Conformational Preferences in Cyclohexanes and Cyclohexenes

Conformational Preferences in Cyclohexanes and Cyclohexenes Frederick R. Jensen and C. Hackett Bushweller DEPARTMENT OF CHEMISTRY, UNIVERSITY OF CALIFORNIA, BERKELEY, CALIFORNIA DEPARTMENT OF CHEMISTRY, WORCESTER POLYTECHNIC INSTITUTE, WORCESTER, MASSACHUSETTS

I. Introduction A. Acyclic Structures B. Cyclohexane C. Cyclohexene D. Nomenclature II. Evaluation of Methods A. The NMR Peak Area Measurement Technique B. Use of Locking Groups to Establish Model Compounds C. Nuclear Magnetic Resonance Chemical Shift Method For Determin­ ing A Values D. Estimation of A Values from Time-Averaged Coupling Constants E. Hydroxylic Proton Chemical Shift Method F. Determination of the Enthalpy (Ai/°) and Entropy (àS°) of the Axial ^ Equatorial Equilibrium in Monosubstituted Cyclohexanes by NMR Spectroscopy G. Determination of the A Value of the Carboxyl Group from Acid Dis­ sociation Constants H. The Kinetic Method for Determining A Values I. A Values from Infrared Spectroscopy J. Equilibration Method for Determining A Values K. Other Methods III. Enthalpy and Entropy Changes for the Axial ^ Equatorial Equilibrium in Monosubstituted Cyclohexanes IV. A Values A. Tabulation and Selection of "Best" A Values B. Discussion of Various A Values C. Solvent Effects on A Values V. Disubstituted Cyclohexanes and the Additivity of A Values VI. Cyclohexene Derivatives 139

140 140 143 147 148 149 149 153 155 160 161 163 164 166 168 170 172 173 173 173 176 185 185 190

140

Frederick R. Jensen and C. Hackett Bushweller

I. Introduction A. ACYCLIC STRUCTURES

Conformational analysis in acyclic and cyclic systems with the ramifications concerning thermodynamics and chemical reactivity was given impetus by the postulation of Kemp and Pitzer1 that there is a barrier to rotation in ethane of approximately 3 kcal/mole. This proposal accounted for the discrepancies between experimental and calculated values for the heat capacity and entropy of ethane. 2 The preferred conformation of ethane is the staggered form with the eclipsed conformer being about 3 kcal/mole higher in energy [Eq. (1)]. indeed, thermodynamic and spectroscopic methods indicate a barrier of

V rH'

n

^ 1

0)

H

approximately 3 kcal/mole in a host of simple ethane derivatives.3 It is interesting to note that the magnitude of the barrier to rotation in pro­ pane (3.3-3.4 kcal/mole)4 with one CH 3 -H and two H-H interactions in the transition state [Eq. (2)] is not significantly greater than the barrier in ethane [Eq. (1)]. It appears that an eclipsed CH 3 -H interaction is only slightly larger CH 3

WT\^

H-V-H

"ir

H

H CH 3

h

*

*

\^+V^ H

H^V^CH3

(2)

(relative to the skew) than the eclipsed H-H interaction. Since the distance be­ tween the two eclipsed hydrogen atoms in the eclipsed conformer of ethane (—2.3 Â) is about equal to the sum of the van der Waals radii of two hydrogen atoms (—2.4 Â), van der Waals repulsions cannot account completely for the barrier in ethane or propane. 5 Hypotheses involving quadrupolar repulsion,6 1

J. D . Kemp and K. S. Pitzer, / . Amer. Chem. Soc. 59, 276 (1937); J. D . Kemp and K. S. Pitzer,/. Chem. Phys. 4, 749 (1936); K. S. Pitzer, ibid. 5, 473 (1937). 2 R. K. Witt and J. D . Kemp, / . Amer. Chem. Soc. 59, 273 (1937). } E. B. Wilson, Jr., Advan. Chem. Phys. 2, 367 (1959). 4 K. S. Pitzer, / . Chem. Phys. 12, 310 (1944). 5 H. Eyring, / . Amer. Chem. Soc. 54, 3191 (1932). 6 E. N . Lassettre and L. B. Dean, J. Chem. Phys. 17, 317 (1949); E. B. Wilson, Proc. Nat. Acad. Sci. U.S. 43, 816 (1957).

141

Cyclohexane and Cyclohexene Conformations

repulsions between bonding electrons,7 and differential hyperconjugative stabilization of the staggered over the eclipsed conformer8 have been postu­ lated to account for the barrier in ethane, but no incisive depiction of the barrier source can be given. In simple ethane derivatives, one eclipsing interaction, commonly referred to as "torsional strain," amounts to about 1 kcal/mole. If the substituents involved are sufficiently bulky, a "normal" steric effect can arise. Butane exists in two stable conformations, the anti [Eq. (3)] and the gauche. The gauche conformer is capable of existing in two equivalent forms thus being favored over the anti by an entropy term (R In 2). The potential maximum when two methyl groups are eclipsed [Eq. (3)] is estimated to be 4.4-6.1 kcal/mole.9 Subtracting the two torsional H-H interactions (~2 kcal/ HÇH

CH 3

(3)

S

^

CH3 H^K^

C H

3

H gauche

CH 3 anti

CH 3

H 3 ÇCH 3 Ί *

Ha 3 CU ^ ^ - N / H,C

Η^Φ^Η H gauche

mole), the CH 3 -CH 3 nonbonded compression energy could be as high as 4.1 kcal/mole. The other eclipsed form of butane in which there is no CH 3 -CH 3 eclipsing is estimated to be about 3.3 kcal/mole higher in energy than the anti form and 2.5 kcal/mole higher in energy than the gauche form. Thus, it would appear that the anti form of butane is about 0.8 kcal/mole more stable than the gauche. 7

L. Pauling, Proc. Nat. Acad. Sci. U.S. 44, 211 (1958). G. H. Stewart and H. Eyring, / . Chem. Educ. 35, 550 (1958). 9 K. Ito, J. Amer. Chem. Soc. 75, 2430 (1953); W. G. Dauben and K. S. Pitzer, in "Steric Effects in Organic Chemistry" (M. S. Newman, ed.), p. 3. Wiley, New York, 1956. 8

142

Frederick R. Jensen and C. Hackett Bushweller

In some structures possessing bulky substituents, the interactions between substituents are not always repulsive. At certain interspatial distances, the forces between atoms or groups are attractive. Indeed, the relative roles of attractive and repulsive forces are not always clear. For example, 1-chlorobutane is reported to prefer the gauche conformer (l), 10 whereas 1-bromobutane prefers the anti (2).11 Br

CI

H

CH2CH3

H H

CH2CH3

(1)

(2)

Although not many data are available, solvent effects are apparently very important for structures possessing polar substituents. Pure meso-2,3-dibvomobutane exists about 30 % in the gauche form (3) with the remainder in the anti conformer (4). In the less polar solvent carbon disulfide, the amount of the

KK H"

•c

-x/Br

CH 3

(·i)

H 3 c^

•0 W

Y

/H ^CH

Br

(<»)

gauche conformer drops to about 20 %.12 The very fact that the ostensibly sterically crowded gauche form of me.S0-2,3-dibromobutane is present at all illustrates the varying roles of attractive versus repulsive forces between proxi­ mate functionalities. Although no concrete examples have been reported in the literature, the internal pressure13 of a given solvent is expected to affect conformational pre­ ferences. The conformer with the effectively smaller molecular volume would be favored in solvents of high internal pressure. This may prove to be an attractive area for research in the future. Electrostatic interactions, i.e., dipole-dipole interactions must be considered important in molecules containing more than one polar substituent. In gaseous 10

T. Ukaji and R. A. Bonham, / . Amer. Chew. Soc. 84, 3631 (1962). F. A. Momany, R. A. Bonham, and W. H. McCoy,/. Amer. Chem. Soc. 85, 3077 (1963). 12 A. A. Bothner-By and C. Naar-Colin, /. Amer. Chem. Soc. 84, 743 (1962); see also N ; Sheppard, Advan. Spectrosc. 1, 295 (1959) concerning 1,2-dichloroethane. 13 J. H. Hildebrand and R. L. Scott, "Solubility of Nonelectrolytes," 3rd ed. Reinhold, New York, 1950. 11

143

Cyclohexane and Cyclohexene Conformations

1,2-dichloroethane, the gauche conformer is unfavorable due not so much to steric repulsions between chlorine atoms but to an unfavorable orientation of bond moments [Eq. (4)]. However, the occurrence of the gauche form in a CI

H.

4Η

'A^CCI

(4)

er

H /χ~3.2

μ= 0

significant amount provides strong evidence for a compensating London attractive force between chlorines. An excellent example illustrating the im­ portance of attractive forces under optimum conditions is the 1,2-dichloroethylenes wherein m-l^-dichloroethylene is preferred over the trans isomer by about 0.5 kcal/mole.14 Thus, conformational analysis involves evaluating the populations of the various conformations of a structure in terms of torsional interactions, steric repulsions, London attractive forces, dipole-dipole interactions, and chargecharge interactions. Cyclohexane and cyclohexene derivatives have been of special interest in conformational analysis because the pertinent interactions are similar in many ways to those important in acyclic structures. B. CYCLOHEXANE

Theoretical calculations15 and experimental data 16 indicate that the twist (5) and boat (6) forms of cyclohexane are of substantially higher energy (~5-7 kcal/mole) than the chair form (7). Consequently, in any investigation of the conformational dynamics or preferences of simple, unencumbered cyclohexane derivatives, one may assume the essentially exclusive presence of

(5) 14

(6)

(7)

H.A. Stuart, Phys.Z. 32, 793 (1931). (a) C. W. Beckett, K. S. Pitzer, and R. Spitzer, /. Amer. Chem. Soc. 69, 2488 (1947); (b) C. W. Beckett, N. K. Freeman, and K. S. Pitzer, ibid. 70, 4227 (1948); (c) R. B. Turner, ibid. 74, 211 (1952); (d) K. E. Howlett, /. Chem. Soc. p. 4353 (1957). 16 (a) W. S. Johnson, J. L. Margrave, V. J. Bauer, M. A. Frisch, L. H. Dreger, and W. N. Hubbard,/. Amer. Chem. Soc. 82,1255 (1960); (b) J. E. Anderson, Quart. Rev. p. 426 (1965). 15

144

Frederick R. Jensen and C. Hackett Bushweller

the chair conformer. However, appropriate structural modifications,17 e.g., introduction of *s/?2-hybridized carbon atoms or large substituents in a specific stereochemical orientation can at least distort the cyclohexane ring from a true chair form or render the twist conformer as the more stable species. In a consideration of the conformational dynamics of monosubstituted cyclohexanes, the existence of chair «± chair isomerism with a substituent (X) equilibrating between axial (Xa) and equatorial (Xe) positions is expected [Eq. (5)]. It would be anticipated that X has unique steric requirements in axial

(5) Xe

(Xa) and equatorial (Xe) positions, and preference for one conformation would be observed. From theoretical considerations, the generally expected trend is preference for the equatorial conformer. Hypotheses which explain this trend have been presented in detail elsewhere.17 However, a brief summary of current theories is appropriate. One theory invokes differential nonbonded compressions between the substituent [X; Eq. (5)] and proximate groups in the axial and equatorial conformers. It is evident from the geometry of the axial conformer that the axial substituent can experience repulsive nonbonded interactions with two l,3-.sy«-axial hydrogens [(8) or (9)]. Such interactions are analogous to those important in the gauche conformer of butane [Eq. (3)], and can be

(8)

(10) 17

E. L. Eliel, N. L. Allinger, S. J. Angyal, and G. A. Morrison, "Conformational Analysis." Interscience, New York, 1966.

145

Cyclohexane and Cyclohexene Conformations

alleviated by conversion to the equatorial conformer (10) or (11). Recent theoretical calculations,18 employing a modified form of the method of Westheimer, and involving consideration of 1,3-syn-axia\ nonbonded repul­ sions, have provided enthalpies (Δ//°) for axial ^ equatorial equilibria [Eq. (5)] for a limited number of monosubstituted cyclohexanes in excellent agreement with reliable experimental values. It is expected that these types of calculations will have a major impact on conformational analysis. TABLE I CONFORMATIONAL PREFERENCES IN MONOSUBSTITUTED CYCLOHEXANES AS A FUNCTION OF BOND LENGTH AND POLARIZABILITY

Substituent F CI Br 1 HgX

Ka

Bond length (À)

Polarizability" (À 3 )

2.10 c 3.90c 3.48c 3.39c 1.00d

1.49 1.76 1.91 2.00 2.18

1.05 3.68 4.80 7.15

—

a

According to Eq. (5). For halide ion, see J. Kleinberg, W. J. Argersinger, Jr., and E. Griswold, "Inorganic Chemistry," p. 163. Heath, Boston, Massachusetts, 1960. c Measured at about -90° in carbon disulfide. [See A. J. Berlin and F. R. Jensen, Chem. Ind. {London) p. 998 (1960) and F. R. Jensen, C. H. Bushweller, and B. H. Beck, J. Amer. Chem. Soe. 91, 344 (1969).] d See Jensen et al. (cited in footnote c above) for measurement at -90° in 70% carbon disulfide/30% pyridine by volume or F. R. Jensen and L. H. Gale [J. Amer. Chem. Soe. 81, 6337 (1959).] in pyridine at 90°. b

Another theoretical treatment using van der Waals functions17 predicts attractive forces between both axial and equatorial substituents and proximate hydrogens in iodo- and chlorocyclohexane. Such calculations predict a greater stabilization, i.e., greater attractive forces, for equatorial versus axial iodine or chlorine. However, the conformational enthalpies calculated using this method are not in agreement with the best experimental data. It is evident from a substantial amount of data that the C-X bond length [Eq. (5)] and the polarizability of X play roles in determining preference for the axial or equatorial position (Table I). As the C-X bond length [Eq. (5)] increases, l,3-sy«-axial repulsions in the axial conformer will decrease. Indeed, 18 N . L. Allinger, J. A. Hirsch, M. A. Miller, and I. J. Tyminski, J. Amer. Chem. Soc. 91, 337 (1969).

