March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

Chapter 4. Stereochemistry and Conformation

4.N. Conformational Analysis

For acyclic molecules with single covalent bonds, there is rotation about those bonds. As a practical matter, such rotation leads to different arrangements of the atoms with respect to a given bond, but all arrangements constitute the same molecule. The different arrangements for a molecule due to such rotation are called rotamers. In principle, there is rotation about every single bond and a near infinite number of rotamers. If two different 3D spatial arrangements of the atoms in an acyclic molecule are interconvertible merely by free rotation about bonds, they are called conformations.²⁶⁹ If they are not interconvertible, they are called configurations.²⁷⁰ Configurations represent isomers that can be separated, as previously discussed in this chapter. Conformations represent conformers, which are rapidly interconvertible and thus nonseparable. The terms “conformational isomer” or more commonly “rotamer”²⁷¹ are used to identify one of many structures that result from rotation about single covalent bonds. Typically, the conformation is the average of the collection of lower energy rotatmers for an acyclic compound. A number of methods have been used to determine conformations.²⁷² These include X-ray and electron diffraction, IR, Raman, UV, NMR,²⁷³ and microwave spectra,²⁷⁴ PES,²⁷⁵ supersonic molecular jet spectroscopy,²⁷⁶ and ORD and CD measurements.²⁷⁷ Ring current NMR anisotropy has been applied to conformational analysis,²⁷⁸ as has chemical shift simulation.²⁷⁹ Some of these methods are useful only for solids. It must be kept in mind that the conformation of a molecule in the solid state is not necessarily the same as in solution.²⁸⁰ Conformations can be calculated by a method called molecular mechanics (Sec. 4.P). A method was reported that characterized six-membered ring conformations as a linear combination of ideal basic conformations.²⁸¹ The term absolute conformation has been introduced for molecules where one conformation is optically inactive but, by internal rotation about a C(sp³)–C(sp³) bond, optically active conformers are produced.²⁸²

Note that “free” rotation about single bonds is not possible in cyclic molecules, but rather pseudorotation that leads to different conformations. This discussion will therefore separate rotation in acyclic molecules from pseudorotation in cyclic molecules.

4.N.i. Conformation in Open-Chain Systems²⁸³

For any open-chain molecule with a single bond that connects two sp³ carbon atoms, an infinite number of rotatmers are possible, each of which has a certain energy associated with it, which leads to an infinite number of conformations. As a practical matter, the number of conformations is much less. If one ignores duplications due to symmetry, the number of conformations can be estimated as being > 3ⁿ, where n = the number of internal C–C bonds. For example, n-pentane, has 11, n-hexane 35, n-heptane 109, n-octane 347, n-nonane 1101, and n-decane 3263.²⁸⁴ For ethane, there are two important rotamers that are taken as the extremes, a conformation of highest (marked eclipsed) and one of lowest (marked staggered) potential energy, depicted in two ways as sawhorse diagrams or Newman projections. In Newman projection formulas, the observer looks at the C–C bond head on. The three lines emanating from the center of the circle represent the bonds coming from the front carbon, with respect to the observer.

The staggered conformation is the conformation of lowest potential energy for ethane. As rotation about the bond occurs, the energy gradually increases until the eclipsed conformation is reached, when the energy is at a maximum. Further rotation decreases the energy again. Figure 4.4 illustrates this finding. The angle of torsion, which is a dihedral angle, is the angle between the X–C–C and the C–C–Y planes, as shown in the diagram. For ethane, the difference in energy is ~2.9 kcal mol⁻¹ (12 kJ mol⁻¹).²⁸⁵ This difference is called the energy barrier or rotational barrier,²⁸⁶ since in free rotation about a single bond there must be enough rotational energy present to cross the barrier every time two hydrogen atoms are opposite each other. There was much speculation about the cause of the barriers and many explanations have been suggested.²⁸⁷ It has been concluded from MO calculations (see Sec. 4.P) that the barrier is caused by repulsion between overlapping filled molecular orbitals.²⁸⁸ The staggered conformation of ethane is lowest in energy because the orbitals of the C–H bonds in this conformation have the least amount of overlap with the C–H orbitals of the adjacent carbon.

