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

Chapter 4. Stereochemistry and Conformation

4.P. Strain

Steric strain⁴¹⁸ exists in a molecule when bonds are forced to make abnormal angles, usually due to repulsion of large atoms or groups attached to those bonds, but not always. This repulsion results in a higher energy than would be the case in the absence of the angle distortions. It has been shown that there is a good correlation between the ¹³C–H coupling constants in NMR and the bond angles and bond force angles in strained organic molecules.⁴¹⁹ There are, in general, two kinds of structural features that result in sterically caused abnormal bond angles. One of these is found in small-ring compounds, where the angles must be less than those resulting from normal orbital overlap.⁴²⁰ Such strain is called small-angle strain or Baeyer strain. The other arises when nonbonded atoms are forced into close proximity by the geometry of the molecule. These are called nonbonded interactions. This latter type of strain is most often associated with the term steric strain.

Strained molecules possess strain energy. That is, their potential energies are higher than they would be if strain were absent.⁴²¹ The strain energy for a particular molecule can be estimated from heat of atomization or heat of combustion data. A strained molecule has a lower heat of atomization than it would have if it were strain-free (Fig. 4.6). As in the similar case of resonance energies (Sec. 2.B), strain energies cannot be known exactly, because the energy of a real molecule can be measured, but not the energy of a hypothetical unstrained model. It is also possible to calculate strain energies by molecular mechanics, not only for real molecules, but also for those that cannot be made.⁴²²

Fig. 4.6 Strain energy calculation.

4.P.i Strain in Small Rings

Three-membered rings have a great deal of angle strain (also called Baeyer strain), since 60° angles represent a large departure from the “normal” tetrahedral angles. Calculations have been interpreted to say that Baeyer strain in small ring systems originates from a decrease in nucleus–electron attraction compared to acyclic compounds,⁴²³ but this has been challenged in later work.⁴²⁴ However, in sharp contrast to other ethers, ethylene oxide is quite reactive, the ring being opened by many reagents (see Sec. 10.G.iii). Ring opening, of course, relieves the strain.⁴²⁵ Cyclopropane,⁴²⁶ which is even more strained⁴²⁷ than ethylene oxide, is also cleaved more easily than would be expected for an alkane.⁴²⁸ Thus, pyrolysis at 450–500°C converts it to propene, bromination gives 1,3-dibromopropane,⁴²⁹ and it can be hydrogenated to propane (though at high pressure).⁴³⁰ Other three-membered rings are similarly reactive.⁴³¹ Alkyl substituents influence the strain energy of small ring compounds,⁴³² and carbonyl substitution also influences the strain energy.⁴³³ gem-Dimethyl substitution, for example, “lowers the strain energy of cyclopropanes, cyclobutanes, epoxides, and dimethyldioxirane by 6–10 kcal mol⁻¹ (25–42 kJ mol⁻¹) relative to an unbranched acyclic reference molecule.”⁴³² The CH bond dissociation energy also tends to increase ring strain in small-ring alkenes.⁴³⁴ Computation of the ring strain energy of 1,1-dimethylcyclobutane, however, shows “no significant enthalpic component of the gem-dimethyl effect as measured by the ring strain energy.”⁴³⁵