146

Frederick R. Jensen and C. Hackett Bushweller

as the C-X bond length becomes longer (Table I), attractive as well as repulsive forces are minimized causing the equatorial versus axial preference to ap­ proach zero. The more polarizable a substituent (Table I), the less severe will be any nonbonded compressions. The combination of these two effects is illustrated dramatically in the case of the acetatomercuri group and the sequence of preferences in the monohalocyclohexanes (Table I). In the absence of specific solvent interactions, e.g., hydrogen bonding, conformational preferences in monosubstituted cyclohexanes are expected to be affected by solvent in compounds containing polar groups and/or when the molecular volumes of the conformers differ, i.e., by the internal pressure of the solvent. The former effect may be substantial and no concrete example of the latter case has been reported. In the general situation, specific solvation, e.g., hydrogen bonding, or complexation will probably tend to stabilize the equatorial form [Eq. (6)]. For HS H X—H—S

m

(6)

(7)

S—H

dipole-dipole solvation [Eq. (7)], the C-X dipole is more exposed in the axial form. It might be expected that this type of interaction will tend to favor the axial conformer. The existence of conformational isomerism in monosubstituted cyclo­ hexanes led Winstein and Holness to define the A value according to Eqs. (5) and (8).19 If the equatorial isomer is preferred, the A value is positive and it is expressed in kcal/mole. Opposition to the use of the term, A value, has arisen A Value = -AG°

RTlnK 1000

(8)

because of the profusion of symbols already in general use. However, in the interest of conciseness and ease of communication, the present authors prefer the term, A value, which conveys immediately the point in discussion. The 19

S. Winstein and N. J. Holness, J. Amer. Chem. Soc. 77, 5562 (1955).

147

Cyclohexane and Cyclohexene Conformations

alternative would be to state the situation something like "the free energy difference in kcal/mole of a substituent equilibrating from the equatorial to the axial position of the chair forms of cyclohexane." C. CYCLOHEXENE

Conformational trends in cyclohexene derivatives have not been studied extensively.20,21 Theory 22 and experiment23 indicate that the half-chair conformer (12) is the only stable conformer of cyclohexene, with the boat form (13) being a potential maximum in the interconversion of the dissymmetric halfchairs. Half-chair equilibration of a 4-substituted cyclohexene will exchange the substituent between axial and equatorial positions [Eq. (9)] and between

(12)

(13)

(9)

pseudoaxial and pseudoequatorial sites in a 3-substituted derivative. The presence of the double bond in cyclohexene with the concomitant bond angle adjustments22 and reduced nonbonded compressions in the 4-position leads to drastically lowered preferences for the equatorial position by 4-substituents. In addition, attractive London dispersion forces may be operative in stabilizing the axial 4-substituent in certain cases. Consistent with the view that appropriate symbolism aids communication, conformational parameters unique to the cyclohexene system have been pro­ posed. For a 4-substituted cyclohexene, the E4 value has been defined according to Eqs. (9) and (10). The definition is analogous to that for the A value. /?7Ίη Κ'

E4 Value =-AG* =-^^20

(10)

See footnote 17, pp. 109-111. E. W. Garbisch, Jr. and K. D . MacKay, Abstr. 155th Nat. Meeting Amer. Chem. Soc, San Francisco, 1968, No. P 0 6 5 . 22 (a) R. Bucourt and D. Hainaut, Bull. Soc. Chim. Fr., p. 4562 (1967); (b) E. J. Corey and R. A. Sneen, / . Amer. Chem. Soc. 77, 2505 (1955). 23 (a) H. B. Orlaff, A. J. Kolka, G. Calingaert, M. E. Griffing, and E. R. Kerr, / . Amer. Chem. Soc. 75, 4243 (1953); (b) R. A. Pasternak, Acta Crystallog. 4, 316 (1951); (c) M. A. Lasheen, ibid. 5, 593 (1952). 21

148 D.

Frederick R. Jensen and C. Hackett Bushweller

NOMENCLATURE

A number of simple ring systems are expected to be studied in the future and appropriate conformational parameters can be defined to represent free energy differences between conformers. Therefore, we propose that the term "value" denote the free energy difference (AG°) between two conformations. By prefixing another symbol, e.g., "Λ" in A value, the system and direction of equilibrium is defined explicitly. Suggested symbolism for a variety of systems are compiled in Table II. Whereas "Λ" could be construed as referring to TABLE II SUGGESTED SYMBOLISMS FOR VARIOUS CONFORMATIONAL EQUILIBRATIONS

(VALUE = [RT \n K]11000)

System

Symbolism

A Value

X

/

E3 Value (eee-three value)

E4 Value

cyclohexflne, "E" refers to cyclohexene. The position of substitution on cyclohexene, i.e., C-3 or C-4, is indicated by the subscripts in E2 or E4. Appropriate "values" could also be proposed for eis- and /raws-decalin, but because of the complexities of these systems and the paucity of the data it is deemed not desir­ able at this time. The isomerizations for cyclohexane and cyclohexene derivatives illustrated in Table II (A value, E values) are, of course, energetically equivalent to ex­ changing the substituent between axial and equatorial positions via ring in­ version. Indeed, it is the occurrence of ring inversion with appropriate barriers which makes possible the measurement of appropriate thermodynamic para­ meters in monosubstituted cyclohexanes or cyclohexenes by spectroscopic techniques.

Cyclohexane and Cyclohexene Conformations

149

Π. Evaluation of Methods The purpose of this section is to compile and evaluate various data concern­ ing the conformational preferences of derivatives of cyclohexane and cyclo­ hexene. The present authors wish to present an alternative to the recent selec­ tion of "best" A values. 17,24 Also, an evaluation of the various methods of determining A values is presented. 17,24 A plethora of techniques including kinetics, 19,25 chemical equilibration, 26,27 pKa measurements,28 electron dif­ fraction,29 infrared spectroscopy,30 Kerr constant measurements,17 and nuc­ lear magnetic resonance (NMR) spectroscopy31 have been applied to the problem. An attempt will be made to evaluate at least partially the various tech­ niques. Emphasis will be placed on the several widely used methods employing NMR spectroscopy to study conformational equilibria. Inherent in any evaluation of a method of measurement is a necessity for critically assigning a limit of uncertainty. The question is frequently posed, for example, if the correct A value is 0.55, is an observed value of 0.32 acceptable ? Since the above values reflect significant differences in the equilibrium con­ stants, they also reflect different predictive abilities concerning the chemistry of the system. Indeed, the voluminous literature in regard to A values attests to the importance of having correct values. In some instances, a technique gives accurate thermodynamic measurements for some groups but not for others. In such a case, the method must be regarded as being unacceptable because the reliability of a value determined by this technique must be checked by an inde­ pendent method.

A. THE NMR

PEAK AREA MEASUREMENT TECHNIQUE

The present authors believe that the only unequivocal technique employing NMR spectroscopy for the determination of A values is the measurement of peak areas corresponding to the conformers in question under conditions of slow exchange on the NMR time scale.31 Unfortunately, the barriers to chairchair interconversion in monosubstituted cyclohexanes (AG+ £ 10 kcal/ 24

J. A. Hirsch, Top. Stereochem. 1, 199 (1967). E. A. Cavell, N. B. Chapman, and M. D. Johnson, /. Chem. Soc. p. 1413 (1960). 26 D. S. Noyce and L. J. Dolby, /. Org. Chem. 26, 3619 (1961). 27 R. J. Ouellette and G. E. Booth, J. Org. Chem. 31, 587 (1966). 28 R. D. Stolow, / . Amer. Chem. Soc. 81, 5806 (1959). 29 P. Andersen, Acta Chem. Scand. 16, 2337 (1962). 30 F. R. Jensen and L. H. Gale, /. Org. Chem. 25, 2075 (1960). 31 F. R. Jensen, C. H. Bushweller, and B. H. Beck, / . Amer. Chem. Soc. 91, 344 (1969). 25

150

Frederick R. Jensen and C. Hackett Bushweller

mole) 32,33 necessitate spectral determinations at —80° or lower temperatures. A spectrum of the axial and equatorial H-C-I resonances of iodocyclohexane is illustrated in Fig. 1. Measurement of the areas under the axial and equatorial H-C-I peaks will give the equilibrium constant directly. Furthermore, if accurate A values are to be obtained by the peak area method, numerous precautions, outlined below, must be taken. Experimental precautions. It is evident [Eq. (8)] that sample temperature must be known accurately in order to obtain valid A values. Although it is possible to use precise methods for measuring temperature, i.e., a carefully calibrated thermocouple, other problems arise in present commercially avail-

y 84.79

S 4.06

FIG. 1. The NMR spectrum (100 MHz) of the axial (δ4.06) and equatorial (84.79) methine protons (H-C-I) of iodocyclohexane at -80°.

able, variable temperature NMR probes. For example, serious and nonreproducible temperature gradients over the sample area (e.g., 2°-4° at —60° and 5°-10° at —100°) are frequently observed in commercial probes. This would, of course, render any enthalpy (Δ//°) or entropy (Δ5°) calculations meaning­ less. The magnitude of the temperature gradients depends on the difference between the sample temperature and room temperature, gas-flow rate, the spinning rate, and tube size. The basic problem appears to be an ineffective insulation of the sample area, i.e., excessive heat leaks from insert to probe. 32

L. W. Reeves and K. O. Str0mme, Can. J. Chem. 38, 1241 (1960). F. A. Bovey, E. W. Anderson, F. P. Hood, and R. L. Kornegay,/. Chem. Phys. 40, 3099 (1964). 33

151

Cyclohexane and Cyclohexene Conformations

Another important source of error in these determinations is due to dif­ ferential saturation effects34 on the axial and equatorial H-C-X resonances. It is important to use radio frequency (rf) power levels such that saturation effects are at least minimized. In the case of different peak shapes and popula­ tions in monosubstituted cyclohexanes, differential saturation effects can be serious. It would not be unexpected that axial and equatorial H-C-X protons would have different relaxation times. 34 In addition, interconversion of the two species allows an additional mechanism for relaxation even if it is assumed that relaxation rates are the same for each entity in the absence of interconversion. In cases where a definite conformational preference exists, the halflife (tl/2) of the molecule in the less stable form will be less than in the stable form. For all intents and purposes, the more populous conformer has more time to absorb rf energy, and if saturation conditions prevail, the area under its resonance decreases relatively more than that of the less stable iso­ mer. The effect can be illustrated dramatically in the case of iodocyclohexane. The peak area ratio of axial : equatorial H-C-I resonances (Fig. 1) as a func­ tion of rf power (Varian HA-100 NMR spectrometer) is compiled in Table III. TABLE III EFFECT OF RADIO FREQUENCY POWER ON THE OBSERVED EQUILIBRIUM CONSTANT (K=

[EQUATORIAL /]/[AXIAL /])

FOR IODOCYCLOHEXANE

Radio frequency power input (db) a 46 43 37 30 25

K 2.96 3.10 3.30 3.39 3.29

± 0.06 ±0.05 ± 0.05 ±0.10 ± 0.29

fl All values determined at same field sweep rate in H R mode on Varian HA-100 spectrometer.

(Since the actual rf power levels vary with the instrument, the behavior illu­ strated in Table III will vary from laboratory to laboratory.) It is evident from Table III that the larger axial proton (H-C-I) resonance is saturating more than that of the corresponding equatorial proton (H-C-I). These authors have observed for several compounds that saturation produces low A values. In order to minimize such difficulties, the rf power is decreased to that point 34

J. W. Emsley, J. Feeney, and L. H. Sutcliffe, "High Resolution Nuclear Magnetic Reso­ nance Spectroscopy," Vol. 1, p. 33. Pergamon Press, New York, 1965.

152

Frederick R. Jensen and C. Hackett Bushweller

where the appropriate peak area ratio is constant at decreased rf power values at the selected field-sweep rate. A Value determinations are then performed at lower power settings than the point determined above. However, even using these precautions, differential saturation effects still may contribute some error to Λ-value measurements. Such effects must be recognized in any deter­ mination of the enthalpy (ΔΗ°) or entropy (Δ5°) of a conformational equili­ brium by NMR spectroscopy. Other instrumental malfunctions may affect peak area measurements. Nonlinearity of the intensity coordinate on the recorder (frequently due to a worn slide wire) is common and can obviously affect the results. Such perform­ ance can be easily checked. The present authors have not found the reproducibility of peak area integrals using available electronic integrators (±8%) to be satisfactory. More acceptable results are obtained by hand planimetry or by using a digital voltmeter, and in each case it must be demonstrated that areas accurately reflect concentrations. Many late model NMR spectrometers have both frequency-sweep and fieldsweep capabilities. Under field-sweep conditions, care should be taken to determine that the sweep is linear. Under frequency-sweep conditions, the Z-coordinate is not linear but rather peaks at the center of the spectrum. The areas under the various resonances depend on the region of the spectrum in which they occur. It is also characteristic of at least one NMR spectrometer (Varian HA-100) that phase changes (absorption versus dispersion mode) occur from one region of the spectrum to another under frequency-sweep conditions. Under field-sweep operation, both of these problems are largely obviated. Sample and solvent purity are obviously of paramount importance. It is use­ ful to run a spectrum of the solvent alone to check for impurity resonances in regions of interest. In the case of monosubstituted cyclohexanes, spectra at low temperatures (slow exchange) and at higher temperatures (both intermediate and fast equilibration) should be taken to examine the spectrum for any anoma­ lous behavior due to impurities. Providing all the above mentioned precautions are taken, the present authors believe the only unequivocal method for determining A values is the NMR peak area method of observing the system of interest under conditions of slow exchange on the NMR time scale. Peak area measurements of carbon-13 NMR spectra obtained at low temperatures have promise of considerable utility. Recently, the axial conformer of methylcyclohexane has been observed by this procedure.343 The estimated A value of 1.6 kcal/mole is in good agreement with the values obtained by other methods. 34a

F. A. L. Anet, C. H. Bradley, and G. W. Buchanan,/. Amer. Chem. Soc. 93, 258 (1971)

153

Cyclohexane and Cyclohexene Conformations

B. USE OF LOCKING GROUPS TO ESTABLISH MODEL COMPOUNDS

In most of the techniques for A value determination to be discussed subse­ quently, it is necessary to have model compounds which presumably reflect accurately the chemical or spectroscopic properties of axial and equatorial forms of the monosubstituted cyclohexane. The approach is to substitute on the cyclohexane ring a large, nonpolar substituent, e.g., alkyl group, which exhibits a strong preference for the equatorial position. In the case of the axial conformer of methylcyclohexane (14), it is evident that nonbonded compressions between the methyl group and the sjw-axial hydrogens are serious. Indeed, the A value of the methyl group is large (1.7

(14)

(15)

(16)