Fig. 4.4 Conformational energy diagram for ethane.

At ordinary temperatures, enough rotational energy is present for the ethane molecule to rotate rapidly, but it spends most of its time at or near the energy minimum. Groups larger than hydrogen cause larger barriers, presumably due to steric interactions between the larger units.²⁸⁹ When the barriers are large enough, as in the case of suitably substituted biphenyls (Sec. 4.C, category 5) or the diadamantyl compound mentioned (see 107 and 108) rotation at room temperature is completely prevented, which is described as a q configuration not a conformations. Even for compounds with small barriers, cooling to low temperatures may remove enough rotational energy for what would otherwise be conformational isomers to become configurational isomers.

A 1,2-disubstituted ethane (YCH₂–CH₂Y or YCH₂–CH₂X,²⁹⁰ e.g., n-butane),²⁹¹ is somewhat more complicated. There are four extremes: a fully staggered conformation, called anti, trans, or antiperiplanar; another staggered conformation, called gauche or synclinal; and two types of eclipsed conformations, called synperiplanar and anticlinal.

An energy diagram for this system is given in Fig. 4.5. Although there is constant rotation about the central bond, it is possible to estimate what percentage of the molecules are in each conformation at a given time. For example, a consideration of dipole moment and polarizability measurements led to the conclusion that for 1,2-dichloroethane in CCl₄ solution at 25°C ~ 70% of the molecules are in the anti and ~ 30% in the gauche conformation.²⁹² The corresponding figures for 1,2-dibromoethane are 89% anti and 11% gauche.²⁹³ The eclipsed conformations are unpopulated and serve only as pathways from one staggered conformation to another. Solids normally consist of a single conformer.

Fig. 4.5 Conformational energy for YCH₂–CH₂Y or YCH₂–CH₂X. For n-butane, ΔE₁ = 4–6, ΔE₂ = 0.9, and ΔE₃ = 3.4 kcal mol⁻¹ (17–25, 3.8, 14 kJ mol⁻¹, respectively).

It may be observed that the gauche conformation of butane (see 106), or any other similar molecule, appears to be chiral. It is not. The lack of optical activity in such compounds arises from the fact that 106 is not a static molecule, but is in dynamic equilibrium with many other conformations, including its mirror image. In effect, they interconvert too rapidly for separation.

For butane and for most other molecules of the forms YCH₂–CH₂Y and YCH₂– CH₂X, the anti conformer is the most stable, but exceptions are known. One group of exceptions consists of molecules containing small electronegative atoms, especially fluorine and oxygen. Thus 2-fluoroethanol,²⁹⁴ 1,2-difluoroethane,²⁹⁵ and 2-fluoroethyl trichloroacetate (FCH₂CH₂OCOCCl₃)²⁹⁶ exist predominantly in the gauche form and compounds, such as, 2-chloroethanol and 2-bromoethanol,²⁹⁴ also prefer the gauche form. It has been proposed that the preference for the gauche conformation in these molecules is an example of a more general phenomenon, known as the gauche effect; that is, a tendency to adopt that structure that has the maximum number of gauche interactions between adjacent electron pairs or polar bonds.²⁹⁷ It was believed that the favorable gauche conformation of 2-fluoroethanol was the result of intramolecular hydrogen bonding, but this explanation does not do for molecules like 2-fluoroethyl trichloroacetate. It has in fact been ruled out for 2-fluoroethanol as well.²⁹⁸ The effect of β-substituents in Y–C–C–OX systems where Y = F or SiR₃ has been examined and there is a small bond shortening effect on C–OX that is greatest when OX is a good leaving group. Bond lengthening was also observed with the β-silyl substituent.²⁹⁹ Other exceptions are known, where small electronegative atoms are absent. For example 1,1,2,2-tetrachloroethane and 1,1,2,2-tetrabromoethane both prefer the gauche conformation,³⁰⁰ even though 1,1,2,2-tetrafluoroethane prefers the anti.³⁰¹ Also, both 2,3-dimethylpentane and 3,4-dimethylhexane prefer the gauche conformation,³⁰² and 2,3-dimethylbutane shows no preference for either.³⁰³ Furthermore, the solvent can exert a powerful effect. For example, the compound 2,3-dinitro-2,3-dimethylbutane exists entirely in the gauche conformation in the solid state, but in benzene, the gauche/anti ratio is 79:21; while in CCl₄ the anti form is actually favored (gauche/anti ratio 42:58).³⁰⁴ In many cases, there are differences in the conformation of these molecules between the gas and the liquid phase (as when X = Y = OMe) because of polar interactions with the solvent.³⁰⁵

