Strain Release in Hydrogen Atom Transfer from 1,4-Disubstituted Cyclohexanes to the Cumyloxy Radical

Abstract

A kinetic, product, and computational study on the reactions of the cumyloxyl radical (CumO^•) with 1,4-dimethyl- and 1,4-diphenylcyclohexanes is reported. The rate constants for hydrogen atom transfer (HAT) from the C–H bonds of these substrates to CumO^•, together with the corresponding oxygenation product distributions reveal the role of strain release on reaction site selectivity. Transition structures and activation barriers obtained by DFT calculations are in excellent agreement with the experimental results. Tertiary/secondary ratios of oxygenation products of 0.6, 1.0, and 3.3 were observed, for trans-1,4-dimethyl-, cis-1,4-dimethyl-, and trans-1,4-diphenylcyclohexane, respectively. With cis-1,4-diphenylcyclohexane, exclusive formation of the diastereomeric tertiary alcohol products was observed. Within the two diastereomeric couples, the tertiary equatorial C–H bond in the cis- isomer is ca. 6 and 27 times more reactive, respectively, than the tertiary axial ones, a behavior that reflects the release of 1,3-diaxial strain in the HAT transition state. The tertiary axial C–H bonds of the four substrates show remarkably similar reactivities in spite of the much greater stabilization of the benzyl radicals resulting from HAT from the 1,4-diphenylcyclohexanes. The lack of benzylic acceleration is discussed in the framework of Bernasconi’s ‘principle of nonperfect synchronization’.

The selective functionalization of unactivated C(sp ³)–H bonds is an important topic in current synthetic chemistry.[1] Because of the multitude of C–H bonds present in organic molecules, site selectivity is an important issue in applying such reactions to synthesis.[2] In general, reactivities are predominantly controlled by thermodynamic, polar, and steric effects.[1b] [2] [3] In addition, torsional effects have been identified as important contributors to the observed site and stereoselectivity in the reactions of cyclohexanes and decalins. For example, torsional effects destabilize the transition states for HAT from the tertiary axial C–H bond (C-1) and secondary C–H bonds at C-2.[4] As shown in Figure [1]A, planarization of the incipient carbon-centered radical forces the C–R bond toward an unfavorable eclipsed interaction with the equatorial C–H bonds at the adjacent positions. In Figure [1]B, planarization forces the remaining C–H bond toward an unfavorable eclipsed interaction with the C–R bond at the adjacent position.

Further examples have been identified in the oxygenation of monosubstituted cyclopentanes and cyclohexanes promoted by the cumyloxyl radical (CumO^•) and ethyl(trifluoromethyl) dioxirane (ETFDO).[5]

A spectacular example of selectivity promoted by strain release was reported by Baran and coworkers, who oxidized the eudesmane terpene dihydrojunenol with methyl(trifluoromethyl) dioxirane (TFDO). Hydroxylation occurred at a single tertiary equatorial C–H₁ bond, in the presence of other four tertiary, ten secondary, and twelve primary C–H bonds (Scheme [1]).[6] The observed site selectivity occurs due to the release of the 1,3-diaxial strain in the transition state for C–H₁ bond oxidation.[4] [7] [8] Dioxiranes insert an O into C(sp ³)–H bonds via a transition state that resembles that for radical HAT.[8,9]

Similar effects are observed in the oxygenation of 1,2-dimethylcyclohexanes and decalins promoted by TFDO and by iron- and manganese-oxo species,[10] where higher tertiary/secondary selectivity is observed for the cis isomer as compared to the corresponding trans isomer. Further examples were obtained in a kinetic study of the reactions of CumO^• with the trans and cis isomers of dimethylcyclohexanes and decalins.[4] Tertiary equatorial C–H bond activation has been recently exploited to direct site selectivity in the oxidation of ring-substituted N-cyclohexyl acetamides and pivalamides with H₂O₂ catalyzed by manganese complexes.[11]

We report here an experimental and theoretical study on the HAT-based oxygenation of cis- and trans-1,4-dimethyl- and 1,4-diphenylcyclohexanes to eliminate the complication of the 1,2-torsional interactions that occur in many of the examples described here. The reactivities and site selectivities with CumO^• are obtained through kinetic and product studies and are analyzed with quantum mechanically computed C–H BDEs and reaction barriers as well as the analysis of transition-state geometries.