(17)

kcal/mole).17 Substitution of one or two alkyl groups for methyl hydrogens, e.g., (15) and (16), does not significantly increase the nonbonded compres­ sions in the axial conformer. The A values of ethyl and isopropyl are ~1.8 and ~2.1 kcal/mole, respectively.17 However, the nonbonded compressions ex­ perienced by an axial /-butyl group (17) are very large {A value ~5 kcal/mole17) and would be expected to cause an essentially exclusive preference for the equatorial /-butyl form, i.e., the cyclohexane ring is "locked." In di-/-butylcyclohexanes in which one /-butyl must be axial if the chair conformation is to be maintained, e.g., /ra/w-l^-di-z-butylcyclohexane, the preferred conforma­ tion is apparently the twist form (18).35 c/^-z-Butyl-l-phthalimidocyclohexane (19) and ds-4-/-butyl-l-succinimidocyclohexane (20) also show a preference for the twist conformer. Consistent with a reduced conformational requirement of methyl as compared to /-butyl, c/.y-2-/-butyl-5-methylcyclohexanone (21) has little twist character. 36 In light of the above observations, 35

D. L. Robinson and D. W. Theobald, Quart. Rev. 21, 314 (1967) and references therein. C. Djerassi, E. J. Warawa, J. M. Berdahl, and E. J. Eisenbraun, / . Amer. Chem. Soc. 83, 3334(1961). 36

154

Frederick R. Jensen and C. Hackett Bushweiler

(18)

(19)

(20)

it is easy to view the i-butyl group as an effective locking group. It might be expected that the conformationally homogeneous eis- and trans-A-t-bwty\cyclohexyl derivatives (22, 23) would reflect the chemical and spectroscopic

(22)

(24)

(23)

(25)

properties of the axial (24) and equatorial (25) isomers of the monosubstituted cyclohexane at least in the region of the C-X bond. However, considerable evidence has accumulated which indicates that the 4-t-butyl derivatives are not satisfactory models for the monosubstituted conformers. It appears that the f-butyl group distorts the ring from the chair conformation. Various data supporting this contention will be presented in subsequent sections. The relatively large A value (2.0-3.1 kcal/mole)17 of the phenyl substituent suggests that it might also be used as a locking group. However, the difference in electronegativity between the ^-hybridized carbon in phenyl and the sp3hybridized carbon in an alkyl group (/-butyl) introduces the possibility of dipole-dipole interactions in the phenyl derivatives. For example, equilibrated 4-phenylcyclohexanecarboxylic acid (89% trans at 195°; AG° = -1.95 kcal/

Cyclohexane and Cyclohexene Conformations

155

mole)37 and 4-/-butylcyclohexanecarboxylic acid (76% trans at 230°; AG = —1.15 kcal/mole)17 do not give equivalent results. In general, the selection of locking groups to establish model compounds in the cyclohexane ring should be done with care. Independent checks on the accuracy of the model compounds in reflecting the system of interest should always be performed. C. NUCLEAR MAGNETIC RESONANCE CHEMICAL SHIFT METHOD FOR DETER­ MINING A VALUES

One technique utilizing NMR spectroscopy is the method of Eliel and coworkers38 involving the use of locked eis- and /r
However, implicit in the use of this method is the assumption that the i-butyl group has no effect on the chemical shift of the axial and equatorial methine proton (H-C-X) resonances, i.e., that the chemical shifts of the axial methine proton [H a -C-X, (23)] and equatorial methine proton [H e -C-X, (22)] of the /-butyl derivatives are the same as the respective H-C-X chemical shifts in the monosubstituted cyclohexane (24, 25). The method has been applied widely with no effective test of the implicit assumptions. Recent studies prove 37

H. E. Zimmerman and H. J. Giallombardo, / . Amer. Chem. Soc. 78, 6259 (1956). (a) E. L. Eliel, Chem. Ind. (London) p. 568 (1959); (b) E. L. ElieJ and R. J. L. Martin, /. Amer. Chem. Soc. 90,682 (1968) ; (c) 90,689 (1968) ; (d) J. Reisse, J. C Celotti, and C Chiurdoglu, Tetrahedron Lett. p. 397 (1965). 38

156

Frederick R. Jensen and C. Hackett Bushweller

the method to be at best inaccurate if not invalid. 39 ' 40 For example, a compari­ son of the chemical shift of the axial H-C-CN proton in trans-4-t-buty\cyclohexyl cyanide at —91° and the chemical shift of the axial H-C-CN proton resonance of cyanocyclohexane at —91° (ring inversion slow on the NMR time scale) revealed a difference of 8.6 Hz. 40 Since the chemical shift between axial and equatorial H-C-CN resonances in cyanocyclohexane is 54.0 Hz (100 MHz), a deviation of 8.6 Hz between the model compound resonance and the resonance in the structure of interest is disastrous. Other deviations (Table IV) TABLE IV METHINE PROTON ( H - C - X ) CHEMICAL SHIFTS (HZ) AT 100 MHz

OF

4-SUBSTITUTED CYCLOHEXANE DERIVATIVES AND MONOSUBSTITUTED CYCLOHEXANES"

Ha

X

Temperature (°C)

CI

-90

Br

CN

R

d.

2a

H CH3 f-Bu

400.1 437.8 435.7

369.6 367.2 365.4

-91

H CH3 r-Bu

459.7 457.4 455.7

387.4 383.4 381.9

-91

H f-Bu

288.6 284.4

234.6 226.0

a Concentration = 0.504 ± 0.012 M i n CS 2 containing 15 % TMS (internal standard) by volume.

were observed consistently from one substituent to another. It is also evident from a perusal of Table IV that the use of the eis- and /ra^-4-methylcyclohexyl derivatives introduces serious discrepancies between the respective methine proton chemical shifts. In all cases, the chemical shifts of the axial and equatorial H-C-X resonances of the monosubstituted cyclohexanes occur downfield from the 4-methyl and 4-i-butyl derivatives. It is evident that serious 39

S. Wolfe and J. R. Campbell, Chem. Commun, p. 872 (1967). (a) F. R. Jensen and B. H. Beck, / . Amer. Chem. Soc. 90, 3251 (1968); (b) E. L. Eliel and R. J. L. Martin, ibid. 90,682, 689 (1968). 40

157

Cyclohexane and Cyclohexene Conformations

error can be introduced into the determination of A values by this method regardless of whether /-butyl or methyl derivatives are used. A further complication arises in the case of the 4-methylcyclohexyl deriva­ tives under conditions of fast exchange on the NMR time scale. If the substi­ tuent (X) has a large A value, it is clear that the trans isomer will exist essentially

X (26)

(27)

X

(28)

CH 3

(29)

exclusively in the diequatorial form [(26), A values additive in this case] in preference to the diaxial (27). In the eis isomer, the "larger" X becomes, the more the conformer with methyl axial will be present. Thus, in this instance, the H-C-X resonance is meaningless as a reference and the methyl group is an ineffective locking substituent. However, for the limited number of functionalities investigated, there ap­ pears to be an essentially direct parallelism between the temperature depend­ ence of the axial and equatorial methine proton (H-C-X) chemical shifts in the monosubstituted cyclohexanes and the corresponding /-butyl derivatives.400 This observation suggests that, at temperatures at which the ring inversion is rapid on the NMR time scale, good estimates of the axial : equatorial isomer ratio can be obtained by assuming that the variations with temperature of the chemical shifts of the axial and equatorial resonances in the cyclohexyl and 4-/-butylcyclohexyl derivatives are the same. Thus, the chemical shift of the individual resonances of the cyclohexyl derivative at room temperature can be approximated by correcting the axial and equatorial H-C-X proton chem­ ical shifts of the monosubstituted cyclohexane at low temperature (chair inversion slow on the NMR time scale) by the change observed between low temperature and room temperature for the corresponding 4-r-butyl deriva­ tives. Although this extrapolation method gives better agreement with A values determined by the unequivocal peak area measurement technique, its validity is not yet well established.400 At this juncture, it seems worthwhile to compare A values determined by the

158

Frederick R. Jensen and C. Hackett Bushweller

NMR peak area measurement method,41 the chemical shift method,38 and the modified chemical shift method.400 Pertinent data are compiled in Table Y. A perusal of Table V indicates that the modified chemical shift method gives A values in good agreement with those obtained by the unequivocal peak area measurement method. Of course, it is expected that entropy would affect the A values determined at low temperature (peak area technique) as compared to the values at room temperature. However, our results indicate that the contri­ bution of entropy in these systems is small (Δ5° = ±1 e.u.) and should not seriously affect the A values at different temperatures. TABLE V A VALUES DETERMINED BY THE VARIOUS N M R

a b c

TECHNIQUES 0

Substituent

Area measurement"

Chemical shift method using "corrected" H - C - X chemical shiftsc

Br— CF3CO2— CI — CH3CO2— N=C—

0.49 0.54 0.53 0.72 0.23

0.55 0.55 0.56 0.63 0.23

Chemical shift method using 4-f-butylcyclohexyl H - C - X chemical shifts at 35° 0.35 0.31 0.38 0.43 -0.04

CS 2 as solvent. Measured at -80°. Measured at 35°.

The serious disagreement between the values obtained by the chemical shift methods casts doubt at least on the validity of using uncorrected 4-/-butylcyclohexyl H-C-X chemical shifts as references. A case in point is the A value of the nitrile group (Table Y). Indeed the validity of the modified chemical shift technique400 involving extrapolation of axial and equatorial H-C-X chemical shifts from low temperature measurements is not yet well established. As has been previously mentioned, the most unequivocal method for determining A values, albeit at a low temperature, appears to be the NMR peak area measurement technique. Comparison of several A values determined at dif­ ferent times and with different instruments (60 and 100 MHz) using this tech­ nique indicates that under optimum conditions, A values accurate to ±0.02 kcal/mole can be obtained (Table VI). The reproducibility of the A values com41

A. J. Berlin and F. R. Jensen, Chem. Ind. {London) p. 998 (1960).

159

Cyclohexane and Cyclohexene Conformations TABLE VI A VALUES OF VARIOUS G R O U P S DETERMINED BY THE PEAK AREA

Group

MEASUREMENT TECHNIQUE AT Low

TEMPERATURE

Operating frequency (MHz)

A Value (kcal/mole)

Refs.fl

Temp. (°C)

F

-81° -80° -55°

60 100 56.4

0.250 0.276 0.242

1 2 3

CI

-81° -73° -80°

60 60 100

0.513 0.510 0.528

1 4 2

Br

-81° -73° (?) -80° -83°

60 60 100 40

0.480 0.474 0.476 0.49

1 4 2 5

1

-81° -73° (?) -80°

60 60 100

0.431 0.454 0.468

1 4 2

a

Key to references: 1. A. J. Berlin and F. R. Jensen, Chem. Ind. (London) p. 998 (1960). 2. F. R. Jensen, C. H. Bushweller, and B. H. Beck, / . Amer. Chem. Soc. 91, 344(1969). 3. (a) F. R. Jensen and B. H. Beck, / . Amer. Chem. Soe. 90, 3251 (1968); (b) E. L. Eliel and R. J. L. Martin, ibid. 90, 682, 689 (1968). 4. W. C. Neikam and B. P. Dailey, / . Chem. Phys. 38, 445 (1965). 5. L. W. Reeves and K. O. Str0mme, Can. J. Chem. 38, 1241 (1960).

piled in Table VI provides evidence for the validity of the peak area measure­ ment technique. The use of the /-butyl group as a locking group to establish model com­ pounds for NMR analysis has also proved to be unsatisfactory in a series of 1,2-disubstituted 4-i-butylcyclohexanes42 and in eis- and ^«^-/-butylcyclohexyl derivatives (30, 31). 38b

X (30)

(31)

S. Wolfe and J. R. Campbell, Chem. Commun, p. 872 (1967).

160

Frederick R. Jensen and C. Hackett Bushweiler

D. ESTIMATION OF A VALUES FROM TIME-AVERAGED COUPLING CONSTANTS

Another NMR technique employing the time-average coupling constants of rapidly equilibrating (on the NMR time scale) systems has been used to esti­ mate A values.43 This method is analogous to the method of Eliel utilizing time-averaged chemical shifts. If a given proton is coupled differently to a neighboring proton in one conformation (/,) then in another (J2), the observed time-average coupling constant (Jayg) under conditions of fast exchange on the NMR time scale will be a weighted average of the two different coupling constants. If the values of the two coupling constants are known, the position of equilibrium may be determined according to Eq. (11a).

KJJp^A

(lla)

The practical application of this technique suffers in several respects, especi­ ally in proton magnetic resonance spectroscopy. Proton-proton coupling constants are usually not very large (0-18 Hz) and in most cases of interest are only 0-11 Hz. Consequently, the small differences between appropriate para­ meters and the inherent inaccuracy with which peak positions can be determined render the equilibrium constants obtained by this method good estimates at best. Indeed, the measurement of true peak positions in spin-spin multiplets is usually very difficult due to peak overlap and second-order coupling effects. The method suffers most when one is forced to predict pertinent coupling constants in the system of interest when it is evident that coupling constants are not predictable to the accuracy necessary. Also, in light of previous discus­ sion concerning the validity of 4-i-butylcyclohexyl derivatives as models for chemical shifts in monosubstituted cyclohexanes, the 4-/-butyl compounds can­ not be justified for prediction of coupling constants. Since the magnitude of a coupling constant is highly sensitive to the geometry of the system, the dis­ torted 4-i-butyl derivatives are an approximate model at best for the monosubstituted cyclohexane. The only unequivocal means of getting the coupling constants of interest is by taking the NMR spectrum of the compound of interest under conditions of slow exchange on the NMR time scale where indi­ vidual spectra of each conformer can be analyzed. However, the use of data obtained at different temperatures must be done with care because the pertinent coupling constants may be temperature dependent. Since NMR line widths depend on magnitudes of the various coupling con­ stants, the width-at-half-height {WXI2) can presumably be used to estimate conformer populations under conditions of fast exchange on the NMR time scale. This technique has been applied especially in cases where the spin-spin 43

(a) H. Booth, Tetrahedron 20, 2211 (1964); (b) W. Hofman L. Stefaniak J. Urbanski, and W. W. Tanowski, /. Amer. Chem. Soc. 86, 554 (1964).

161

Cyclohexane and Cyclohexene Conformations

splitting pattern is not clearly resolved. It is evident that the method suffers for the same reasons given immediately above. Again, for purposes of comparison, A values determined by the time-average coupling constant and line width techniques as well as the low-temperature peak area measurement method are compiled in Table VII. Although good agreement is observed in certain cases, we believe that the accuracy of the coupling constant and line width methods leaves something to be desired. The experimental deviations reported for these techniques support this attitude (Table VII). TABLE VII A VALUES DETERMINED BY TIME-AVERAGE COUPLING CONSTANT, TIME-AVERAGE LINE W I D T H , AND PEAK AREA MEASUREMENT TECHNIQUES

Group

Technique

A Value (kcal/mole)

Refs."