In one case, two conformational isomers of a single aliphatic hydrocarbon, 3,4-di(1-adamantyl)-2,2,5,5-tetramethylhexane, have proven stable enough for isolation at room temperature.³⁰⁶ The two isomers 107 and 108 were separately crystallized, and the structures were proven by X-ray crystallography. The actual dihedral angles are distorted from the 60° angles shown in the drawings, due to steric hindrance between the large adamantyl and tert-butyl groups.

All the conformations so far discussed have involved rotation about sp³–sp³ bonds. Many studies have also been made of compounds with sp³–sp² bonds.³⁰⁷ For example, propanal (or any similar molecule) has four extreme conformations, two of which are called eclipsing and the other two bisecting. For propanal, the eclipsing conformations have lower energy than the other two, with 109 favored over 110 by ~1 kcal mol⁻¹ (4 kJ mol⁻¹).³⁰⁸ As already pointed out (Sec. 4.K.i), for a few of these compounds, rotation is slow enough to permit cis-trans isomerism, although for simple compounds rotation is rapid. The cis conformer of acetic acid was produced in solid Ar,³⁰⁹ and it was reported that acetaldehyde has a lower rotational barrier (~1 kcal mol⁻¹ or 4 kJ mol⁻¹) than ethane.³¹⁰ Calculations have examined the rotational barriers around the CO and CC bonds in formic acid, ethanedial, and glycolaldehyde molecules.³¹¹

Other carbonyl compounds exhibit rotation about sp³–sp³ bonds, including amides.³¹² In N-acetyl-N-methylaniline, the cis- conformation (111) is more stable than the trans- (112) by 3.5 kcal mol⁻¹ (14.6 kJ mol⁻¹).³¹³ This is due to destabilization of (S) due to steric hindrance between two methyl groups, and to electronic repulsion between the carbonyl lone-pair electrons and the phenyl π-electrons in the twisted phenyl orientation.³¹³

A similar conformational analysis has been done with formamide derivatives,³¹⁴ with secondary amides,³¹⁵ and for hydroxamide acids.³¹⁶ It is known that thioformamide has a larger rotational barrier than formamide, which can be explained by a traditional picture of amide “resonance” that is more appropriate for the thioformamide than formamide itself.³¹⁷ Torsional barriers in α-keto amides have been reported,³¹⁸ and the C–N bond of acetamides,³¹⁹thioamides,³²⁰ enamides³²¹ carbamates (R₂N–CO₂R′),³²² and enolate anions derived from amides³²³ have been examined. It is known that substituents influence rotational barriers.³²⁴

In Section 4.C, category 5, atropisomerism was possible when ortho substituents on biphenyl derivatives and certain other aromatic compounds prevented rotation about the bond. The presence of ortho-substituents can also influence the conformation of certain groups.³²⁵ In 113, R = alkyl and the carbonyl unit is planar, with the trans C=OF conformer is more stable when X = F. When X = CF₃, the cis and trans are planar and the trans predominates.³²⁶ When R = alkyl, there is one orthogonal conformation, but there are two interconverting nonplanar conformations when R = O-alkyl.³²⁶ In 1,2-diacylbenzenes, the carbonyl units tend to adopt a twisted conformation to minimize steric interactions.³²⁷

