axial conformation. For tert-butyl the predicted A-value of −2.00 kcal mol−1 represents a change of nearly −8 kcal mol−1 from the normal equatorial preference in tert-butylcyclohexane.30,31
Calculated A-valuea (kcal mol−1) | Expt. A-valueb (kcal mol−1) | |||
---|---|---|---|---|
R | ||||
a ΔG° calculated at 25 °C, M06-2X/6-311++G(2d,2p), SMD = acetone. b Experimental value determined by 1H NMR at −78 °C in d6-acetone. | ||||
Me | +1.95 | +1.76 | −0.09 (δ = −2.04) | +0.05 |
Et | +2.06 | +1.90 | −0.89 (δ = −2.95) | −0.46 |
iPr | +2.33 | +3.27 | −2.10 (δ = −4.43) | <–1.5 |
CH2OH | +1.98 | +1.71 | −1.01 (δ = −2.99) | −0.72 |
Bn | +1.85 | +1.78 | −1.10 (δ = −2.95) | −0.75 |
tBu | +5.83 | +3.44 | −2.00 (δ = −7.83) | <–1.5 |
We examined these species experimentally to corroborate the computational results. We prepared the spirocyclopropane substrates by cyclopropanation32 of the corresponding alkenes, themselves generated by olefination33 of the corresponding ketones (Scheme 1 and ESI†). We measured the equilibrium ratios of axial and equatorial conformers by 1H NMR at −78 °C in d6-acetone. Axial and equatorial isomers were assigned from coupling constants while confirmation that specific protons were interconverting was achieved by saturation transfer in selective irradiation experiments.34 Notably, in the spirocyclopropyl system, the α-equatorial protons are significantly shielded by anisotropy,35 which facilitated the assignment.
The predicted effect of a spiro-cyclopropane was borne out experimentally. For the substrate bearing a methyl group, a 53:
47 ratio of equatorial to axial conformers was observed. Although the equatorial isomer was very slightly preferred, the observed A-value of +0.05 kcal mol−1 was close to the predicted value and, importantly, the ratio was significantly different from the normal ∼95
:
5 ratio in methylcyclohexane. Moreover, for all other isomers, the axial isomer was clearly preferred. For instance, for an ethyl group, the axial isomer predominated in a 77
:
23 ratio, indicating an A-value of −0.46 kcal mol−1. Larger groups such as benzyl, isopropyl and tert-butyl more heavily favored the axial conformer – for the latter two substrates the equatorial isomers could not be observed at −78 °C. We estimated our limit of detection of the minor conformer to be roughly 2% of the major conformer, setting an upper limit for measuring the magnitude of A-values at 1.5 kcal mol−1 at −78 °C for these examples. We note that the DFT calculations slightly overestimated the effect of the cyclopropane by 0.1–0.4 kcal mol−1, with the ethyl group having the largest error. Examination of other computational methods for ethyl substitution afforded either similar (B3LYP-D3 (ref. 36–40)) or more significant (WB97XD,41,42 MP2 (refs. 43 and 44)) prediction errors (see ESI†) and thus the M06-2X functional was maintained for subsequent calculations.
We next examined the effects of spirocyclopropanes on heteroatom substitution (Table 2). As with alkyl substituents, in all cases, we predicted a decrease in the A-value with absolute changes ranging from −1.2 to −4.0 kcal mol−1 and the axial conformation preferred for all substitution patterns. Notably, even small groups such as fluoro were predicted to have significant negative A-values. We prepared all but the chloro and bromo substrates, as the latter were prone to ring-opening of the cyclopropane. The heteroatom substrates were prepared by Simmons–Smith cyclopropanation of 2-methylene-1-cyclohexanol followed by functional group interconversions (see ESI† for details). We found that the calculated A-value reflected well the observed equilibrium concentrations in almost all cases. A slightly larger discrepancy between predicted and observed values was observed with ammonium and acetamide groups, with the latter being the only incorrect prediction of axial preference. We tentatively attribute the difference in the latter case to potential hydrogen bonding (either to itself or to solvent d6-acetone) which was not modeled explicitly by DFT, while the error in the former case may also reflect the difficulty in properly modelling solvation of the cation.