_N=C=0

Line width (35°) Peak area (-80°)

0.48 ±0.15 0.51 ±0.02

1 2

—Br

Coupling constant (20°) Peak area (-81°)

0.70 ± 0.20 0.48 ± 0.02

3 2

—N0 2

Coupling constant (20°) (?) Peak area (-90°)

Exclusively equatorial 1.0 ±0.14

4 2

—OAc

Coupling constant (28°) Peak area (-88°)

0.66 ± ? 0.71 ± 0.05

5 2

a

Key to references: 1. G. C. Corfield, A. Crawshaw, and W. A. Thomas, Chew. Commun, p. 1044 (1967). 2. F. R. Jensen, C. H. Bushweller, and B. H. Beck, / . Amer. Chem. Soc. 91, 344 (1969). 3. H. Booth, Tetrahedron 20, 2211 (1964). 4. W. Hofman, L. Stefaniak, J. Urbanski, and W. W. Tanowski, J. Amer. Chem. Soc. 86, 554 (1964). 5. F. A. L. Anet, / . Amer. Chem. Soc. 84, 1053 (1962). E. HYDROXYLIC PROTON CHEMICAL SHIFT METHOD

Another NMR technique analogous to the method of Eliel, previously described, involves the use of the chemical shift of the hydroxyl proton in pertinent compounds. 44 For example, the hydroxyl proton chemical shifts in eis- and /röra-4-/-butylcyclohexanol (32, 33) are used as reference values to which the time-average hydroxyl proton chemical shift of cyclohexanol is 44

(a) J. J. Uebel and H. W. Goodwin, / . Org. Chem. 31, 2040 (1966); (b) R. J. Ouellette, J. Amer. Chem. Soc. 86, 4378 (1964).

162

Frederick R. Jensen and C. Hackett Bushweller OH

(32)

(33)

compared. An apparent equilibrium constant can be calculated in a straight­ forward manner, e.g., see Eq. (11). However, the use of this method implies two critical assumptions: (1) that the hydroxyl group in the model com­ pounds is solvated and/or is hydrogen-bonded in exactly the same manner as m the conformations of interest; and (2) that the chemical shifts of the hydroxyl proton in the model compounds, which will be a function of the degree of hydrogen bonding and the geometry of the model, reflect accurately those shifts in axial and equatorial cyclohexanol. The hydrogen-bonding prob­ lem can be obviated by extrapolating a plot of alcohol concentration versus the hydroxyl proton chemical shift to infinite dilution. 440 In none of the cases studied to date by this technique has the validity of the model compounds been tested unequivocally. Without such a test, the accuracy of the A values obtained must be suspect for reasons stated previously concerning the use of model compounds in NMR spectroscopy. Various A values for the hydroxyl group determined by this method are compiled in Table VIII. Although the A values TABLE VIII A VALUES OF THE HYDROXYL G R O U P DETERMINED BY THE HYDROXYL PROTON CHEMICAL SHIFT TECHNIQUE

Group

Temp. (°C)

—OH

25 ? 40 40 25 ?

Solvent DMSO

ecu DMSO, DMSO

pyr.

A Value

Refs.b

0.66° 0.75 0.80 0.85

1 2 2 1

a

Utilized a technique requiring assumption of additivity of A values. Key to references: 1. J. J. Uebel and H. W. Goodwin, / . Org. Chem. 31, 2040 (1966). 2. R. J. Ouellette, / . Amer, Chem. Soc. 86, 4378 (1964). b

reported in Table VIII are somewhat consistent, the deviations between inde­ pendently determined values are significantly greater than those observed from the low-temperature NMR peak area measurement technique (Table V). We feel that the hydroxyl proton chemical shift method gives at best good estimates of the hydroxyl A value.

163

Cyclohexane and Cyclohexene Conformations

A modification of the hydroxyl proton chemical shift technique has been used to estimate the A value of the ethynyl group. 45 The model compounds were l-ethynyWrö«s-4-?-butylcyclohexanol (34) and l-ethynyl-m-4-/-butylcyclohexanol (35) and the system of interest, 1-ethynylcyclohexanol [Eq. (12)]. By the method described above, the position of equilibrium for Eq. (12) was

OH

(34)

(35)

H C

III

OH

established using model compounds (34) and (35). By assuming an A value for hydroxyl {A = 0.78 kcal/mole) and assuming additivity of A values, the A value of ethynyl was determined to be 0.18 kcal/mole. Again, the validity of the model compounds is not established in this case and the additivity of A values in a case of geminai disubstitution has been seriously challenged recently.46 The A value of the ethynyl group determined by this method (0.18 kcal/mole at 41°) is at variance with that determined by the low-temperature peak area method (0.41 kcal/mole at -80°). 31 F.

DETERMINATION OF THE ENTHALPY (Δ//°) AND ENTROPY (Δ5°) OF THE AXIAL ^EQUATORIAL EQUILIBRIUM IN MONOSUBSTITUTED CYCLOHEXANES BY NMR SPECTROSCOPY

The direct peak area measurement method for determining A values gives accurate and reproducible (±20 cal/mole) data. It seems reasonable that a 45

R. J. Ouellette, J. Amer. Chem. Soc. 86, 3089 (1964). N. L. Allinger, J. A. Hirsch, M. A. Miller, and I. J. Tyminski, /. Amer. Chem. Soc. 91, 337 (1969). 46

164

Frederick R. Jensen and C. Hackett Bushweller

variable temperature study utilizing this technique should give meaningful enthalpies and entropies for monosubstituted cyclohexanes.* A series of reports purporting to have measured the enthalpies for axialequatorial equilibration in a number of monosubstituted cyclohexanes using the chemical shift method at various temperatures 48 must be viewed critically. The invalidity of the 4-/-butylcyclohexyl model compounds has been unequi­ vocally demonstrated, 403 and consequently, any agreement of these values with the correct value must be fortuitous. G. DETERMINATION OF THE A VALUE OF THE CARBOXYL GROUP FROM ACID DISSOCIATION CONSTANTS

Stolow49 has proposed a method for the determination of the A value of the carboxyl group using the acid dissociation constants of model compounds, e.g., eis- and /ra^-4-i-butylcyclohexanecarboxylic acids (36, 37), as reference values for the axial (Ka) and equatorial (Ke) carboxyl dissociation constants in C0 2 H

(36)

(37)

C0 2 H

^

=~ £zL»

(,3)

* Repeated attempts47 to measure AS° for a number of axial-equatorial equilibrations in monosubstituted cyclohexanes under the carefully controlled conditions described previously resulted in entropies of apparently the wrong sign, i.e., the calculated enthalpy changes (AH°) deviated seriously from a number of values obtained by variable temperature infrared spectroscopy. The problem observed with the NMR method is not clear. It is possible that even using minimal rf power levels, saturation is still a problem. Saturation effects will depend on inherent relaxation times of the pertinent nuclei and possibly on the conformer populations and rate of exchange. The more populous conformer, e.g., equatorial substituent and axial proton, will always have a longer half-life than the axial conformer and consequently, will have more time to absorb rf energy and become differentially saturated. Indeed, this is the trend as illustrated previously (Table III). 47

C. H. Bushweller, Ph.D. Dissertation, University of California, Berkeley, 1966. (a) J. Reisse, J. C. Celotti, D. Zimmermann, and G. Chiurdoglu, Tetrahedron Lett. p. 2145 (1964); (b) J. Reisse, J. C. Celotti, and G. Chiurdoglu, ibid. p. 397 (1965); (c) J. C. Celotti, J. Reisse, and G. Chiurdoglu, Tetrahedron 22, 2249 (1966). 49 (a) R. D. Stolow, / . Amer. Chem. Soc, 81, 5806 (1959); (b) also see footnote 17, pp. 186-187. 48

165

Cyclohexane and Cyclohexene Conformations

the rapidly equilibrating cyclohexanecarboxylic acid [Eq. (13)]. The experi­ mentally determined acid dissociation constant of cyclohexanecarboxylic acid (K) will then be a weighted average depending on the mole fraction of the axial (Na) and equatorial (7Ve) conformers [Eq. (13)]. The observed acid dissociation constant (K) is related to the acid dissociation constants of the model compounds, i.e., Ka from (36) and Kc from (37), by Eq. (14). In this K=NcKc

+ NaKa

(14)

instance, only two conformers are involved [Eq. (14)] and Ne = (1 - Na). The practical application of this technique 49 suffers from small differences between pertinent acid dissociation constants, and the resultant A values for carboxyl (1.0-2.0 kcal/mole)49 show significant spread. A presumably more accurate A value for carboxyl (1.7 ± 0.2 kcal/mole) was obtained from an investigation of the eis- and iraHS-4-methylcyclohexanecarboxylic acids in which an A value for methyl was assumed. Other reports concerning the rotational orientation of the carboxyl group deduced from acid dissociation constants have appeared. 50 Various A values for carboxyl determined from acid dissociation constants are compiled in Table IX. TABLE IX A VALUE OF CARBOXYL DETERMINED FROM A C I D DISSOCIATION CONSTANTS

oo o o o o

1 1 1

Group

Temp. (°C) 25 25 25

Solvent 66% DMF-34% H 2 0 66% DMF-34% H 2 0 80% CH3OCH2CH2OH

A Value

Refs.c

1.7 ±0.2* 1.0-2.0" 1.6 ±0.3"

1 1 2

β

Used 4-methylcyclohexanecarboxylic acids. Used 4-f-butylcyclohexanecarboxylic acids. c Key to references: 1. R. D . Stolow, / . Amer. Chem. Soc. 81, 5806 (1959). 2. M. Tichy, J. Jonâ§, and J. Sicher, Collect. Czech. Chem. Commun. 24, 3434 (1959). b

In light of an observed quantitative relationship between the pKa of cyclo­ hexanecarboxylic acids and the number of syn-axial hydrogens,51 the validity of the 4-alkylcyclohexanecarboxylic acids as model compounds is question­ able. If the 4-alkyl substituent significantly distorts the cyclohexane ring, i.e., 50

H. van Bekkum, P. E. Verkade, and B. M. Wepster, Tetrahedron Lett. p. 1401 (1966). (a) P. F. Sommer, V. P. Arya, and W. Simon, Tetrahedron Lett. p. 18 (1960); (b) P. F. Sommer, C. Pascual, V. P. Arya, and W. Simon, Helv. Chim. Acta 46, 1734 (1963). 51

166

Frederick R. Jensen and C. Hackett Bushweller

the orientation of carboxyl with respect to the syn-ax'm\ protons, the acid dis­ sociation constant should change and not be representative ofthat constant in cyclohexanecarboxylic acid. The present authors feel that such distortion is inevitable in the case of/-butyl, but may not be serious in the case of methyl. H. THE KINETIC METHOD FOR DETERMINING A VALUES

The ultimate goal of any study of conformational preferences is to relate the results to the chemistry of the system. It would be expected that the axial conformer of a monosubstituted cyclohexane would exhibit different reactivity, e.g., in an E2 elimination of a halocyclohexane, than the equatorial form. This postulate forms the basis of another l v a l u e determination method. Once again, it is necessary to employ model compounds. The technique will be illustrated using a second-order reaction, but concen­ tration terms may be added or deleted depending on the kinetic order. The reactions of the axial and equatorial isomers are then considered as separate reactions of two distinct species which do interconvert rapidly at room tem­ perature. The rate of reaction of the two conformers can then be written according to Eqs. (15) and (16), and the total rate of the reaction (axial and X +

^

Y

>

Products

Rate (axial) = &a[axial form][Y]

(15)

—X

/ ^ l

-f

Y

>

Products

Rate (equatorial) = fce[equatorial form][Y]

(16)

Total rate = ka [axial form][Y] +fce[equatorial form][Y]

(17)

equatorial conformers) according to Eq. (17). By a suitable manipulation of the above equations17 and a knowledge of the observed total rate constant (kt), an expression for the equilibrium constant (K) for axial ^ equatorial equilibration can be derived [Eqs. (18) and (19)]. Since monosubstituted cyclohexanes interconvert very rapidly at room temperature, it is impossible to X

167

Cyclohexane and Cyclohexene Conformations

(38)

(39)

obtain ka and ke directly. Therefore, conformationally homogeneous A-tbutylcyclohexyl derivatives (38) and (39) are used as model compounds to obtain ka and kc. It is difficult to assess the accuracy of these models in a kinetic TABLE X VARIOUS A VALUES DETERMINED BY THE KINETIC METHOD

Group —Br —Br —CH 2 OTs —C0 2 H CU2Cri2^H3

—OH —OH —OH —OAc —OAc —OTs —P-ONB —NH 2 α

Temp. (°C) 25 25 100 30 25 25 25 40 40 15-63 25 25 25

Solvent 87%Ethanol 87%Ethanol Acetic acid Absolute ethanol 70%Ethanol Pyridine Pyridine 75 % Acetic acid Water-dioxane Water-dioxane 90% Ethanol 80% Acetone 98% Ethanol

A Value (kcal/mole)

Refs.fl

0.6 0.7 1.7-1.8 0.7 1.0-1.2 0.52-0.55 0.56 0.8 1.5 1.6 0.7 0.98 1.8

1 2 3 4 5 6 7 8 9 10 11 12 13

Key to references: 1. E. L. Eliel and R. G. Haber, Chem. Ind. {London) p. 264 (1958). 2. E. L. Eliel and R. G. Haber, / . Amer. Chem. Soc. 81, 1249 (1959). 3. N . Mori, Bull. Chem. Soc. Japan 35, 1755 (1962). 4. N . B. Chapman, J. Shorter, and K. J. Toyne, / . Chem. Soc. p. 1077 (1964). 5. E. L. Eliel, H. Haubenstock, and R. V. Acharya,/. Amer. Chem. Soc. 83, 2351 (1961). 6. E. L. Eliel and C. A. Lukach, / . Amer. Chem. Soc. 79, 5986 (1957). 7. E. L. Eliel and F . J. Biros, J. Amer. Chem. Soc. 88, 3334 (1966). 8. R. K. Witt and J. D . Kemp, / . Amer. Chem. Soc. 59, 273 (1937). 9. N . B. Chapman, R. E. Parker, and P. J. A. Smith, / . Chem. Soc. p. 3634 (1960). 10. E. A. S. Cavell, N . B. Chapman, and M. D . Johnson, / . Chem. Soc. p. 1413 (1960). 11. E. L. Eliel and R. S. Ro, / . Amer. Chem. Soc. 79, 5995 (1957). 12. G. F . Hennion and F . X. O'Shea, / . Amer. Chem. Soc. 80, 614 (1958). 13. E. L. Eliel, E. W. Delia, and T. H. Williams, Tetrahedron Lett. p. 831 (1963).