4.N.ii. Conformation in Six-Membered Rings³²⁸

For cyclic compounds, complete rotation (360°) about a single bond is impossible. However, repulsion between atoms and groups leads to motion about each bond called pseudorotation. Pseudorotation leads to a variety of different conformations, depending on the size of the ring. In many such conformations, the ring is said to be puckered. For cyclohexane, there are two extreme conformations in which all the angles are tetrahedral (the C–C–C angles in cyclohexane are actually 111.5°).³²⁹ These are called the boat and the chair conformations. The chair conformation is the low-energy structure that participates in a dynamic equilibrium (there are two chair conformations that are equivalent in energy for cyclohexane), and the boat form is a higher energy form³³⁰ in equilibrium with a somewhat more stable form

known as the twist conformation. The twist form is ~1.5 kcal mol⁻¹ (6.3 kJ mol⁻¹) more stable than the boat because it has less eclipsing interaction (see below).³³¹ The chair form is more stable than the twist form by ~5 kcal mol⁻¹(21 kJ mol⁻¹).³³² In the vast majority of compounds containing a cyclohexane ring, the molecules exist almost entirely as equilibrating chair forms.³³³ It is known that the boat or twist form exists transiently. In some cases, chair and twist–boat conformations have actually been observed (cis-1,4-di-tert-butylcyclohexane, e.g.).³³⁴

An inspection of the chair form shows that six of its bonds are directed differently from the other six. On each carbon, one bond is directed up or down and the other more or less in the “plane” of the ring. The up or down bonds are called axial and the others are equatorial. The axial bonds point alternately up and down. If a molecule were frozen into a chair form, there would be isomerism in monosubstituted cyclohexanes. For example, there would be an equatorial methylcyclohexane and an axial isomer. This result is incorrect, however, as it has never been possible to isolate isomers of this type at room temperature.³³⁵ In order for the two types of methylcyclohexane to be nonseparable, there must be rapid interconversion of one chair form to another (in which all axial bonds become equatorial and vice versa) and this is possible only if the boat or twist conformations are transient species. Conversion of one chair form to another requires an activation energy of ~10 kcal mol⁻¹ (42 kJ mol⁻¹)³³⁶ and is very rapid at room temperature.³³⁷ However, by working at low temperatures, Jensen and Bushweller³³⁸ were able to obtain the pure equatorial conformers of chlorocyclohexane and trideuteriomethoxycyclohexane as solids and in solution. Equatorial chlorocyclohexane has a half-life of 22 years in solution at −160°C.

In some molecules, the twist conformation is actually preferred.³³⁹ Of course, in certain bicyclic compounds, the six-membered ring is forced to maintain a boat or twist conformation, as in norbornane or twistane.

In monosubstituted cyclohexanes, the substituent normally prefers the equatorial position because there is an interaction between the substituent and the axial hydrogens in the axial 3 and 5 positions, but the extent of this preference depends greatly on the nature of the group.³⁴⁰ Alkyl groups have a greater preference for the equatorial position than polar groups. For alkyl groups, the preference increases with size, although size seems to be unimportant for polar groups. Both the large HgBr³⁴¹ and HgCl³⁴² groups and the small F group have been reported to have little or no conformational preference (the HgCl group actually shows a slight preference for the axial position). Table 4.3 gives approximate values of the free energy required for various groups to go from the equatorial position to the axial (these are called A values),³⁴³ although it must be kept in mind that they vary somewhat with physical state, temperature, and solvent.³⁴⁴ Values for other groups in kcal mol⁻¹ include D³⁴⁵ (0.008), NH₂³⁴⁶ (1.4), CH=CH₂³⁴⁷ (1.7), CH₃³⁴⁸ (1.74), C₆H₁₁³⁴⁹ (2.15), Si(CH₃),³⁵⁰ (2.4–2.6), OCH₃³⁵¹ (0.75), C₆H₅³⁵² (2.7), and t-(CH₃)₃C³⁵³ (4.9).