Calculated A-valuea (kcal mol−1) | Expt. A-valueb (kcal mol−1) | |||
---|---|---|---|---|
R | ||||
a ΔG° calculated at 25 °C, M06-2X/6-311++G(2d,2p), SMD = acetone. b Experimental value determined by 1H NMR at −78 °C in d6-acetone, except as note. c Determined in d2-dichloromethane. | ||||
OH | +0.89 | +0.83 | −0.37 (δ = −1.26) | −0.13 |
OMe | +0.87 | +0.74 | −0.67 (δ = −1.54) | −0.42 |
OAc | +0.74 | +0.53 | −0.54 (δ = −1.28) | −0.57 |
NH2 | +1.41 | +1.36 | −0.15 (δ = −1.56) | −0.24c |
NH3+ | +2.21 | +0.84 | −1.83 (δ = −4.04) | −1.23c |
NHAc | +0.91 | +0.84 | −0.57 (δ = −1.48) | +0.19 |
N3 | +0.63 | +0.86 | −0.92 (δ = −1.55) | −0.72 |
F | +0.31 | +0.29 | −1.05 (δ = −1.36) | −0.82 |
Cl | +0.63 | +1.16 | −1.81 (δ = −2.44) | nd |
Br | +0.61 | +1.21 | −2.23 (δ = −2.84) | nd |
Finally, we examined a range of π- and electron withdrawing groups (Table 3). As with alkyl and heteroatom groups, all substituents also displayed a shift towards a more negative A-value. For phenyl the shift was not sufficient to prefer the axial conformation, although the absolute change is still significant (−2.04 kcal mol−1) and for vinyl an equal population of axial and equatorial was predicted. In contrast, alkynes and all electron withdrawing groups were predicted to have a negative A-value, with the CF3 group having the most significant change relative to a simple cyclohexane among this group and the largest predicted negative A-value among all substituents examined. We prepared four examples from this series; the phenyl substrate was indeed equatorial (92:
8 ratio) as predicted, for ester and acid substrates the axial conformer was favored by roughly 70
:
30 ratios at −78 °C and for a cyano group the ratio was 80
:
20, again favoring axial.
Calculated A-valuea (kcal mol−1) | Expt. A-valueb (kcal mol−1) | |||
---|---|---|---|---|
R | ||||
a ΔG° calculated at 25 °C, M06-2X/6-311++G(2d,2p), SMD = acetone. b Experimental value determined by 1H NMR at −78 °C in d6-acetone. | ||||
Ph | 3.03 | 3.76 | 0.99 (δ = −2.04) | +0.95 |
CH![]() |
1.80 | 1.74 | −0.02 (δ = −1.82) | nd |
C![]() |
0.46 | 0.96 | −0.23 (δ = −0.69) | nd |
CO2H | 1.16 | 1.52 | −0.75 (δ = −1.31) | −0.38 |
CO2Me | 1.34 | 1.59 | −0.59 (δ = −1.93) | −0.32 |
CN | 0.13 | 0.62 | −0.69 (δ = −0.82) | −0.54 |
NO2 | 1.02 | 1.31 | −2.02 (δ = −3,04) | nd |
CF3 | 2.50 | 1.66 | −3.02 (δ = −5.52) | nd |
An important question was whether this effect could be extended to other spiro ring systems. We probed this computationally with small (Me, Et), medium (iPr) and large (tBu) substituents with a variety of different ring sizes and rings incorporating oxygen (Table 4). Calculations showed that the effect was generally maintained with cyclobutane, albeit with a partial loss of expected axial preference. However, when the ring expands to a cyclopentane, the equatorial isomer is now preferred for all group sizes, though still less compared to a simple dimethyl substituted system. Examining other three-membered rings, we found that spiro-epoxides were predicted to have a decrease in A-values, although the magnitude of the effect was reduced and dependent on the relative stereochemistry. For small substituents, the equatorial isomers are often still preferred, though by a much smaller margin than for a regular cyclohexane. However, for larger groups such as isopropyl or tert-butyl, the axial conformers are again predicted to be dominant. We examined cyclopropene substitution and noted that while A-values were again diminished, it was not sufficient to favor the axial isomer for groups other than for isopropyl. We also examined cyclobutanone and oxetane units which have been extensively employed as isosteres. Oxetane had a significant effect on medium and large groups, though its effects on smaller groups was not sufficient to prefer the axial conformer and the effect of cyclobutanone was also muted even with large groups (Table 4).