168

Frederick R. Jensen and C. Hackett Bushweller

experiment. It would be expected that /-butyl would not exert a significant polar effect on any remote substituent, but distortion of the cyclohexane ring seems inevitable. Any distortion resulting in different nonbonded compressions, e.g., between the axial substituent and sjw-axial hydrogens in the ds-4-i-butylcyclohexyl derivative, as compared to the monosubstituted cyclohexane would change the steric driving force in the reaction as well as the geometry of the transition state and invalidate the model at least in kinetics experiments. This technique has been applied by using a variety of chemical reactions including oxidation of cyclohexanols by chromic anhydride, 19 saponification of acid phthalates,19 solvolysis of appropriate cyclohexy 1 tosylates,19 esterification, 52 displacement of tosylate by thiophenolate ion,53 saponification of alkyl cyclohexane carboxylates,54 hydrolysis of methylcyclohexyl acetates,55 and the reaction of thiophenolate with alkylcyclohexyl bromides.56 Some of the data are compiled in Table X. Some rather serious discrepancies are observed within Table X (e.g., - C 0 2 H and -C0 2 CH 2 CH 3 ) and certain values (-OAc and - C 0 2 H ) are at strong variance with the values preferred by the pre­ sent authors. It would seem that A values determined by the kinetic method are not unequivocal unless some independent check of the data is performed. I. A VALUES FROM INFRARED SPECTROSCOPY

Infrared (IR) spectroscopy is potentially a powerful tool for the direct measurement of A values or enthalpies (Δ//°) of conformational equilibria. In some monosubstituted cyclohexanes, the axial C-X IR stretching frequency (vax) is significantly different from the equatorial C-X stretching frequency (veq). Some representative values are compiled in Table XI. TABLE XI EQUATORIAL (veq) AND AXIAL (Vax)

C-X

STRETCHING FREQUENCIES FOR M O N O SUBSTITUTED CYCLOHEXANES

52

X

veq (cm ')

vax (cm l)

—CI —Br

731 688

683 659

E. L. Eliel and C. A. Lukach, J. Amer. Chem. Soc. 79, 5986 (1957). E. L. Eliel and R. S. Ro, / . Amer. Chem. Soc. 79, 5995 (1957). 54 (a) E. L. Eliel, H. Haubenstock, and R. V. Acharya,/. Amer. Chem. Soc. 83,2351 (1961); (b) E. A. S. Cavell, N. B. Chapman, and M. D. Johnson,/. Chem. Soc p. 1413 (1960). 55 N . B. Chapman, R. E. Parker, and P. J. A. Smith, / . Chem. Soc. p. 3634 (1960). 56 E. L. Eliel and R. G. Haber, / . Amer. Chem. Soc. 81, 1249 (1959). 53

169

Cyclohexane and Cyclohexene Conformations

A study of the pertinent band intensities as a function of temperature will give presumably the enthalpy (Δ//°) of the conformational equilibrium, e.g., axial versus equatorial equilibration in a monosubstituted cyclohexane.57 From the Beer-Lambert law and the equilibrium constant expression [K, Eq. (20)], the IR band intensities and Kcan be related [Eq. (20)]. A van't Hoff plot [Eq. (21)] using K determined at various temperatures will yield the enthalpy [equatorial X] _ log [7//0]eq eax l u; [axial X] log [7//0]„ eeq e = extinction coefficient log I/IQ = optical density dT

RT2

K

}

(Δ//°) of the conformational equilibrium. In this method, it is necessary to assume that the pertinent extinction coefficients [eax, €eq, Eq. (20)] are inde­ pendent of temperature. Although this assumption seems sound, i.e., that the variation of e with temperature is within experimental error, this behavior has not been unequivocally tested to the authors' knowledge. Such a test would seem useful and necessary if the enthalpies determined by this method are to be considered valid. If the extinction coefficients for the respective C-X stretching frequencies are known, the situation is simplified considerably. In a number of reports, the axial and equatorial C-X extinction coefficients were assumed to be equal to those in the 4-alkylcyclohexyl derivatives, making possible the calculation of free energy differences, i.e., A values. It is not valid to assume equality or even near equality of the pertinent extinction coefficients.58 For example, the ratio of the equatorial C-Br extinction coefficient (eeq) to axial C-Br extinction coefficient (eax) in 4-methylcyclohexyl bromide is eeq/eax = 1.85.30 In addition, the respective extinction coefficients in 4-methylcyclohexyl bromide and cyclohexyl bromide are nearly identical.30 Various A values determined by the IR method are listed in Table XII. Distinction is made between enthalpies (Δ//°) determined by the variable temperature technique and A values deter­ mined using extinction coefficients from model compounds. It seems clear from an examination of Table XII that the consistency in A values determined in different laboratories by the IR methods leaves something to be desired. A comparison with the consistency of A values determined by the low-temperature NMR peak area method (Table V) is illuminating. 57 G. Chiurdoglu, L. Kleiner, W. Masschelein, and J. Reisse, Bull. Soc. Chim. Belg. 69, 143 (1960). 58 C. G. Le Févre, R. J. W. Le Févre, R. Roper, and R. K. Pierens, Proc. Chem. Soc. p. 117 (1960).

170

Frederick R. Jensen and C. Hackett Bushweller TABLE XII A VALUES DETERMINED BY IR

Group

Temp. (°C)

Solvent

25(?)

25(?) 25

Neat Neat Cyclohexane Gas phase CS 2 CH 3 OAc Gas phase Ether, CS 2

25(?) 25(?) 25(?) 30

Neat Cyclohexane H-Butanol CS 2

— — — — —

—

Neat(?)

METHODS

-Δ/Γ (kcal/mole)

A Value (kcal/mole)

—

0.84°

— — — — —

0.3-0.4 0.38-0.40 0.34 0.33 0.44 0.52

0.41"

Refs. c

— — — — — —

0.65

1 2 3 4 4 4 5 3

1.04a 1.09a 1.45 0.61"

1 1 6 7

—

8

a

Assumed axial and equatorial C-X extinction coefficients to be equal. Using 4-methyl derivatives, eeq/eax = 1.85. c Key to references: 1. C. G. Le Févre, R. J. W. Le Févre, R. Roper, and R. K. Pierens, Proc. Chem. Soc. p. 117(1960). 2. G. Chiurdoglu, L. Kleiner, W. Masschelein, and J. Reisse, Bull. Soc. Chim. Belg. 69, 143 (1960). 3. J. A. Hirsch, in "Topics in Stereochemistry" (N. L. Allinger and E. L. Eliei, eds.), Vol. 1, p. 199. Interscience, New York, 1967. 4. K. Kozima and K. Sakashita, Bull. Chem. Soc. Japan 31, 796 (1958). 5. J. Reisse, J. C. Celotti, and G. Chiurdoglu, Tetrahedron Lett. p. 397 (1965). 6. E. L. Eliel, Chem. Ind. {London) p. 568 (1959). 7. F. R. Jensen and L. H. Gale, / . Org. Chem. 25, 2075 (1960). 8. G. Chiurdoglu, J. Reisse, and M. Vander Stichelen Rogier, Chem. Ind. {London) p. 1874 (1961). b

J. EQUILIBRATION METHOD FOR DETERMINING A VALUES

The fact that monosubstituted cyclohexanes interconvert via ring inversion between axial and equatorial conformers makes possible the application of various spectroscopic techniques to the determination of A values. However, if the cyclohexane ring can be rendered rigid in the chair conformer, A values might be determined by epimerization at the carbon bearing the substituent of interest. Thus, the /-butyl group has been employed to render the cyclohexane ring immobile. Chemical equilibration of the eis- and ira«.s-4-/-butylcyclo-

171

Cyclohexane and Cyclohexene Conformations

hexyl derivatives [Eq. (22)] should give directly the A value of substituent X. Of course, this technique is valid only if the /-butyl group does not affect the geometry of the cyclohexane ring with regard to the nonbonded compression experienced by the axial and equatorial substituent, a situation which is highly unlikely. ί-Butyl has been used as a locking group in equilibration studies of the ethoxycarbonyl, 26 ' 543 ' 59 methoxycarbonyl,60 nitro, 27 cyano, 61 formyl,62

catalyst

/

-*

-

'

(22)

hydroxymethyl,62 and hydroxyl63-64 groups. The methyl group has been used apparently effectively in the measurement of the A value of the sterically "small" bromomercuri group. 65 Indirect equilibration techniques involving epimerization of a particular functionality in a molecule containing the group of interest have been applied in a number of instances.17 One example is the hydroxy acid-lactone method [Eq. (23)].26 From measurement oiKohs [Eq. (24)] for the case in which R = H

- / (23)

*obs = #

K2

(24)

and R = X, the A value of X can be determined. A number of A values determined by the direct and indirect techniques are listed in Table XIII. It should be noted that any equilibration of cyclohexanol derivatives using aluminum isopropoxide as catalyst is open to scrutiny17 59

N . L. Allinger and R. J. Curby, / . Org. Chem. 26, 933 (1961). B. J. Armitage, G. W. Kenner, and M. J. T. Robinson, Tetrahedron 20, 747 (1964). 61 (a) N . L. Allinger and W. Szkrybalo, / . Org. Chem. 27,4601 (1962) ; (b) B. Rickborn and F. R. Jensen, ibid. 27, 4606 (1962). 62 E. L. Eliel, D. G. Neilson, and E. C. Gilbert, Chem. Commun, p. 360 (1968). 63 G. Chiurdoglu and W. Masschelein, Bull. Soc. Chim. Belg. 70, 767 (1961). 64 E. L. Eliel and R. S. Ro, / . Amer. Chem. Soc. 79, 5992 (1957). 65 F. R. Jensen and L. H. Gale, J. Amer. Chem. Soc. 81, 6337 (1959). 60

172

Frederick R. Jensen and C. Hackett Bushweiler TABLE XIII VARIOUS A VALUES DETERMINED BY THE EQUILIBRATION METHOD

Group υθ2^ίΊ2ί-'Π3

—C0 2 CH 3 —C=N —N02 -HgX —MgX —OH

Temp. ( ° Q 78 25 66 25 25 95 25 90 110 82

Solvent

Catalyst

A Value

EtOH MeOH THF f-BuOH i-BuOH pyr Et 2 0

NaOEt NaOMe i-BuOK r-BuOK i-BuOK (<£C02)2

—

Raney Ni Raney Ni AI(isoPrO)3

1.2 1.1 0.25 0.15 1.16 0 ~2 0.54 0.41 0.94

Cyclohexane isoPrOH-Acetone

—

Refs. 1 2 3 4 5 6 7 8 9 10

a

Key to references: 1. E. L. Eliel, H. Haubenstock, and R. V. Acharya,/. Amer. Chem. Soc. 83,2351 (1961). 2. B. J. Armitage, G. W. Kenner, and M. J. T. Robinson, Tetrahedron, 20, 747 (1964). 3. N . L. Allinger and W. Szkrybalo, / . Org. Chem., 27, 4601 (1962). 4. B. Rickborn and F. R. Jensen, / . Org. Chem. 27, 4606 (1962). 5. R. J. Ouellette and G. E. Booth, J. Org. Chem. 31, 587 (1966). 6. F. R. Jensen and L. H. Gale, / . Amer. Chem. Soc. 81, 6337 (1959). 7. F. R. Jensen and K. L. Nakamaye, / . Amer. Chem. Soc. 90, 3248 (1968). 8. E. L. Eliel and C. A. Lukach, / . Amer. Chem. Soc. 79, 5986 (1957). 9. G. Chiurdoglu and W. Masschelein, Bull. Soc. Chim. Belg. 70, 767 (1961). 10. E. L. Eliel and R. S. Ro, / . Amer. Chem. Soc. 79, 5992 (1957).

because of the formation of aluminate complexes which would, of course, have different A values than free hydroxyl. The direct equilibration method may be an effective means of obtaining A values. In this case, a variable temperature study should be performed to deter­ mine ΔΗ° and ΔΞ° enabling the calculation of an A value at any temperature. This calculated A value should be compared with the A value of the substituent determined by some unequivocal method, e.g., low-temperature NMR peak area measurements. Available equilibration data for nitro 27 enables the calcu­ lation of an A value at -90° (1.09 kcal/mole) in excellent agreement with the low-temperature NMR peak area value (1.05 kcal/mole at -90°). 31 K. OTHER METHODS

A variety of other techniques including electron diffraction,29,66 Kerr con­ stant measurements,17·58 ultrasonic techniques,67 polarographic reduction,68 66 67 68

V. A. Atkinson, Ada Chem. Scand. 15, 599 (1961). M. E. Pedinoff, / . Chem. Phys. 36, 777 (1962). F. L. Lambert and K. Kobayashi, / . Amer. Chem. Soc. 82, 5324 (1960).

Cyclohexane and Cyclohexene Conformations

173

and acoustical measurements17 have been applied to the A value problem. However, we believe that the accuracy of these methods is not as great as that of the previously described techniques.

III. Enthalpy and Entropy Changes for the Axial ^ Equatorial Equilibrium in Monosubstituted Cyclohexanes It is obvious that the most generally useful thermodynamic parameters for conformational equilibration in monosubstituted cyclohexanes are the enthalpy (Δ//°) and entropy (AS°) changes. However, the situation in this regard is at best incomplete. Although much work has been done concerning alkyl groups, 17 we will restrict our consideration to other substituents. Some pertinent data are compiled in Table XIV. From previous considerations, it is clear that Δ / Γ and Δ5 0 determined by the NMR chemical shift method 48 are to be viewed critically. However, the variable temperature NMR peak area measurement technique is not without problems as described previously. Providing the pertinent extinction coefficients (e) are known accurately and no substantial variation of e with temperature occurs, IR spectroscopy could give accurate enthalpy changes. Although the experimental results from equilibration studies are probably unequivocal for the specific system, it is not clear what effect the locking group, e.g., i-butyl or methyl, has on the environ­ ments of the substituent of interest, i.e., axial versus equatorial orientation. Any distortion would render the locked compound invalid as a model for the monosubstituted cyclohexane.