Table 4.3 Free-Energy Differences between Equatorial and Axial Substituents on a Cyclohexane Ring^a,b

[Reprinted with permission from Corey, E.J.; Feiner, N.F. J. Org. Chem. 1980, 45, 765. Copyright © 1980 American Chemical Society.]

a. See Ref. 343.

b. The A values or A^1,3-strain.

For alkyl groups in disubstituted compounds, the conformation is such that as many groups as possible adopt the equatorial position. This conformation will minimize the axial interactions (known as A^1,3-strain), and will be the lower energy conformation. The preference for one chair conformation over the other depends on the groups attached to the cyclohexane ring, and their relative positions on that ring. In a cis-1,2-disubstituted cyclohexane, one substituent must be axial and the other equatorial. In a trans-1,2, compound both may be equatorial or both axial. This finding is also true for 1,4-disubstituted cyclohexanes, but the reverse holds for 1,3-compounds: the trans isomer must have the age conformation and the cis isomer may be a or ee. For alkyl groups, the ee conformation predominates over the a, but for other groups this is not necessarily so. For example, both trans-1,4-dibromocyclohexane and the corresponding dichloro compound have the ee and a conformations about equally populated³⁵⁴ and most trans-1,2-dihalocyclohexanes exist predominantly in the a conformation.³⁵⁵ Note that in the latter case the two halogen atoms are anti in the a conformation, but gauche in the ee conformation.³⁵⁶

Since compounds with alkyl equatorial substituents are generally more stable, trans-1,2 compounds, which can adopt the ee conformation, are thermodynamically more stable than their cis-1,2 isomers, which must exist in the ageconformation. For the 1,2-dimethylcyclohexanes, the difference in stability is ~2 kcal mol⁻¹ (8 kJ mol⁻¹). Similarly, trans-1,4 and cis-1,3 compounds are more stable than their stereoisomers.

An interesting anomaly is all-trans-1,2,3,4,5,6-hexaisopropylcyclohexane, in which the six isopropyl groups prefer the axial position, although the six ethyl groups of the corresponding hexaethyl compound prefer the equatorial position.³⁵⁷ The alkyl groups of these compounds can of course only be all axial or all equatorial, and it is likely that the molecule prefers the all-axial conformation because of unavoidable strain in the other conformation.

Incidentally, it is now apparent, at least in one case, why the correct number of stereoisomers could be predicted by assuming planar rings, even though they are not planar (Sec. 4.K.ii). In the case of both a cis-1,2-X,X-disubstituted and a cis-1,2-X,Y-disubstituted cyclohexane, the molecule is nonsuperimposable on its mirror image; neither has a plane of symmetry. However, in the former case (114) conversion of one chair form to the other which of course happens rapidly, turns the molecule into its mirror image, while in the latter case (115) rapid interconversion does not give the mirror image, but merely the conformer in which the original axial and equatorial substituents exchange places. Thus the optical inactivity of 114 is not due to a plane of symmetry, but to a rapid interconversion of the molecule and its mirror image. A similar situation holds for cis-1,3 compounds. However, for cis-1,4 isomers (both X,X and X,Y) optical inactivity arises from a plane of symmetry in both conformations. All trans-1,2- and trans-1,3-disubstituted cyclohexanes are chiral (whether X,X or X,Y), while trans-1,4 compounds (both X,X and X,Y) are achiral, since all conformations have a plane of symmetry. It has been shown that the equilibrium is very dependent on both the solvent and the concentration of the disubstituted cyclohexane.³⁵⁸ A theoretical study of the 1,2-dihalides showed a preference for the diaxial form with X = Cl, but predicted that the energy difference between diaxial and diequatorial was small when X = F.³⁵⁹

The conformation of a group can be frozen into a desired position by putting a large alkyl group into the ring (most often tert-butyl), which introduces significant A^1,3-strain and leads to a preference for the chair with the groups in the equatorial position.³⁶⁰ It is known that silylated derivatives of trans-1,4- and trans-1,2-dihydroxycyclohexane, some monosilyloxycyclohexanes and some silylated sugars have unusually large populations of chair conformations with axial substituents.³⁶¹ Adjacent silyl groups in the 1,2-disubstituted series show a stabilizing interaction in all conformations, generally leading to unusually large axial populations.