X | Me | Et | iPr | tBu |
---|---|---|---|---|
a ΔG° values calculated at 25 °C at M06-2X/6-311++(2g,2p), SMD = acetone and reported in kcal mol−1. Experimental values determined at −78 °C in d6-acetone in parentheses. b Determined at −98 °C. | ||||
CH2 | +1.95 | +2.06 | +2.33 | +5.83 |
CMe2 | +1.76 | +1.90 | +3.27 | +3.44 |
![]() |
−0.09 (+0.3) | −0.89 (−0.46) | −2.10 (<−1.5) | −2.00 (<−1.5) |
![]() |
+0.26 | −0.25 | −0.52 | −0.72 (<0) |
![]() |
+0.67 | +0.66 | +1.46 | +0.11 |
![]() |
+0.69 | 0.00 | −1.31 | −1.64 (<−1.5) |
![]() |
+0.24 | −0.42 | −0.98 | −0.57 (−0.20)b |
![]() |
+1.47 | +1.07 | +0.42 | +1.14 |
![]() |
+0.17 | +0.15 | −1.80 | −1.91 |
![]() |
+0.16 | +0.18 | −0.28 | −0.27 (−0.23) |
We examined experimentally several different ring systems bearing tert-butyl groups (see ESI† for synthesis) and all were found to be generally in line with the calculations (see values in parentheses, Table 4). Due to overlapping signals, the ratio in the cyclobutane substrate could not be quantified. However, using computational NMR shift prediction with the GIAO method45 and cross-peak intensity in low-temperature HSQC, the axial conformer was assigned as the major isomer. The anti-epoxide46 heavily favored the axial conformer, as predicted, with no equatorial isomer observed while the corresponding syn-epoxide had a lower preference for axial, again as predicted. The tert-butyl substituted spirocyclobutanone could be quantified and was found to have a 64:
36 ratio. Although we were unable to assign the conformers with NOEs alone, again NMR chemical shift prediction allowed us to assign the major conformer as axial (see ESI†), indicating an A-value of −0.23 kcal mol−1 which was consistent with the computations.
Finally, the trends observed in cyclic frameworks were expected to have parallels in acyclic structures. Specifically, there should be an energetic penalty to place an alkyl group above a small ring, similar to the equatorial placement in the spiro systems above. We examined the orientation of an isopropyl group situated on a 1-methylcyclopropane, -cyclobutane and -oxetane. In all cases, the preferred conformation where the hydrogen of the isopropyl group was situated above the ring, was favored by 1.2–1.6 kcal mol−1 (Fig. 3). It would be expected that other similar substitutions, such as secondary stereocenters, would adopt a similar conformation. The acyclic directing effect of oxetanes has been previously noted22 and is highly relevant in their use as bioisosteres, as it alters the normal preference for syn-periplanar orientation of alpha groups in ketones.47
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Fig. 4 Conformational control in 2-spirocyclopropyl piperidines. (A) Calculated piperidine A-values (B) X-ray crystal structure of 3·HCl. |
Piperazines are among the most common heterocycles in active pharmaceutical ingredients, being found in almost 10% of the top selling small-molecule drugs.51 We prepared mono- and bis-cyclopropyl piperazines by Kulinkovich reaction of N,N′-dibenzyldiketopiperazine to afford a mixture of 4 and 5 (Scheme 2A). Lactam 5 could be further reduced with lithium aluminum hydride to afford mono-cyclopropyl piperazine 6. All three piperazines (4–6) were found to display a single conformation at low temperature. While it was not possible to establish the conformations by NOE, the expected preference for diaxial conformation in 4 was observed in an X-ray crystal structure (Scheme 2b). Similarly, mono-cyclopropane 6 when crystallized as a hydrated bis-p-toluenesulfonic acid salt displayed an axial/equatorial conformation with the benzyl group adjacent to the cyclopropane selectively forced into the axial position (Scheme 2c). These studies establish the ability to modulate the conformation of 6-membered ring heterocycles by straightforward incorporation of spirocyclic cyclopropanes. Notably, comparing 4, 5, and 6, it is possible to maintain one benzyl group axial while displaying the other axial, pseudo-equatorial, or equatorial, respectively, depending upon the identity of the adjacent group.