IV. A Values A. TABULATION AND SELECTION OF "BEST" A VALUES

In this section, an attempt will be made to evaluate the numerous A value determinations and to select "best" values. Emphasis will be placed on those substituents having A values of about 1 kcal/mole or less, i.e., excluding alkyl groups. Alkyl substituents have been treated thoroughly in previous writings. 16 · 24 Although such a selection has been done in the past, 16,24 our opinion as to the best techniques and thus, the best A values, differ from that of a recent report. 24 Accurate A values may have been omitted in this tabulation, but the omissions are accidental. The selection of the "best" methods for y4-value determination involves a consideration of theoretical accuracy and directness of the technique. In other

-COCI COCH3 -CI

-CO2-K+

-C02-/-Pr -C02H

C0 2 CH2Cri3

C0 2 CH 3

Group

Method 0

DIFFERENCES FOR AXIAL ;

TABLE XIV

MeOH EtOH /-PrOH Dodecane Aqueous diglyme Aqueous diglyme HOCH2CH2OH Dodecane MeOH Neat Gas phase c/s-Decalin

Solvent

ON THE CYCLOHEXANE RlNG

AND ENTROPY (AS )

Equilibration Equilibration Equilibration Equilibration Equilibration Equilibration Equilibration Equilibration Equilibration Infrared Infrared NMR chemical shift

ENTHALPY (ΔΗ°)

0

1.12 1.09 0.9 1.64 1.56 1.71 2.13 1.39 1.17 0.3-0.4 0.52 0.33

-AH0 (kcal/mole)

0.27

— —

0.50 0.4 -0.1 -0.85 -0.68 -0.87 -0.56 -0.32 1.16

AS° (e.u.)

EQUATORIAL EQUILIBRATION

4 5 6

1,2 3 2

Refs. c

0.629 0.9 -0.01 0.41 0.04 0.2

Neat Isooctane Isooctane CS2 Isooctane ? ί-BuOH CS2

NMR chemical shift Mod. NMR chemical shift NMR chemical shift Infrared Equilibration Mod. NMR chemical shift

—

0.5 0.2-0.38 0.256 0.4 0.3-0.41 1.24

CS2 Neat ; gas phase c/s-Decalin

Mod. chemical Shift Infrared NMR chemical shift Mod. NMR chemical shift Infrared NMR chemical shift

0.7 0

—

-0.61 0.8 0.86

-1.21

—

0.45 0.6

—

0.2

6 7 6 9 10 7

7 8 5 7 4 6

"Infrared = variable temperature IR technique; NMR chemical shift = method of Eliel; mod. NMR chemical shift = combination of modified NMR chemical shift method of Jensen and Beck (see ref. 7 in footnote c) and low-temperature peak area measurements. * -OTs = /?-methylbenzenesulfonate (tosylate). c Key to references: 1. E. L. Eliel and M. C. Reese, /. Amer. Chem. Soc. 90, 1560 (1968). 2. B. J. Armitage, G. W. Kenner, and M. J. T. Robinson, Tetrahedron 20, 747 (1964). 3. R. J. Ouellette and G. E. Booth, /. Org. Chem. 31, 587 (1966). 4. G. Chiurdoglu, L. Kleiner, W. Masschelein, and J. Reisse, Bull. Soc. Chim. Belg. 69, 143 (1960). 5. J. Reisse, J. C. Cellotti, and G. Chiurdoglu, Tetrahedron Letters, p. 397 (1965). 6. J. C. Celotti, J. Reisse, and G. Chiurdoglu, Tetrahedron 22, 2249 (1966). 7. F. R. Jensen and B. H. Beck, unpublished result. 8. J. A. Hirsch, Top. Stereochem. 1, 199 (1967). 9. G. Chiurdoglu, J. Reisse, and M. Vander Stichelen Rogier, Chem. Ind. {London) p. 1874 (1961). 10. B. Rickborn and F. R. Jensen, /. Org. Chem. 27, 4606 (1962).

—OTs6 —S H -C=N

—OC—CH3

Î

—OH

—Br

176

Frederick R. Jensen and C. Hackett Bushweller

words, those techniques for which the theory is quantitatively based, e.g., NMR and IR spectroscopy, are considered sound. The use of equilibration techniques involving locked structures is considered valid. The use of methyl as a locking group is more acceptable than /-butyl because of minimal distor­ tion of the cyclohexane ring by methyl as compared to /-butyl. Thus, the "best" techniques include low-temperature NMR peak area measurements, IR studies in which pertinent extinction coefficients are known, and equilibration using locking groups. A compilation of what the present authors consider to be best values is given in Table XV. Table XV is selective rather than exhaustive since a com­ plete listing of A values has appeared recently.24 In a number of cases,24 including -NH 2 , - 0 2 C - C 6 H 5 - N 0 2 , - O N 0 2 , -NHCH 3 , -N(CH 3 ) 2 , -+NH 3 , SOCH3, and S0 2 CH 3 , the technique of measurement was indirect and cannot be regarded as unequivocal. Therefore, it is very difficult to select best values. B. DISCUSSION OF VARIOUS A VALUES

It is the purpose of this section to assess the various A values in terms of the factors presented in the introduction to this chapter. In order to maintain some consistency in the conditions under which the A values to be discussed were measured, the report of Jensen, Bushweller, and Beck31 will be used for the most part. The observed A -value sequence for the halogens (F < I < Br < Cl; Table XIV) has been rationalized previously.41 The observation that fluorine has the smallest A value is not surprising in light of its small van der Waals radius (1.4 Â). 69 However, the remainder of the sequence obviously does not parallel van der Waals radii. The trend can be explained on the basis of bond lengths and polarizabilities (Table I). Some pertinent data are summarized in Table XVI. As the carbon-halogen bond becomes longer (Table XVI), the center of the electron cloud surrounding the halogen atom in the axial isomer moves farther above the average plane of the cyclohexane chair and farther away from the two sjw-axial hydrogens [e.g., (40) through (43)]. It is also evident that the increasing C-X bond length also involves an increasing polarizability of the halogen atom (Table I). Thus, the long C-I bond length and highly polarizable iodine atom both cause dramatically reduced nonbonded compressions for axial iodine than those predicted on the basis of the van der Waals radius alone, i.e., on the basis of a hard sphere model. The van der Waals radii of "divalent" sulfur (1.85 Â) 69 and oxygen (1.40 Â) 69 seem to play important roles in determining the A values of substituents 69 L. Pauling, "Nature of the Chemical Bond," 2nd ed. Cornell Univ. Press, Ithaca, New York, 1940.

—OTs —0SO2CH3

—0—c--H

I

0

—0—c--CF 3

0

— 0 — c - -CH 3

I

0

—OCD 3

—1

—Br

—CI

—F

Group

area area area area

area area area

area area area peak area area

N M R peak area N M R peak area N M R peak area

N M R peak area

N M R peak area

N M R peak N M R peak N M R peak N M R ( 19 F) N M R peak Infrared N M R peak N M R peak N M R peak Infrared N M R peak N M R peak N M R peak N M R peak

Method

-80 -80 -88

-83

-88

-81 -81 -81 30 -80 -73 -96 -82

—

-86 -93 -91 -55 -81

Temp. (°C)

CS 2 CS 2 CS2

CS 2

CS 2

Neat liquid CS 2 CS 2 CS 2 CS 2 CS 2 CS 2 CD 2 CDCI CS 2

cs2

cs2 cs2 CCI3F

CS 2

Solvent or phase

0.59 0.515 0.56

0.54

0.71

—

0.51 0.476 0.48 0.61-0.63 0.468 0.46 0.56 0.547

0.276 0.25 0.27 0.24 0.528

A Value (kcal/mole)

" B E S T " A VALUES AND ENTHALPIES ( Δ / / 0 ) FOR MONOSUBSTITUTED CYCLOHEXANES

TABLE XV

— —

—

—

— — — — — — — —

0.3-0.4

— — — —

-AH° (kcal/mole)

1 1 1

9

1

1 2 3 3 1 4 2,5 1 5,6 7 1 5 8 1

Refs."

-HgBr -HgOAc -SiCI3 -MgBr

-C-CHj

II

0

-c-CI

I1

0

-COZH -cozy

--COZCHzCH,

-C=CH --COzCH,

-NZC -N=C=O -N=C=S -N=C=N-CGHII -C=N

-S H -SCD, -S-C=N -NO2

25 25

Direct equilibration Direct equilibration

Direct equilibration Direct equilibration NMR peak area NMR peak area NMR peak area NMR peak area 25 95 -19 -80 -83 -75

25

-90 -80 -80 -19 -80 25 76 80 66 -79 -80 25 -78 25

NMR peak area NMR peak area NMR peak area NMR peak area NMR peak area Direct equilibration Direct equilibration Direct cquilibration Direct equilibration NMR peak area NMR peak area Direct equilibration NMR peak area Direct equilibration

Direct equilibration

-80 -79 -79 25

NMR peak area NMR peak area NMR peak area Direct equilibration

n-Dodecane

Diglyme-H,O Ethylene glycol

t-BuOH

cs2 csz cs2

TABLE XV- (continued)

1.17 0 0 0.61 0.459 0.784

1.3

1.36-1.46 1.96

0.19 0.19 0.25 0.240 0.41 1.27-1.28 1.31 1.1-1.2

0.15

1.05 0.21 0.506 0.284 0.96

1.20 1.07 I .23 1.16

0.98 ( A T = 0.6 e.u.) 1

20 20

1 1

18 19

18

11 12 13 12 14 1 1 13 1 10.15 16,17 17 13, 17

1

1 1 I

10

T

z

! e v1

6

? 3:

E

W

t v) D

tD

4

?

k

6’

1

a

P

NMR peak area NMR peak area NMR peak area NMR peak area NMR peak area NMR peak area -84 -82 -83 -83 83 83 Me 2 0 Et 2 0 CS2 Toluene Acetone CD3OD

0.247 0.525 0.97 0.92 0.97 1.04

Key to references: 1. F. R. Jensen, C. H. Bushweiler, and B. H. Beck, /. Amer. Chem. Soc. 91, 344 (1969). 2. A. J. Berlin and F. R. Jensen, Chem. Ind. (London) p. 998 (1960). 3. F. A. Bovey, E. W. Anderson, F. P. Hood, and R. L. Kornegay, /. Chem. Phys. 40, 3099 (1964). 4. G. Chiurdoglu, L. Kleiner, W. Masschelein, and J. Reisse, Bull. Soc. Chim. Belg. 69, 143 (1960). 5. W. C. Neikam and B. P. Dailey, /. Chem. Phys. 38, 445 (1965). 6. J. Kleinberg, W. J. Argersinger, Jr., and E. Griswold, "Inorganic Chemistry," p. 163. Heath, Boston, Massachusetts, 1960. 7. F. R. Jensen and L. H. Gale, /. Org. Chem. 25, 2075 (1960). 8. F. R. Jensen and C. H. Bushweller, /. Amer. Chem. Soc. 88, 4279 (1966). 9. F. R. Jensen and B. H. Beck, unpublished results. 10. R. J. Ouellette and G. E. Booth, / . Org. Chem. 31, 587 (1966). 11. C. H. Bushweller and J. W. O'Neil, /. Org. Chem. 35, 276 (1970). 12. B. Rickbora and F. R. Jensen, J. Org. Chem. 27, 4606 (1962). 13. M. Tichy, F. Sipos, and J. Sicher, Collect. Czech. Chem. Commun. 31, 2889 (1966). 14. N. L. Allinger and W. Szkrybalo, / . Org. Chem. 27, 4601 (1962). 15. E. L. Eliel, H. Haubenstock, and R. V. Acharya, /. Amer. Chem. Soc. 83, 2351 (1961) 16. N. L. Allinger and R. J. Curby, /. Org. Chem. 26, 933 (1961). 17. E. L. Eliel and M. C. Reese, /. Amer. Chem. Soc. 90, 1560 (1968). 18. J. A. Hirsch, Top. Stereochem. 1, 199 (1967). 19. F. R. Jensen and L. H. Gale, /. Amer. Chem. Soc. 81, 6337 (1959). 20. F. R. Jensen and K. L. Nakamaye, /. Amer. Chem. Soc. 90, 3248 (1968). 21. C. H. Bushweller, J. A. Beach, J. W. O'Neil, and A. V. Rao, /. Org. Chem. 35, 2086 (1970).

a

—OD

-OH

—MgC6Hn

20 20 21 21 21 21

180

Frederick R. Jensen and C. Hackett Bushweller

(40)

(41)

(42)

(43)

with sulfur or oxygen bonded to the cyclohexane ring. Indeed, it appears that sulfur is not as polarizable as bromine or iodine and/or that the lone pairs on sulfur and oxygen have significant directional character, i.e., "steric bulk." The A values in the oxygen series are not all identical, but do lie in a relatively narrow range (0.5-0.7 kcal/mole ; Table XV). Those of the sulfur analogs occur in a comparable narrow range (1.0-1.2 kcal/mole), but are of substantially TABLE XVI A VALUES, C-X

BOND LENGTHS, AND VAN DER WAALS RADII OF HALOGENS IN HALOCYCLOHEXANES

a b

Halogen

C-X bond length (AT

van der Waals radius (A°)

A Value6 (kcal/mole)

F CI Br 1

1.49 1.76 1.91 2.00

1.4 1.8 2.0 2.2

0.27 0.53 0.48 0.47

See G. W. Wheland, "Resonance in Organic Chemistry." Wiley, New York, 1955. Measured at -80° in CS2.

greater magnitude. A meaningful comparison (Table XV) can be made be­ tween the -OCD3 A value (0.55 kcal/mole at -82° in CS2)41 and the -SCD 3 A value (1.07 kcal/mole at —79° in CS2).41 From a consideration of structures (44) and (45) (assuming lone pairs on sulfur and oxygen to have significant directional character), it is clear that nonbonded compressions between synaxial hydrogens and the lone pair of the axial substituent will be greater in the

181

Cyclohexane and Cyclohexene Conformations

(44)

(45)

case of sulfur. This rationalization would seem to be consistent with the significantly reduced A value of trifluoroacetoxy (0.54 kcal/mole at —83° in CS 2 ; Table XV)31 as compared to acetoxy (0.71 kcal/mole at -88° in CS 2 ) 31 and the effectiveness of the electron-withdrawing trifluoromethyl to remove electron density from the lone pairs on oxygen. The somewhat lower A value for the formyl group (0.59 kcal/mole at —80° in CS 2 ) 31 as compared to acetoxy suggests that even though the methyl group of acetoxy is relatively remote from the cyclohexane ring, it experiences enhanced nonbonded compressions compared to hydrogen of the formyl group. It is interesting to note the difference between the A value of the /?-toluenesulfonate (-OTs; Table XV) group (0.52 kcal/mole at -80° in CS2-CDC13)31 and the methanesulfonate group (0.56 kcal/mole at -88° in CS2-CDC13).31 It would seem that the /?-methylphenyl group can assume a conformation or conformations in the axial conformer which involve a diminution of nonbonded compressions compared to methanesulfonate. However, it also seems possible that the more electronegative /?-methylphenyl group as compared to methyl withdraws electron density from the lone pairs on divalent oxygen (on the cyclohexane ring) thus reducing the A value. As stated previously, the A values of substituents with divalent sulfur attached to the cyclohexane ring are consistently high (1.0-1.2 kcal/mole). Examination of cyclohexanethiol at 1.0 and 2.0 Min CS 2 at —80° gave essenti­ ally the same A value (1.17 and 1.20 kcal/mole)31 suggesting no appreciable association in this concentration range. The A value of the thiocyanate group (-SCN; 1.23 kcal/mole at -79° in CS 2 ) 31 is comparable to -SH, but the A value of-SCD 3 is significantly smaller (1.07 kcal/mole at —79° in CS2). This "deviation" is outside experimental error and the reasons for it are not clear, especially in light of methyl (A ^ 1.8 kcal/mole)24 being a substantially "larger" group than cyano (A = 0.24 kcal/mole at -79° in CS 2 ). 31 Functionalities which are cylindrically symmetrical have relatively low A values (Table XIV). The linear nature of these substituents apparently reduces nonbonded compressions in the axial isomer. Thus, the A values of nitrile (0.24 kcal/mole a t - 7 9 ° in CS 2 ), 31 isonitrile ( - N ^ C , 0.21 kcal/mole at -80° in CS 2 ), 31 and ethynyl (0.41 kcal/mole at -80° in CS 2 ) 31 groups are small relative to other substituents, e.g., -C0 2 CH 3 , - N 0 2 , etc., which lack cylind­ rical symmetry.