CumO^• was generated by 355 nm laser flash photolysis (LFP) of argon-saturated acetonitrile or chlorobenzene solutions (T = 25 °C) containing 1.0 M dicumyl peroxide.[12] The reactions of CumO^• with the disubstituted cyclohexanes were studied using the LFP technique following the decay of the CumO^• visible absorption band (λ_max = 485 nm) as a function of substrate concentration (see the Supporting Information). The k _H values measured in acetonitrile, for the reaction of CumO^• with cis-1,4-dimethylcyclohexane (cis-1) and trans-1,4-dimethylcyclohexane (trans-1), were available from a previous study.[4] With trans-1,4-diphenylcyclohexane (trans-2), a ≤80 mM solubility limit was determined in chlorobenzene, hence only an upper limit to k _H could be obtained. The measured k _H values for the reaction of CumO^• with cis- and trans-1,4-dimethyl and 1,4-diphenylcyclohexane are presented in Table [1].

Table 1 Second-Order Rate Constants (k _H) for the Reaction of the Cumyloxyl Radical (CumO^•) with 1,4-Disubstituted Cyclohexanes^a

Substrate	k H [M–1 s–1]
trans-1,4-dimethylcyclohexane (trans-1)	1.10±0.02·106 d
cis-1,4-dimethylcyclohexane (cis-1)	2.05±0.06·106 d
trans-1,4-diphenylcyclohexane (trans-2)	≤7·105 b,c,e
cis-1,4-diphenylcyclohexane (cis-2)	7.56±0.08·106 e

^a Measured in argon-saturated acetonitrile solution at T = 25 °C employing 355 nm LFP, [dicumyl peroxide] = 1.0 M.

^b Measured in PhCl solution.

^c Because of the low solubility displayed by this substrate, only an upper limit to k _H could be obtained.

^d Ref. 4.

^e This work.

Product analyses of the reactions of CumO^• with cis- and trans-1,4-dimethyl- and 1,4-diphenylcyclohexane were performed. CumO^• was generated by 310 nm steady-state photolysis of oxygen-saturated acetonitrile or chlorobenzene solutions containing 0.1 M dicumyl peroxide, according to a previously described procedure.[5] In the presence of the substrate (0.08–0.30 M), HAT from the aliphatic C–H bonds occurs, and the carbon-centered radicals thus formed are rapidly trapped by oxygen to give peroxyl radical intermediates that evolve to the oxidation products (ketones and secondary and tertiary alcohols, Scheme [2]).

The reactions of cis-1, trans-1, and cis-2 were carried out in acetonitrile at T = 25 °C for an irradiation time of 9 h. Because of the solubility issues discussed above, the reaction of trans-2 was carried out in chlorobenzene. The full details of these studies and the product distributions obtained are reported in the Supporting Information.[13]

Table 2 Calculated (ΔG ^‡(cal)) and Experimental (ΔG ^‡(exp)) Activation Barriers for HAT from the C–H Bonds of cis- and trans-1,4-Disubstituted Cyclohexanes to the Cumyloxyl Radical (CumO^•) and Pertinent C–H BDEs

	C–H	ΔG ‡(cal) (ΔG ‡(exp)a)b	C–H BDEb,c
cyclohexane	ax	12.1	96.7
	eq	11.9	96.7
	C-1	9.9 (ca. 9.2)	93.1
	C-2(ax)	11.1 (10.8)	97.0
	C-2(eq)	14.1	97.0
	C-3(ax)	13.2	96.7
	C-3(eq)	11.6	96.7
	C-4	10.7 (10.2)	94.5
	C-1	10.6 (10.2)	94.6
	C-2(ax)	11.5 (10.8)	97.1
	C-2(eq)	12.6	97.1
	C-1	8.4 (8.1)	84.3
	C-2(ax)	10.6	97.2
	C-2(eq)	15.1	97.2
	C-3(ax)	15.2	94.8
	C-3(eq)	10.1	94.8
	C-4	10.4 (≥10.1)	87.0
	C-1	10.5 (≥10.1)	86.9
	C-2(ax)	12.5	97.2
	C-2(eq)	11.6 (≥11.6)	97.2

^a ΔG ^‡(exp) is obtained from the Eyring equation based on the normalized rate constants provided in the text.