![]() | ||
Scheme 2 (A) Synthesis and conformation of spirocyclopropylpiperazines (B) SCXRD of 4 (C) SCXRD of 6·(TsOH)2·H2O (tosylates and water have been removed for clarity – see ESI† for full structure). |
Our study has demonstrated that small rings commonly used as isosteres can also be used for elements of conformational control in cyclohexanes, six-membered ring heterocycles and in acyclic systems. Compared to simple di-alkyl substitution, small constrained rings shift the equilibria of adjacent groups towards axial conformers for most substituents.
The main origin of the effect for alkyl groups is a change in steric strain. In a simple geminal dimethyl system, the torsion angle between an equatorial substituent (e.g. methyl) and the two methyl groups is 60° ± 5° (Fig. 5A). The constraint of the cyclopropane ring significantly reduces this angle (34° and 38°), resulting in increased steric interactions. In addition, in the axial form, the torsion angle in the cyclopropane is opened significantly from 47° to 77°, suggesting a potential reduction of steric interactions. An NBO-STERIC calculation52,53 indicated the relative difference between axial and equatorial conformers is reduced by 2.08 kcal mol−1 when comparing the dimethyl (2.72 kcal mol−1) to cyclopropyl (0.64 kcal mol−1) substituents. This 2 kcal mol−1 reduction in steric interactions is consistent with the change in A-value observed experimentally. To examine this effect in more depth, butane was used to model the steric interactions of individual torsion components. Freezing butane torsion angles at the equivalent angles from the cyclohexane system revealed that the smaller torsional angles in the equatorial form for the cyclopropane add 1.96 kcal mol−1 in steric interactions relative to the torsional angles in a dimethyl group (Fig. 5b). Conversely, in the axial form, the steric interactions are lower by −0.81 kcal mol−1 for the cyclopropane.54 While only an approximation, these results are suggestive of a combination of destabilization of the equatorial form and a net stabilization (relative to dimethyl) in the axial form for spirocyclopropanes. These steric strain effects are presumably increased in N-heterocycles (e.g.1–6) due to reduced bond length along the torsion axis (1.45 vs.1.52 Å) as well as with larger groups (e.g. tert-butyl).
While simple torsional strain arguments can be used to explain the preference in alkyl-substituted cyclohexanes, the trends with halides and other electron poor groups suggest that stereoelectronic factors also contribute. For instance, both fluoro and chloro groups have smaller van der Waals radius than methyl55,56 but both clearly prefer the axial conformation whereas for methyl the axial and equatorial conformations are roughly equal in energy. One potential stabilizing factor may be hyperconjugative donation from the cyclopropyl group into the C–X antibonding orbitals.21 While the C–C bond axis is not well aligned for donation, the electron density of the cyclopropane lies outside of the bond axis and is positioned appropriately to donate to σ* (Fig. 6). Notably, an NBO analysis revealed stronger donation into the C–X σ* from the cyclopropane vs. an axial methyl, on the order of 0.8–1 kcal mol−1 for both F and Cl. This hyperconjugative stabilization presumably stabilizes the axial form and, in combination with increased torsional strain in the equatorial isomer, results in a more significant preference for axial orientation. Notably, the hyperconjugation is significantly reduced in the corresponding cyclobutyl fluoride (predicted A-value: +0.15 kcal mol−1, σ–σ* donation only 0.2 kcal mol−1 greater than methyl).
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Fig. 6 NBO orbital overlap of cyclopropane C–C σ-bond with axial C–F σ*, calculated at the M06-2X/6-311++G(2d,2p) level. |
Footnote |
† Electronic supplementary information (ESI) available. CCDC 2375096–2375098. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4sc05470a |
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