The principles involved in the conformational analysis of six-membered rings containing one or two trigonal atoms. For example, cyclohexanone and cyclohexene, are similar.^362–364 The barrier to interconversion in cyclohexane has been calculated to be 8.4–12.1 kcal mol⁻¹(35.2–50.7 kJ mol⁻¹).³⁶⁵ Cyclohexanone derivatives also assume a chair–conformation. Substituents at C-2 can assume an axial or equatorial position depending on steric and electronic influences. The proportion of the conformation with an axial X group is shown in Table 4.4 for a variety of substituents (X) in 2-substituted cyclohexanones.³⁶⁶

Table 4.4 Proportion of Axial Conformation in 2-Substituted Cyclohexanones, in CDCl₃^a

Reprinted with permission from Basso, E.A.; Kaiser, C.; Rittner, R.; Lambert, J.B. J. Org. Chem. 1993, 58, 7865. Copyright © 1993 American Chemical Society.

X

% Axial Conformation

F

17 ± 3

Cl

45 ± 4

Br

71 ± 4

I

88 ± 5

MeO

28 ± 4

MeS

85 ± 7

MeSe

(92)

Me₂N

44 ± 3

Me

(26)

a. See Ref. 366.

4.N.iii. Conformation in Six-Membered Rings Containing Heteroatoms

In six-membered rings containing heteroatoms,³⁶⁷ the basic principles are the same; that is, there are chair, twist, and boat forms, axial, and equatorial groups. The conformational equilibrium for tetrahydropyridines, for example, has been studied.³⁶⁸ In certain compounds, a number of new factors enter the picture. Only two of these will be examined.³⁶⁹

1. In 5-alkyl-substituted 1,3-dioxanes, the 5-substituent has a much smaller preference for the equatorial position than in cyclohexane derivatives;³⁷⁰ the A^1,3-strain is much lower. This fact indicates that the lone pairs on the oxygens have a smaller steric requirement than the C–H bonds in the corresponding cyclohexane derivatives. There is some evidence of a homoanomeric interaction in these systems.³⁷¹ Similar behavior is found in the 1,3-dithianes,³⁷² and 2,3-disubstituted-1,4-dithianes have also been examined.³⁷³ With certain non-alkyl substituents (e.g., F, NO₂, SOMe,³⁷⁴ NMe₃⁺) the axial position is actually preferred.³⁷⁵

2. An alkyl group located on a carbon α to a heteroatom prefers the equatorial position, which is of course the normally expected behavior, but a polar group in such a location prefers the axial position. An example of this phenomenon, known as the anomeric effect,³⁷⁶ is the greater stability of α-glucosides over β-glucosides. A number of explanations have been offered for the anomeric

effect.³⁷⁷ The one³⁷⁸ that has received the most acceptance³⁷⁹ is that one of the lone pairs of the polar atom connected to the carbon (an oxygen atom in the case of 117) can be stabilized by overlapping with an antibonding orbital of the bond between the carbon and the other polar atom:

This can happen only if the two orbitals are in the positions shown. The situation can also be represented by this type of hyperconjugation (called “negative hyperconjugation,” see Sec. 2.M):

It is possible that simple repulsion between parallel dipoles in 116 also plays a part in the greater stability of 117. It has been shown that aqueous solvation effects reduce anomeric stabilization in many systems, particularly for tetrahydropyranosyls.³⁸⁰ In contrast to cyclic acetals, simple acyclic acetals rarely adopt the anomeric conformation, apparently because the eclipsed conformation better accommodates steric interactions of groups linked by relatively short carbon–oxygen bonds.³⁸¹ In all cis-2,5-di-tert-butyl-1,4-cyclohexanediol, hydrogen bonding stabilizes the otherwise high-energy form³⁸² and 1,3-dioxane (118) exists largely as the twist conformation shown.³⁸³The conformational preference of 1-methyl-1-silacyclohexane (121) has been studied.³⁸⁴ A strongly decreased activation barrier in silacyclohexane was observed, as compared to that in the parent ring, and is explained by the longer endocyclic Si–C bonds.