^b All values in kcal mol^–1.

^c BDEs for the secondary sites are in all cases identical for both the axial and equatorial C–H bonds because they give the same radical.

The reactions of CumO^• with cis-1, trans-1, and trans-2 gave the diastereomeric tertiary alcohols, along with products arising from HAT at methylene sites, namely secondary alcohol and corresponding ketone products (Scheme [3]A). Because of the competitive and facile overoxidation of the initially formed secondary alcohol products, no information on the cis-trans stereoselectivity was obtained. In order to simplify product identification and quantitative GC analysis, the reaction mixtures were oxidized with chromic acid, which results in quantitative conversion of all secondary alcohols into the corresponding ketones.

Tertiary/secondary ratios of oxygenation products of 0.6, 1.0, and 3.3 were observed, for trans-1, cis-1, and trans-2, respectively. With cis-2, exclusive formation of the diastereomeric tertiary alcohols was observed (Scheme [3]B).

The structures of reactants and transition states for the reaction of CumO^• with the four substrates were optimized with the density functional UωB97X-D[14] with the 6-31G (d) basis set. Frequency analyses were carried out on these stationary points to verify that they are energy minima or saddle points (transition states). Single point energies with a more extensive basis set were carried out with UωB97X-D/6-311++G (d, p) on the optimized geometries. Solvent effects for acetonitrile were included with the CPCM[15] model. All calculations were performed with Gaussian 16.[16] Cartesian coordinates and energies for each substrate and TS are provided in the Supporting Information.

The DFT activation barriers for the reactions of CumO^• with cis-1, trans-1, cis-2, and trans-2 are listed in Table [2], with comparison to the corresponding data obtained for cyclohexane. Also collected in Table [2] are the pertinent C–H BDEs computed at the same level. In general, the computed barriers (ΔG ^‡(cal)) are within 1 kcal/mol of those derived by transition state theory from experimental rate constants (ΔG ^‡(exp)).

The transition structures for HAT from the different C–H bonds of the four substrates to CumO^• are displayed in Table [3]. The extent of H transfer is similar in all cases, but the lower barriers are associated with ‘earlier’ transition states (smaller extent of H transfer).

Table 3 Transition Structures for HAT from the C–H Bonds of cis- and trans-1,4-Disubstituted Cyclohexanes to the Cumyloxyl (CumO^•) Radical

C–Hs	C-1	C-2(ax)	C-2(eq)
C–Hs	C-4	C-3(ax)	C-3(eq)
Cyclohexane (ax)		Cyclohexane (eq)