There is much evidence, chiefly derived from NMR coupling constants, that the bonding in cyclopropanes is not the same as in compounds that lack small-angle strain.⁴³⁶ For a normal carbon atom, one s and three p orbitals are hybridized to give four approximately equivalent sp³ orbitals, each containing ~25% s character. But for a cyclopropane carbon atom, the four hybrid orbitals are far from equivalent. The two orbitals directed to the outside bonds have more s character than a normal sp³ orbital, while the two orbitals involved in ring bonding have less, because the more p-like they are the more they resemble ordinary p orbitals, whose preferred bond angle is 90° rather than 109.5°. Since the small-angle strain in cyclopropanes is the difference between the preferred angle and the real angle of 60°, this additional p character relieves some of the strain. The external orbitals have ~33% s character, so that they are ~sp² orbitals, while the internal orbitals have ~17% s character, so that they may be called ~sp⁵ orbitals.⁴³⁷ Each of the three carbon–carbon bonds of cyclopropane is therefore formed by overlap of two sp⁵ orbitals. Molecular-orbital calculations show that such bonds are not completely s in character. In normal C–C bonds, sp³ orbitals overlap in such a way that the straight line connecting the nuclei becomes an axis about which the electron density is symmetrical. But in cyclopropane, the electron density is directed away from the ring.⁴³⁸ Figure 4.7 shows the direction of orbital overlap.⁴³⁹ For cyclopropane, the angle (marked θ) is 21°. Cyclobutane exhibits the same phenomenon but to a lesser extent, θ being 7°.⁴³⁹ Molecular orbital calculations also show that the maximum electron densities of the C–C σ orbitals are bent away from the ring, with θ = 9.4° for cyclopropane and 3.4° for cyclobutane.⁴⁴⁰ The bonds in cyclopropane are called bent bonds (sometimes, banana bonds), and are intermediate in character between σ and π, so that cyclopropanes behave in some respects like double-bond compounds.⁴⁴¹ For one thing, there is much evidence, chiefly from UV spectra,⁴⁴² that a cyclopropane ring is conjugated with an adjacent double bond. The conjugation is greatest for the conformation shown in Fig. 4.8a and is least or absent for the conformation shown in 4.8b, since overlap of the double-bond π orbital with two of the p-like orbitals of the cyclopropane ring is greatest in conformation a. However, the conjugation between a cyclopropane ring and a double bond is less than that between two double bonds.⁴⁴³ For other examples of the similarities in behavior of a cyclopropane ring and a double bond (see Sec. 4.O.iv).

Fig. 4.7 Orbital overlap in cyclopropane. The arrows point toward the center of electron density.

Fig. 4.8 Conformations of α-cyclopropylalkenes. Conformation (a) leads to maximum conjugation and conformation (b) to minimum conjugation

Four-membered rings also exhibit angle strain, but much less than three-membered rings, and for that reason are less easily opened. Cyclobutane is more resistant than cyclopropane to bromination, and although it can be hydrogenated to butane, more strenuous conditions are required. Nevertheless, pyrolysis at 420°C gives two molecules of ethylene. As mentioned earlier (Sec. 4.O.iv), cyclobutane is not planar.

Many highly strained compounds containing small rings in fused systems have been prepared,⁴⁴⁴ showing that organic molecules can exhibit much more strain than simple cyclopropanes or cyclobutanes.⁴⁴⁵ Table 4.5 shows a few of these compounds.⁴⁴⁶ Perhaps the most interesting are cubane, prismane,⁴⁶⁰ and the substituted tetrahedrane, since preparation of these ring systems had been the object of much endeavor. Prismane is tetracyclo[2.2.0.0^2,6.0^3,5]hexane and many derivatives are known,⁴⁶¹ including bis(homohexaprismane) derivatives.⁴⁶² The bicyclobutane molecule is bent, with the angle θ between the planes equal to 126 ± 3°.⁴⁶³ The rehybridization effect, described above for cyclopropane, is even more extreme in this molecule. Calculations have shown that the central bond is essentially formed by overlap of two p orbitals with little or no

s character.⁴⁶⁴ Propellanes are compounds in which two carbons, directly connected, are also connected by three other bridges. [1.1.1]Propellane is in the table and it is the smallest possible propellane.⁴⁶⁵ It is in fact more stable than the larger [2.1.1]propellane and [2.2.1]propellane, which have been isolated only in solid matrixes at low temperature.⁴⁶⁶ The bicyclo[1.1.1]pentanes are related to the propellanes except that the central connecting bond is missing, and several derivatives are known.⁴⁶⁷ Even more complex systems are known.⁴⁶⁸

Table 4.5 Some Strained Small-Ring Compounds.

In certain small-ring systems, including small propellanes, the geometry of one or more carbon atoms is so constrained that all four of their valences are directed to the same side of a plane (inverted tetrahedron), as in 124.⁴⁶⁹ An example is 1,3-dehydroadamantane, 125, which is also a propellane.⁴⁷⁰ X-ray crystallography of the 5-cyano derivative of 125 shows that the four carbon valences at C-1 and C-3 are all directed “into” the molecule and none point outside.⁴⁷¹ Compound 125 is quite reactive; it is unstable in air, readily adds hydrogen, water, bromine, or acetic acid to the C-1–C-3 bond, and is easily polymerized. When two such atoms are connected by a bond (as in 125), the bond is very long (the C-1–C-3 bond length in the 5-cyano derivative of 125 is 1.64 Å), as the atoms try to compensate in this way for their enforced angles. The high reactivity of the C-1–C-3 bond of 125 is not only caused by strain, but also by the fact that reagents find it easy to approach these atoms since there are no bonds (e.g., C–H bonds on C-1 or C-3) to get in the way.