182

Frederick R. Jensen and C. Hackett Bushweller

Although the A value of the nitro group (1.05 kcal/mole at -90° in CS 2 ) 31 is large, the A values of some other groups with nitrogen bonded to the cyclohexane ring are much smaller and show an interesting trend. It appears that the A value of these groups is a function of the hybridization of the lone pair on nitrogen, i.e., a function of the directional character of the lone pair (Table XVII). The A values (Table XVII) of the isocyanate (—N=C==0), isothiocyanate (—N=C=S), and isonitrile (—N=^C) groups are relatively low, as TABLE XVII A VALUES OF VARIOUS GROUPS WITH NITROGEN BONDED TO THE CYCLOHEXANE RING"

Group

A Value (kcal/mole)

—ISÖC _N=C=S _N=C=0 _N=C=N—CßHn — N02

0.210 0.284 0.506 0.96" 1.05

a See F. R. Jensen, C. H. Bushweller, and B. H. Beck, J. Amer. Chem. Soc. 91, 344 (1969). All A values measured at —80° in CS 2 . b See C. H. Bushweller and J. W. O'Neil. / . Org. Chem. 35, 276 (1970).

expected from the reduced conformational requirements of linear, cylindrical functionalities. However, one might predict on the basis of van der Waals radii that if either group should be larger, isothiocyanate would be larger than isocyanate. The obvious inconsistency of the results with such a prediction suggests that canonical structures such as (47a) are more important in iso­ thiocyanate than in isocyanate (47b). Indeed, as the contribution of canonical

N=C=X

(46)

(47)

(a) X = S (b) X = 0

(c) X ^ N - C ß H ^

Cyclohexane and Cyclohexene Conformations

183

forms such as (47) decreases, it seems reasonable that the directional character of the lone pair on nitrogen will increase (46). It further seems reasonable that as the directional character of the lone pair on nitrogen increases, nonbonded compressions in the axial isomer will increase (48), and the A value will

H

<ζ\/

(48)

increase. Indeed, in the case of the carbodiimido (—N=C=N—C 6 Hi {) group, the directional character of the lone pair is substantial (Table XVII) suggesting the preponderance of canonical form (46c). The effect of long bond length and polarizability is reflected again in the A values for the trichlorosilyl (0.61 kcal/mole at —80° in CS 2 ), 31 acetatomercuri (0.01 kcal/mole at -79° in CS 2 -pyr), 31 bromomercuri (0 kcal/mole at 95° in pyr), 65 bromomagnesium (0.459 kcal/mole at —83° in Me 2 0), 7 0 and cyclohexylmagnesium (0.247 kcal/mole at —84° in Me 2 0) 7 0 groups. The group radius of the -S1CI3 functionality is almost certainly larger than methyl (A value ^ 1.8 kcal/mole),24 but the substantially longer carbon-silicon bond apparently reduces nonbonded compressions in the axial conformer. The effects of elon­ gated bonds and polarizability are also evident in the observation that mercury has essentially no preference for the axial or equatorial position (Table XV). It is apparent that a long carbon-magnesium bond also lowers the A value of magnesium from a value predicted on the basis of van der Waals radii. TABLE XVIII A VALUES OF VARIOUS ALKYL G R O U P S

Group —CH 3 —CF 3 -CH2CH3 -CH(CH3)2 -C(CH3)3

A Value (kcal/mole) -1.70 2.4-2.5a -1.75 -2.15 >4

a See E. W. Delia, / . Amer. Chem. Soc. 89, 5221 (1967). 70

F. R. Jensen and K. L. Nakamaye, / . Amer. Chem. Soc. 90, 3248 (1968).

184

Frederick R. Jensen and C. Hackett Bushweller TABLE XIX A VALUES FOR VARIOUS GROUPS AS A FUNCTION OF SOLVENT

Group

Method

Solvent

A Value Temp. (°C) (kcal/mole) Refs. a

—F

N M R peak area N M R peak area N M R peak area

CFCI3 CS 2 CD 2 CDCI

-55 -86 -84

0.24 0.28 0.25

1 2 3

—CI

N M R peak area N M R peak area

CD 2 CDCI

cs2

-81 -88

0.53 0.51

2 3

cs2

-81 -85

0.48 0.48

2 3

—Br

N M R peak area N M R peak area

CD 2 CDCI

N M R peak area N M R peak area

CD 2 CDCI

cs2

-80 -86

0.47 0.44

2 3

—OH —OD

N M R peak area N M R peak area

Toluene CD3OD

-83 -83

0.92 1.04

4 4

—MgBr

N M R peak area N M R peak area

(CH3)20 (CH3CH2)20

-83 -75

0.46 0.78

5 5

—HgBr

Equilibration

pyr

95

0

6

—HgOAc

N M R peak area

CS 2 -pyr

-79

0

2

—1

a

Key to references: 1. F. A. Bovey, E. W. Anderson, F. P. Hood, and R. L. Kornegay, J. Chem. Phys. 40, 3099 (1964). 2. F. R. Jensen, C. H. Bushweller, and B. H. Beck,/. Amer. Chem. Soc. 91, 344(1969). 3. C. H. Bushweller, Ph.D. Dissertation, University of California, Berkeley, 1966. 4. C. H. Bushweller, J. A. Beach, J. W. O'Neil, and F. V. Rao, / . Org. Chem. 35, 2086 (1970). 5. F. R. Jensen and K. L. Nakamaye, / . Amer. Chem. Soc. 90, 3248 (1968). 6. F. R. Jensen and L. H. Gale, J. Amer. Chem. Soc. 81, 6337 (1959).

However, the variation of the A value (Table XV) of magnesium with solvent (Me 2 0 or Et 2 0) attests to the effectiveness with which ethers complex divalent magnesium. The effect of dimethyl or diethyl ether on the A value of mag­ nesium provides one of very few dramatic examples of the effect of complexation on A values. The A values of the various alkyl groups (Table XVIII) fit a trend discussed previously in this chapter, 24 i.e., no significant break in the A value occurs until three alkyl groups are attached to the carbon attached to the cyclohexane ring. Indeed, the definite possibility of the very large /-butyl group actually distorting the cyclohexane ring from a "true chair" has been considered previously.

Cyclohexane and Cyclohexene Conformations

185

C. SOLVENT EFFECTS ON A VALUES

The situation with regard to solvent effects on the equatorial : axial isomer ratio in monosubstituted cyclohexanes is far from clear. The vast amount of available data from various techniques using different solvents (see preceding sections) further clouds the issue because the validity of certain methods is questionable. Dipole-dipole solvation, ligand complexation, London dis­ persion forces, and hydrogen bonding must all play roles to varying degrees. Therefore, an attempt will be made to select A values for certain substituents which have been determined by a method which these authors believe to be unequivocal, or by a technique which may not give extremely accurate A values, but will give a meaningful relative sequence. These data are compiled in Table XIX and are selective rather than exhaustive. It is clear from Table XIX that the halogens show no really significant varia­ tions in the solvents studied. The trend toward higher A values for hydroxyl in solvents capable of hydrogen bonding appears to be general. The solvent dependence of the A value for -MgBr group dramatically shows the effect of ligand size in determining an A value. The invariance of the A value for-Hg-X in different solvents attests to the effect of the long carbon-mercury bond length. A series of recent reports 48 purport to have measured the A values of a series of substituents (also Δ//° and Δ5°) in a variety of solvents. However, the validity of these data is questionable because of the technique (NMR chemical shift method) employed. V. Disubstituted Cyclohexanes and the Additivity of A Values The effect of multisubstitution in the cyclohexane ring on the apparent A values of the substituents has received some attention. Much work has been expended to predict and measure the preferred conformations of di- and polyalkylcyclohexanes.15,17 Indeed, the introduction of more than one sufficiently bulky substituent, e.g., /-butyl,71 phenyl, 72 and phthalimido, 73 in specific stereochemical orientations can cause at least a lowering of the chair/twist energy difference, if not a preference for the twist conformer.74 This section will not be concerned further with the effects of alkyl groups on conformational preferences, but will attempt to elucidate the influence of one substituent (X) 71 (a) R. D. Stolow and A. A. Gallo, Tetrahedron Lett. p. 3331 (1968); (b) H. Kessler, V. Gusowski, and M. Hanack, ibid. p. 4665 (1968); (c) S. Wolfe and J. R. Campbell, Chem. Commun, p. 872(1967). 72 E. W. Garbisch, Jr., and D. B. Patterson, J. Amer. Chem. Soe. 85, 3228 (1963). 73 H. Booth and G. C. Gidley, Tetrahedron Lett. p. 1449 (1964). 74 D. L. Robinson and D. W. Theobald, Quart. Rev. 21, 314 (1967).

186

Frederick R. Jensen and C. Hackett Bushweller

n o

Pi

O <

o

C

o © o

xυ

§

υ

Q U

~ 7 i

X w o u

o

7 7 ?' 7

Z

ω

O I

vb vb vo ^H o o ON o

o

<

o

<υ

C n c C U « ä 2 3 « 3 j2

Έ H

Q o "o U H H

»o r- m 00

1 1 1

1

X Q PQ

< op 4

DÌ

PH

< o Cri

O

MH

Z O U

o

(J

11

>-

11

X

CÛ o==o1 1 m 1 l/ o - Il V

ω>

Il >- o Il 11

X X

1 \\ / / II / X \ 11

>■

MgBr

-79

Ether

Acetone-CKCF

Benzene Methanol-Cl3CF Acetone

-0.78 c

~ -0.6"

0.6* ~ -0.6 b -0.53°

<-1.25

0.35

0.1 0.01 0.16

8

6

6 6 7

β Calculated from data in E. W. Garbisch, Jr. and K. D. MacKay, Abstr. 155th Nat. Meeting Amer. Chem. Soc, San Francisco, 1968 No. P065. * See R. J. Ouellette and G. E. Booth, / . Org. Chem. 26, 3619 (1961). c See F. R. Jensen and K. L. Nakamaye (see ref. 8 in footnote d below). This value assumes phenyl to be an effective locking group with no distortion of the ring. d Key to references: 1. G. Wood and E. P. Woo, Can. J. Chem. 45, 2477 (1967). 2. K. Kozima and T. Yoshino, / . Amer. Chem. Soc. 75, 166 (1953). 3. V. Atkinson and O. Hassel, Acta Chem. Scand. 13, 1737 (1959). 4. G. Wood, E. P. Woo, and M. H. Miskow, Can. J. Chem. 47, 429 (1969). 5. G. W. Wood and E. P. Woo, Can. J. Chem. 45, 1293 (1967). 6. R. D. Stolow, T. W. Giants, and J. D. Roberts, Tetrahedron Lett. p. 5777 (1968). 7. S. L. Spassov, D. K. Griffith, E. S. Glazer, K. Nagarajan, and J. D. Roberts, / . Amer. Chem. Soc. 89, 88 (1967). 8. F. R. Jensen and K. L. Nakamaye, / . Amer. Chem. Soc. 90, 3248 (1968).

MgBr

= ΓΛ

-104

X=F;Y=—O—C-/

J

33 -93 -75

X = C I ; Y = — OH X = F ; Y = — OH X = F ; Y = CI 0

188

Frederick R. Jensen and C. Hackett Bushweller

on another (Y) when the C-X and C-Y bond moments are nonnegligible. A reasonable amount of data is available concerning cyclohexanes substituted at the 1- and 4-positions. They are summarized in Table XX. In Table XX, the observed difference in free energy (AG°bs) is tabulated along with a calculated free energy (AG°dd) difference assuming additivity of A values. From a perusal of Table XX, it is evident that deviation from an additivity relationship is the rule. Indeed, it is clear that dipole-dipole interactions are a significant factor in conformational preferences. A rationalization for the observed trends has been reported 70,75 and can be understood with the aid of structures (49) and (50) [Eq. (25)]. Equation (25) illustrates the case in which

I

δ+ δ -

δ-Υ (49)

(50)

the C-X and C-Y bond moments are oriented in the same direction. It is evident in structure (50) that the negative monopole (δ—) associated with a given dipole is at a maximum distance from the positive monopole (δ+) of the other dipole. By converting to structure (49) the positive monopoles (δ+) are not moved with respect to one another, but the negative monopoles (δ-) are moved significantly closer to the positive monopoles (δ+) of the other dipoles, i.e., a < b. The net result is a more effective charge neutralization and tendency to stabilize the diaxial conformer (49). Indeed, in certain instances (Table XX), it appears that a net preference for the axial position exists. The situation in the case of eis- and tomy-4-phenylcyclohexylmagnesium bromide (Table XX) may reflect a destabilizing charge-charge interaction in the eis isomer [Eq. (26)]. Since phenyl is known to be a large substituent ô+

MgBr

(51)

δ+

(52)

(A value = 2-3 kcal/mole)24 it is an effective locking group. Indeed, the devia­ tion from additivity in eis- and /ra«s-4-phenylcyclohexylmagnesium bromide (Table XX) may be a consequence of ring distortion by phenyl. However, dipolar interactions cannot be ruled out as important factors in this equilibrium a Wood and E. P. Woo, Can. J. Chem. 45, 2477 (1967).