Taking cyclohexane as the reference substrate, the analysis of the computed C–H BDEs displayed in Table [2] points toward identical BDEs of 96.7 kcal mol^–1 for the axial and equatorial C–H bonds of this substrate. Replacement of hydrogen by methyl leads to a sizable decrease in BDE for the tertiary C–H bonds, exemplified by cis-1, for which BDE = 93.1 and 94.5 kcal mol^–1 for the tertiary equatorial and axial C–H bonds, respectively. The latter value is in excellent agreement with the calculated BDEs for the tertiary axial C–H bonds of trans-1 and of methylcyclohexane (94.6 and 94.5 kcal mol^–1, respectively). An analogous trend was observed with the corresponding phenyl-substituted substrates: BDE = 84.3 and 87.0 kcal mol^–1 for the tertiary equatorial and axial C–H bonds of cis-2, with the latter value being again in excellent agreement with the calculated BDEs for the tertiary axial C–H bonds of trans-2 and of phenylcyclohexane (86.9 and 86.8 kcal mol^–1, respectively). BDEs ranging between 96.7 and 97.2 kcal mol^–1, i.e. very close to those calculated for cyclohexane, were obtained for the secondary C–H bonds of the four substrates. The only exception to this are the C₃–H bonds of cis-2, for which BDE = 94.8 kcal mol^–1. On thermodynamic grounds, tertiary equatorial C–H bonds appear to be activated toward HAT over the corresponding axial ones, with the extent of activation increasing with steric bulk of the substituent (ΔBDE(ax - eq) = 1.4 and 2.7 kcal mol^–1 for cis-1 and cis-2, respectively). In summary, Me and Ph reduce the BDE of axial C–H bonds by ca. 2 and 10 kcal mol^–1, respectively. The corresponding equatorial C–H bonds have an additional lowering of 1.5 and 2.6 kcal mol^–1, due to the release of the 1,3-diaxial strain in these compounds.

A different picture arises, however, from the analysis of the results of product and kinetic studies on the reactions of CumO^• with the four substrates and of the calculated activation free energies (ΔG ^‡(cal)) for these reactions displayed in Table [2] that identify kinetic effects as additional contributors to the observed selectivity patterns.[17]

The site selectivities normalized on a per-hydrogen basis, observed in the reactions of CumO^• with trans-1 and trans-2, could be derived from the product distributions and are displayed in Figure [2]A. The normalized site selectivities for the reaction of CumO^• with cis-1 and cis-2 are displayed in Figure [2]B. These values were instead obtained indirectly by combining the results of the product studies of the reactions of the four substrates with the corresponding k _H values collected in Table [1]. Full details of this procedure are provided in the Supporting Information.

From these site selectivities and taking into account the k _H values collected in Table [1], the following normalized rate constants for HAT from a tertiary axial or equatorial C–H bond (k _H(tert,ax) or k _H(tert,eq), respectively) and from a secondary C–H bond (k _H(sec)) of the four substrates to CumO^• could be derived as described in the Supporting Information. These values are displayed in Table [4].

These values allow a general comparison between the reactivity of all C–H bonds of the four substrates toward ­CumO^•. The normalized C–H bond reactivities relative to the least reactive secondary C–H bonds of trans-2 are displayed in Figure [3].

The values displayed in Figure [3] show that within both diastereomeric couples, the tertiary equatorial C–H bond is significantly more reactive than the tertiary axial ones (ca. 6- and 27-fold for 1 and 2, respectively), highlighting the strong activation of the former C–H bonds via release of the 1,3-diaxial strain in the HAT transition state. When comparing the four substrates, very similar reactivities are displayed by the tertiary axial C–H bonds, irrespective of the nature of the ring substituents. On the other hand, the tertiary equatorial C–H bond reactivity increases by a factor of ca. 6 going from cis-1 to cis-2, indicating that the contribution of strain release to the HAT reactivity increases with increasing steric bulk of the axial substituent. The tertiary/secondary reactivity ratio is observed to increase significantly going from trans-1 to trans-2, a behavior that can be accounted for in terms of the operation of deactivating torsional effects for HAT from C-2 (Figure [1]B)[4] that are expected to increase with increasing steric bulk of the ring substituent.

The computed activation barriers displayed in Table [2] lend support to this picture, showing an excellent agreement with the experimental findings (compare the ΔG ^‡(cal) values with the ΔG ^‡(exp) ones). Within both diastereomeric couples, the ΔG ^‡(cal) value for HAT from the tertiary equatorial C–H bond of the cis isomer is lower than the value obtained for HAT from the tertiary axial C–H bond of the corresponding trans isomer (ΔG ^‡(cal) = 9.9 and 10.6 kcal mol^–1 for cis-1 and trans-1, and 8.4 and 10.5 kcal mol^–1 for cis-2 and trans-2, respectively).