4.P.ii. Strain in Other Rings⁴⁷²

In rings larger than four-membered, there is no strain due to small bond angles, but there are three other kinds of strain. In the chair form of cyclohexane, which does not exhibit any of the three kinds of strain, all six carbon–carbon bonds have the two attached carbons in the gauche conformation. However, in five-membered rings and in rings containing from 7 to 13 carbons, any conformation in which all the ring bonds are gauche contains transannular interactions, that is, interactions between the substituents on C-1 and C-3 or C-1 and C-4, and so on. These interactions occur because the internal space is not large enough for all the quasi-axial hydrogen atoms to fit without coming into conflict. The molecule can adopt other conformations in which this transannular strain is reduced, but then some of the carbon–carbon bonds must adopt eclipsed or partially eclipsed conformations. The strain resulting from eclipsed conformations is called Pitzer strain. For saturated rings from 3- to 13-membered (except for the chair form of cyclohexane) there is no escape from at least one of these two types of strain. In practice, each ring adopts conformations that minimize both sorts of strain as much as possible. For cyclopentane, as seen in Section 4.O.iv, this means that the molecule is not planar. In rings larger than nine-membered, Pitzer strain seems to disappear, but transannular strain is still present.⁴⁷³ For 9- and 10-membered rings, some of the transannular and Pitzer strain may be relieved by the adoption of a third type of strain, large-angle strain. Thus, C–C–C angles of 115–120° have been found in X-ray diffraction of cyclononylamine hydrobromide and 1,6-diaminocyclodecane dihydrochloride.⁴⁷⁴

Strain can exert other influences on molecules. 1-Aza-2-adamantanone (126) is an extreme case of a twisted amide.⁴⁷⁵ The overlap of the lone-pair electrons on nitrogen with the π-system of the carbonyl is prevented.⁴⁷⁵ In chemical reactions, 126 reacts more or less like a ketone, giving a Wittig reaction (16-44) and it can form a ketal (16-7). A twisted biadamantylidene compound has been reported.⁴⁷⁶

The amount of strain in cycloalkanes is shown in Table 4.6,⁴⁷⁷ which lists heats of combustion per CH₂ group. As can be seen, cycloalkanes > 13-membered are as strain-free as cyclohexane.

Table 4.6 Heats of Combustion in the Gas Phase for Cycloalkanes, per CH₂ Group^a

[Reprinted with permission. Gol'dfarb, Ya.L.; Belen'kii, L.I. Russ. Chem. Rev. 1960, 29, 214, p. 218].

a. See Ref. 472.

Transannular interactions can exist across rings from 8- to 11-membered and even larger.⁴⁷⁸ Such interactions can be detected by dipole and spectral measurements. For example, that the carbonyl group in 127a is affected by the nitrogen (127b is probably another canonical form) has been demonstrated by photoelectron spectroscopy, which shows that the ionization potentials of the nitrogen n and C=O π orbitals in 127 differ from those of the two comparison molecules 128 and 129.⁴⁷⁹ It is significant that when 127 donates electrons to a proton, it goes to the oxygen rather than to the nitrogen. Many examples of transannular reactions are known, including the following:

Ref. 480

Ref. 481

where DMF = N, N-dimethylformamide (Solvent)

In summary, saturated rings may be divided into four groups, of which the first and third are more strained than the other two.⁴⁸²

1. Small rings (three- and four-membered). Small-angle strain predominates.

2. Common rings (five-, six-, and seven-membered). Largely unstrained. The strain that is present is mostly Pitzer strain.

3. Medium rings (8- to 11-membered). Considerable strain; Pitzer, transannular, and large-angle strain.

4. Large rings (12-membered and larger). Little or no strain.⁴⁸³

4.P.iii. Unsaturated Rings⁴⁸⁴

Double bonds can exist in rings of any size. As expected, the most highly strained are the three-membered rings (e.g., cyclopropene). Small-angle strain, which is so important in cyclopropane, is even greater in cyclopropene⁴⁸⁵because the ideal angle is more distorted. In cyclopropane, the bond angle is forced to be 60°, ~50° smaller than the tetrahedral angle; but in cyclopropene, the angle, also ~60°, is now ~60° smaller than the ideal angle of 120° for an alkene Thus, the angle of cyclopropene is ~10° more strained than in cyclopropane. However, this additional strain is offset by a decrease in strain arising from another factor. Cyclopropene, lacking two hydrogens, has none of the eclipsing strain present in cyclopropane. Cyclopropene has been prepared⁴⁸⁶ and is stable at liquid-nitrogen temperatures, although on warming even to −80°C it rapidly polymerizes. Many other cyclopropenes are stable at room temperature and above.⁴⁶⁴ The highly strained benzocyclopropene,⁴⁸⁷ in which the cyclopropene ring is fused to a benzene ring, has been prepared⁴⁸⁸ and is stable for weeks at room temperature, although it decomposes on distillation at atmospheric pressure.