Second-row heteroatoms are known to show a substantial anomeric effect.³⁸⁵ There appears to be evidence for a reverse anomeric effect in 2-aminotetrahydropyrans,³⁸⁶ but it has been called into question whether a reverse anomeric effect exists at all.³⁸⁷ In 119, the lone-pair electrons assume an axial conformation and there is an anomeric effect.³⁸⁸ In 120, however, the lone-pair electron orbitals are oriented gauche to both the axial and equatorial α-CH bond and there is no anomeric effect.³⁸⁸

4.N.iv. Conformation in Other Rings³⁸⁹

Three-membered saturated rings are usually planar, but other small rings can have some flexibility. Cyclobutane³⁹⁰ is not planar, but exists as in 122, with an angle between the planes of ~35°.³⁹¹ The deviation from planarity is presumably caused by eclipsing in the planar form (see Sec. 4.Q.i). Oxetane is closer to

planarity because there is less eclipsing, with an angle between the planes of ~10°.³⁹² Cyclopentane might be expected to be planar, since the angles of a regular pentagon are 108°, but it is not so, also because of eclipsing effects.³⁹³There are two puckered conformations for cyclopentane, the envelope and the half-chair. There is little energy difference between these two forms and many five-membered ring systems have conformations somewhere in between them.³⁹⁴ Although in the envelope conformation one carbon is shown above the others,

ring motions cause each of the carbons in rapid succession to assume this position. The puckering rotates around the ring in what is called a pseudorotation³⁹⁵ (see Sec. 4.O.ii). In substituted cyclopentanes and five-membered rings in which at least one atom does not contain two substituents [e.g., tetrahydrofuran (THF), cyclopentanone, C₃- and C₇-monosubstituted and disubstituted hexahydroazepin-2-ones (caprolactams),³⁹⁶ tetrahydrothiophene S-oxide³⁹⁷], one conformer may be more stable than the others. The barrier to planarity in cyclopentane has been reported to be 5.2 kcal mol⁻¹ (22 kJ mol⁻¹).³⁹⁸ Contrary to previous reports, there is only weak stabilization (<2 kcal mol⁻¹; <8 kJ mol⁻¹) of three-, four-, and five-membered rings by gem-dialkoxycarbonyl substituents (e.g., COOR).³⁹⁹

Rings larger than six-membered are always puckered⁴⁰⁰ unless they contain a large number of sp² atoms (see the section on strain in medium rings, Sec. 4.Q.ii). The energy and conformations of the alkane series cycloheptane to cyclodecane has been reported.⁴⁰¹ The conformation shown for oxacyclooctane (123), for example, appears to be the most abundant one.⁴⁰² The conformations of other large-ring compounds have been studied, including cycloundecane,⁴⁰³ 11-membered ring lactones,⁴⁰⁴ 10- and 11-membered ring ketones,⁴⁰⁵ and 11- and 14-membered ring lactams.⁴⁰⁶ Dynamic NMR was used to determine the conformation large-ring cycloalkenes and lactones,⁴⁰⁷and C–H coupling constants have been used for conformational analysis.⁴⁰⁸ Strain estimates have been made for small-ring cyclic allenes and butatrienes.⁴⁰⁹ Note that axial and equatorial hydrogens are found only in the chair conformations of six-membered rings. In rings of other sizes, the hydrogens protrude at angles that generally do not lend themselves to classification in this way,⁴¹⁰ although in some cases the terms “pseudo-axial” and “pseudo-equatorial” have been used to classify hydrogens in rings of other sizes.⁴¹¹