The 1.5 kcal mol^–1 decrease in ΔG ^‡(cal) for HAT from the tertiary equatorial C–H bond (1.1 kcal mol^–1 decrease in ΔG ^‡(exp)), calculated going from cis-1 to cis-2, despite a difference in C–H BDE of 8.8 kcal mol^–1, is in line with an earlier transition state for the latter reaction as compared to the former one, where C–H bond cleavage has progressed to a limited extent and benzylic stabilization of the tertiary radical plays a minor role, an observation that is well supported by the transition structures displayed in Table [3], with the C₁–H bond distance that decreases from 1.24 to 1.22 Å and the O–H bond distance that increases from 1.31 to 1.36 Å going from cis-1 to cis-2. This observation can be accounted for on the basis of Bernasconi’s ‘principle of nonperfect synchronization’ (PNS),[18] where conjugation of the incipient radical center with stabilizing unsaturation is not manifested in the HAT transition state.[19]

The structure deviation observed in the reaction of ­CumO^• with cis-2 going from the reactants to the transition state is displayed in Figure [4]. Calculations evidence the release of the 1,3-diaxial strain in the transition state for HAT from the tertiary equatorial C–H bond associated to the planarization of an incipient carbon-centered radical that accounts for the observed C–H bond activation as is observed in BDEs. Conjugation with stabilizing unsaturation is not manifested in the transition structure with the axial phenyl group that rotates into an unfavorable conformation to stabilize the developing radical center.

As shown in Figure [4], the distances from C1 of the axial 1-phenyl to the 3- and 5-axial Hs are 3.03 and 2.85 Å, the latter slightly smaller than the sum of the van der Waals radii of C and H (1.7 and 1.2 Å), while in the transition state for HAT both distances (2.98 and 2.90 Å) are equal or larger than the sum of the van der Waals radii of C and H. The van der Waals repulsion in the substrate is replaced by van der Waals attraction in the transition state.

The indication of very similar reactivities for the tertiary axial C–H bonds of the four substrates is nicely reflected in the ΔG ^‡(cal) values obtained for HAT from the tertiary axial C–H bonds to CumO^• (ΔG ^‡(cal) = 10.7, 10.6, 10.4, and 10.5 kcal mol^–1 for cis-1, trans-1, cis-2, and trans-2, respectively). This behavior can be rationalized on the basis of the increase in the relative importance of deactivating torsional effects for HAT from the tertiary axial C–H bonds (Figure [1]A),[4] associated to the increased steric bulk of the ring substituent. The observation that these effects override the favorable enthalpic gap determined by the benzylic nature of the tertiary C–H bonds of substrates 2 (for example C₁–H BDE = 94.6 and 86.9 kcal mol^–1 for trans-1 and trans-2, respectively), can be again accounted for on the basis of the PNS principle.[17]

Concerning the reactivities of the secondary C–H bonds, all four substrates display significantly higher barriers for HAT compared to the tertiary ones and, within each substrate, the difference in ΔG ^‡(cal) between the secondary and tertiary C–H bonds characterized by the lowest barrier (ΔΔG ^‡(cal) = 0.9, 1.2, 1.1, and 1.7 kcal mol^–1 for trans-1, cis-1, trans-2, and cis-2, respectively, see Table [2]) supports the experimental observation that only with cis-2 HAT to ­CumO^• occurs selectively from the tertiary sites with no competition from secondary ones. As compared to cyclohexane, for which almost identical ΔG ^‡(cal) values have been obtained for HAT from the equatorial and axial C–H bonds (ΔG ^‡(cal) = 11.9 and 12.1 kcal mol^–1, respectively), the data displayed in Table [2] show that the presence of an adjacent substituent amplifies this energy difference that becomes particularly pronounced with the cis isomers, increasing on going from cis-1 to cis-2, for which ΔΔG ^‡(cal) values of 4.5 and 5.1 kcal mol^–1 have been calculated for HAT from the secondary C–H bonds at C-2 and C-3, respectively. Most interestingly, the axial substituent appears to increase the activation barrier for HAT from the equatorial C–H bond at C-2 and from the axial C–H bond at C-3 (cis) and to decrease the activation barrier for HAT from the axial C–H bond at C-2 and the equatorial C–H bond at C-3 (trans), with the magnitude of this effect that increases with increasing steric bulk of the axial group. A combination of torsional and steric effects may account for these intriguing observations.