Cyclohexane and Cyclohexene Conformations

189

[Eq. (26)]. Consistent with the previous discussion concerning dipolar inter­ actions, it is clear that repulsion between positive monopoles (S+) is maximized in structure (51) and minimized in structure (52). In light of this explanation, the enhanced preference for the trans isomer (52) is not surprising. A limited amount of data is available concerning 1,2- and 1,3-dipolar17 interactions in cyclohexane derivatives. In these cases the effects of electrostatic and nonbonded repulsions are evident. Selected data for trans-\,2-aiha\ocyclohexanes are compiled in Table XXI. Calculated values assuming additivity are also included. The general tendency toward a greater preference for the diaxial conformer (Table XXI) attests to the effectiveness of dipolar reTABLE XXI CONFORMATIONAL PREFERENCES OF /ri7AÎJ-l,2-DlSUBSTITUTED C Y C L O H E X A N E S

X

Substituents

Y Temp. (°C)

X = Y = CI X = Y=Br

-100 -100 -100 -100

X = CI; Y = l

Solvent

cs2 cs 2 Acetone CS 2

AG° add (kcal/mole)a

AG° obs (kcal/mole)

Refs.fc

-1.06 -0.96 -0.96 -1.0

-0.21 0.31 ~0 0.24

1,2 1-3 1 4

α Calculated from data in F. R. Jensen, C. H. Bushweiler, and B. H. Beck, /. Amer. Chem. Soc. 91, 344 (1969). b Key to references: 1. R. B. Kelley, Can. J. Chem. 35, 149 (1957). 2. E. Premuzic and L. W. Reeves, Can. J. Chem. 40, 1870 (1962). 3. P. Klaeboe, J. J. Lothe, and K. Lunde, Acta Chem. Scand. 11, 1677 (1957). 4. J. P. Mazaleyrat and Z. Welvart, Chem. Commun, p. 485 (1969).

pulsions in the diequatorial conformer. Indeed, the increase in the amount of the diequatorial conformer of fra«.s-l,2-dibromocyclohexane (Table XXI) in acetone as compared to carbon disulfide indicates more effective solvation by the more polar acetone of the greater net dipole moment of the diequatorial over the diaxial isomer. However, the greater preference of trans-\,2-C\Y\OTOiodocyclohexane (Table XXI) for the diaxial conformer when compared to /ra«,y-1,2-dichlorocyclohexane suggests the intervention of van der Waals repulsive forces in addition to dipolar repulsions.

190

Frederick R. Jensen and C. Hackett Bushweller

In the case of a 1,1-disubstituted cyclohexane in which the substituents are different, the preferred conformation will be the one in which the group with the largest A value is equatorial [Eq. (27)]. A very limited amount of data is available concerning the additivity of A values in this case,76 but it appears that

A/

V

- \^v

<27)

Y

the additivity relationship does not hold. In the case of 1-chloro-l-methylcyclohexane, Allinger and co-workers46 have pointed out that in the conformer with chlorine axial, the chlorine will bend out from the ring to relieve sjw-axial repulsions. In so doing, nonbonded repulsion between the chlorine and methyl hydrogens is increased. Since an axial methyl group has much less of a tendency to bend in this manner, the energy of the conformer with chlorine axial is raised more relative to the conformer with chlorine equatorial. Such considerations cast further doubt on the validity of A values determined using techniques employing model compounds with geminai disubstitution. 45,77 VI. Cyclohexene Derivatives A six-membered carbocyclic compound with an endocyclic double bond, i.e., cyclohexene, is predicted to exist exclusively in the half-chair conformation (12). 20,21 Angyal78 has calculated the distance between the ends of the carbon chains in c/5-2-butene (2.88 Â), the trans conformer of butane (2.94 Â), and the eclipsed butane conformer (2.56 Â). Thus, the cz>2-butene unit "fits" the trans conformer of butane with substantially less angle strain than the eclipsed form, thus favoring formation of the half-chair. Indeed, theoretical calculations21 indicate that the boat conformer (13) is a potential maximum on the reaction coordinate for the half-chair inversion process [Eq. (28)]. Barton and co-workers79 predicted the overall geometry of the cyclohexene half-chair with the double bond restricting C-l, C-2, C-3, and C-6 to a coplanar relationship. All the carbon-hydrogen bonds are staggered to varying degrees with respect to one another. A vector analysis22 of the half-chair indicates that the protons on C-4 and C-5 are not exactly axial or equatorial. The introduction 76

J. P. Mazaleyrat and Z. Welvart, Chem. Commun, p. 485 (1969). R. J. Ouellette, K. Liptak, and G. E. Booth, / . Org. Chem. 31, 546 (1966). 78 S. J. Angyal, Progr. Stereochem. 1, 81 (1954). 79 D. H. R. Barton, R. C. Cookson, W. Klyne, and C. W. Shoppe, Chem. Ind. (London) p. 21 (1964). 77

191

Cyclohexane and Cyclohexene Conformations

of a double bond into the cyclohexane ring causes a change in orientation in both the allylic and homoallylic carbon-hydrogen bonds. The axial C-H bonds in cyclohexane are very nearly parallel to the vertical axis (53). However, the

(28)

corresponding allylic C-H bonds in cyclohexene are displaced by 23° from the vertical and the homoallylic axial C-H bonds 11 ° from the vertical toward the center of the ring (54). It is clear that an axial substituent on C-4 of cyclohexene will be in close proximity to the π cloud of the carbon-carbon double bond. The consequences of this orientation may be quite important in a rationaliza­ tion of data to be presented subsequently. As compared to the C-H bonds in

>^-=

(53)

(54)

the chair form of cyclohexane, ds-allylic and homoallylic substituents on adjacent carbons in cyclohexene experience increased eclipsing. Garbisch and MacKay 21 have presented evidence from NMR spectroscopic data that the C-H bonds in the homoallylic CH 2 -CH 2 fragment are essentially perfectly staggered. The effect of bond angle distortion and eclipsing interactions may be manifested in the greater heat of hydrogénation for cyclohexene (—28.6 kcal/mole) than trans-2-butenç (—27.6 kcal/mole).80 Direct experimental evidence has corroborated the preference for the halfchair form in cyclohexene. Electron diffraction and X-ray crystallographic data i0

K. S. Pitzer, Science 101, 672 (1945V

192

Frederick R. Jensen and C. Hackett Bushweller

confirm the half-chair conformer in 3,4,5,6-tetrachlorocyclohexene,23a pentachlorocyclohexene,23b and naphthalene tetrachloride.23c The half-chair form of cyclohexene is a dissymmetric molecule with interconversion between the two equivalent forms [Eq. (28)] resulting in racemization. The rate of half-chair inversion in cyclohexene (Δ<7* = 5.3 kcal/mole at —165°)81 and 4-substituted cyclohexenes (AG* = 5.2-6.2 kcal/mole at about —165°)81b>c has been determined to be very fast indeed at room temperature. In this regard, unsuccessful attempts have been made to resolve the enantiomers of cyclohexene-d^^-dicarboxylic acid.82 Thus, the conformational idiosyncrasies of substituted cyclohexenes in solution may be determined by studying the rapidly equilibrating systems by making necessary assump­ tions or by using "locked" compounds. Infrared and NMR spectroscopy have been applied to the problem with NMR techniques being applied to the rapidly (on the NMR time scale) or slowly equilibrating systems. Available data concerning 4-substituted cyclohexenes are compiled in Table XXII. The conformational preferences, i.e., axial versus equatorial, are expressed in terms of the E4 value defined according to Eqs. (9) and (10). If the E4 value is positive, the equatorial isomer predominates. The substantial reduction in the conformational preference for the equa­ torial position in 4-substituted cyclohexenes (Table XXII) as compared to the monosubstituted cyclohexanes (Table XV) is remarkable. Some of the reasons for this behavior are clear. Compared to an axial substituent on the cyclohexane ring, it is evident from models that a C-4 axial substituent on the cyclo­ hexene ring should experience a marked decrease in nonbonded compressions. In monosubstituted cyclohexanes, two «syn-axial interactions hinder an axial substituent. In the cyclohexene ring, the presence of the double bond eliminates one sjw-axial interaction and minimizes the other interaction with an allylic C-H bond via a 23° tilt from the vertical (54). In addition, it appears that the increased eclipsing of the cis-a\\y\ic C-H bond and the 4-substituent destabi­ lizes the axial and equatorial isomers to about the same degree. An additional effect which may be operative in the reduced conformational preferences in the 4-halocyclohexenes is a mutual polarization of the halogen atom and the π cloud of the double bond, i.e., an attractive intramolecular London dispersion force. Since the axial C-4 halogen is closer to the double bond than the equatorial C-4 halogen, due to being axial and to being bent toward the center of the cyclohexene ring, an attractive force is more favorable for axial C-4 halogen than for the more removed equatorial halogen (55) and (56). The effect would seem to be manifested in the E4 value for iodine (—0.016 kcal/mole at —157°) in which the axial isomer is slightly preferred. Postulation 81

(a) F. A. L. Anet and M. Z. Haq, /. Amer. Chem. Soc. 87, 3147 (1965); (b) F. R. Jensen and C. H. Bushweller, /. Amer. Chem. Soc. 87, 3285 (1965); (c) 91, 5774 (1969). 82 J. Boeseken and W. J. F. de Rijck van der Gracht, Ree. Trav. Chim. 56, 1203 (1937).

Cyclohexane and Cyclohexene Conformations

193

TABLE XXII CONFORMATIONAL PREFERENCES OF 4-SUBSTnTJTED CYCLOHEXENES

-X

E4 Value = Substituent (X) -CH3 —C6H5 —F -CI —Br —1

RT\nK 1000

Method

Temp. (°C)

Solvent

Epoxidation rates NMR coupling constants NMR peak area NMR peak area NMR peak area NMR peak area Infrared NMR peak area

25 25 -166 -157 -157 -157 — -157

Et20 ? CD2CDCI CD2CDCI CD2CDCI CD2CDCI Neat CD2CDCI

E4 Value (kcal/mole) Refs/ -1.0 0.99 0.014 0.20 0.077 0.093° 0.0505 -0.016

1 2 3 3 3 3 4 3

a

4-Bromocyclohexene-2,3,3,5,5,6,6-i/7 according to the equation above. This value is actually ΔΗ° = -0.050 kcal/mole. c Key to references: 1. C. B. Rickborn and S. Lwo, / . Org. Chem. 30, 2212 (1965). 2. E. W. Garbisch, Jr. and K. D. MacKay, Abstr. 155th Nat. Meeting Amer. Chem. Soc, San Francisco, 1968, No. P065. 3. F. R. Jensen and C. H. Bushweller, / . Amer Chem. Soc. 91, 5774 (1969). 4. K. Sakashita, Nippon Kagaku ZasshU 80, 972 (1959).

b

of such an effect is not without precedent. Other workers have rationalized the preference for the eis isomers of 1-bromopropene83 and 1,2-dichloroethylene84 via London dispersion forces. Dipole moment studies indicate the preferred conformation of 0,0'-dichlorobiphenyl to be that with the two chlorine atoms close together, but not the planar form. 85

^ (55) 83 84 85

e>a

(56)

K. S. Pitzer and J. L. Hollenberg / . Amer. Chem. Soc. 76, 1493 (1954). N. L. Allinger, / . Amer. Chem. Soc. 79, 3443 (1957). C. Hampson and A. Weissberger, / . Amer. Chem. Soc. 58, 2111 (1936).

194

Frederick R. Jensen and C. Hackett Bushweller

The £4-value sequence for chlorine, bromine, and fluorine is the same as the A value sequence, i.e., Cl > Br > F. However, iodine-deviates. Thus, it appears that the bond length and polarizability hypothesis advanced for the halocyclohexanes (see previous sections) also applies to the 4-halocyclohexenes with the intervention of differential London dispersion forces causing the "anomalous" behavior for iodine. Since iodine possesses the highest polariz­ ability of the halogens, this result is not unexpected. The E4 values of polar substituents will probably be observed to be solventdependent. Cyclohexene possesses a dipole moment of 0.75 D, 86 whereas the carbon-halogen bond moments are about 1.8 D 17 . Consequently, the net dipole moment of an axial 4-halocyclohexene will be greater (vectors additive) than an equatorial 4-halocyclohexene (vectors opposed). It would be expected that less polar solvents will favor the equatorial C-4 halogen form. A paucity of data is available concerning conformational preferences in 3substituted cyclohexenes. It is possible for a substituent to occupy either a pseudoaxial (57) or pseudoequatorial (58) position and exchange positions via half-chair inversion [Eq. (29)]. Garbiseli87 examined the width at half-height

/ (57)

►

^/—^-x

(29)

(58)

of the C-6 proton NMR signals of a number of 6-substituted-l-phenylcyclohexenes finding that more bulky substituents, e.g., 6-i-butyl, prefer the pseudoaxial conformation (57). In this case, nonbonded compressions between the phenyl group and the 6-substituent may account for the observed preferences, but even without the phenyl group, a pseudoequatorial 6-substituent and the adjacent olefinic proton are almost eclipsed. Variable temperature infrared spectroscopic data indicate significant preferences for the pseudoaxial position (57) in 3-chlorocyclohexene (Δ//° = 0.64 kcal/mole)86 and 3-bromocyclohexene (Δ#° = 0.70 kcal/mole).86 Evidence for mutually interconvertible isomers in more highly substi­ tuted cyclohexenes, e.g., 4,5-dichlorocyclohexene88 and 4,5-dimethylcyclohexene, 81c · 89 has also been obtained.

86

K. Sakashita, Nippon KagakuZasshi81,49 (1960); Chew. Abstr. 54,12015b (1960). E. W. Garbisch, Jr., /. Org. Chem. 27, 4249 (1962). 88 K. Sakashita, J. Chem. Soc. Japan, Pure Chem. Sect. 74, 315 (1953); Chem. Abstr., 48, 1087e (1954). 89 H. Peters, R. A. Archer, and H. S. Mosher, /. Org. Chem. 32, 1382 (1967). 87