In conclusion, a quantitative evaluation of the role of the 1,3-diaxial strain release effects on the C(sp ³)–H bond reactivity in the reactions of CumO^• with 1,4-dimethyl- and 1,4-diphenylcyclohexanes has been obtained through a combined approach involving kinetic, product, and computational studies. With the trans isomers and with cis-1,4-dimethylcyclohexane competitive oxygenation at secondary and tertiary sites is observed. With cis-1,4-diphenylcyclohexane oxygenation selectively occurs at the tertiary sites. A ca. 6- and 35-fold increase in the HAT rate constant (k _H) has been measured going from the least reactive tertiary axial C–H bond of trans-1,4-dimethylcyclohexane to the tertiary equatorial C–H bonds of cis-1,4-dimethyl and cis-1,4-diphenylcyclohexane, respectively. This highlights the impact of the 1,3-diaxial strain release in the HAT transition state for the activation of these bonds. The increase in k _H approaches a factor 350 when extending the comparison to secondary C–H bonds. Transition structures and activation barriers obtained by DFT calculations show an excellent agreement with the experimental results and, together with C–H BDEs, uncover the features associated to C–H bond reactivity and the origin of the observed site selectivities. The lack or limited extent of benzylic activation observed in the reactions of the 1,4-diphenylcyclohexanes is rationalized on the basis of Bernasconi’s ‘principle of nonperfect synchronization’ and represents an additional example of its operation in HAT reactions from C(sp ³)–H bonds.

Conflict of Interest

The authors declare no conflict of interest.

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Corresponding Authors

Publication History

Received: 11 December 2024

Accepted after revision: 22 January 2025

Accepted Manuscript online:
22 January 2025

Article published online:
11 March 2025

© 2025. Thieme. All rights reserved

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• References and Notes

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  Search in Google Scholar
• 1b White MC, Zhao J. J. Am. Chem. Soc. 2018; 140: 13988
  Search in Google Scholar
• 1c Chu JC. K. Rovis T. Angew. Chem. Int. Ed. 2018; 57: 62
  Search in Google Scholar
• 1d Hartwig JF. J. Am. Chem. Soc. 2016; 138: 2
  Search in Google Scholar
• 1e Yamaguchi J, Yamaguchi AD, Itami K. Angew. Chem. Int. Ed. 2012; 51: 8960
  Search in Google Scholar
• 1f Gutekunst WR, Baran PS. Chem. Soc. Rev. 2011; 40: 1976
  Search in Google Scholar
• 2 Newhouse T, Baran PS. Angew. Chem. Int. Ed. 2011; 50: 3362
  Search in Google Scholar
• 3a Galeotti M, Salamone M, Bietti M. Chem. Soc. Rev. 2022; 51: 2171
  Search in Google Scholar
• 3b Ravelli D, Fagnoni M, Fukuyama T, Nishikawa T, Ryu I. ACS Catal. 2018; 8: 701
  Search in Google Scholar
• 4 Salamone M, Ortega VB, Bietti M. J. Org. Chem. 2015; 80: 4710
  Search in Google Scholar
• 5 Martin T, Galeotti M, Salamone M, Liu F, Yu Y, Duan M, Houk KN, Bietti M. J. Org. Chem. 2021; 86: 9925
  Search in Google Scholar
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• 7 Chen K, Eschenmoser A, Baran PS. Angew. Chem. Int. Ed. 2009; 48: 9705
  Search in Google Scholar
• 8 Zou L, Paton RS, Eschenmoser A, Newhouse TR, Baran PS, Houk KN. J. Org. Chem. 2013; 78: 4037
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• 9 Yang Z, Yu P, Houk KN. J. Am. Chem. Soc. 2016; 138: 4237
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• Supplementary Material