As previously mentioned, double bonds in relatively small rings must be cis. A stable trans double bond⁴⁸⁹ first appears in an eight-membered ring (trans-cyclooctene, Sec. 4.C, category 6), although the transient existence of trans-cyclohexene and cycloheptene has been demonstrated.⁴⁹⁰ Above ~11 members, the trans isomer is more stable than the cis.²³² It has proved possible to prepare compounds in which a trans double bond is shared by two cycloalkene rings (e.g., 130). Such compounds have been called [m.n]betweenanenes, and several have been prepared with m and n values from 8 to 26.⁴⁹¹ The double bonds of the smaller betweenanenes, as might be expected from the fact that they are deeply buried within the bridges, are much less reactive than those of the corresponding cis–cis isomers.

The smallest unstrained cyclic triple bond is found in cyclononyne.⁴⁹² Cyclooctyne has been isolated,⁴⁹³ but its heat of hydrogenation shows that it is considerably strained. There have been a few compounds isolated with triple bonds in seven-membered rings. 3,3,7,7-Tetramethylcycloheptyne (131) is known and dimerizes within 1 h at room temperature,⁴⁹⁴ but the thia derivative (132), in which the C–S bonds are longer than the corresponding C–C bonds in 131, is indefinitely stable even at 140°C.⁴⁹⁵ Cycloheptyne itself has not been isolated, although its transient existence has been shown.⁴⁹⁶ Cyclohexyne⁴⁹⁷ and its 3,3,6,6-tetramethyl derivative⁴⁹⁸ have been trapped at 77 K, and in an Ar π matrix at 12 K, respectively. Its IR spectra have also been

obtained. Transient six- and even five-membered rings containing triple bonds have also been demonstrated.⁴⁹⁹ A derivative of cyclopentyne has been trapped in a matrix.⁵⁰⁰ Although cycloheptyne and cyclohexyne have not been isolated at room temperatures, Pt(0) complexes of these compounds have been prepared and are stable.⁵⁰¹ The smallest cyclic allene⁵⁰² so far isolated is 1-tert-butyl-1,2-cyclooctadiene (133).⁵⁰³ The parent 1,2-cyclooctadiene has not been isolated. It has been shown to exist as a transient species, but rapidly dimerizes.⁵⁰⁴ Incorporation of the tert-butyl group apparently prevents this. The transient existence of 1,2-cycloheptadiene has also been shown,⁵⁰⁵ and both 1,2-cyclooctadiene and 1,2-cycloheptadiene have been isolated in Pt complexes.⁵⁰⁶ 1,2-Cyclohexadiene has been trapped at low temperatures, and its structure has been proved by spectral studies.⁵⁰⁷ Cyclic allenes in general are less strained than their acetylenic isomers.⁵⁰⁸ The cyclic cumulene 1,2,3-cyclononatriene also has been synthesized and is reasonably stable in solution at room temperature in the absence of air.⁵⁰⁹

There are many examples of polycyclic molecules and bridged molecules that have one or more double bonds. There is flattening of the ring containing the C=C unit, and this can have a significant effect on the molecule. Norbornene (bicyclo[2.2.1]hept-2-ene, 134) is a simple example and it has been calculated that it contains a distorted π-face.⁵¹⁰ The double bond can appear away from the bridgehead carbon atoms, as in bicyclo[4.2.2]dec-3-ene (135), which flattens that part of the molecule. The C=C units in pentacyclo[8.2.1.1^2,5.1^4,7.1^8,11]hexadeca-1,7-diene (136) are held in a position where there is significant π–π interactions across the molecule.⁵¹¹

Double bonds at the bridgehead of bridged bicyclic compounds are impossible in small systems. This result is the basis of Bredt's rule,⁵¹² which states that elimination to give a double bond in a bridged bicyclic system (e.g., 137) always leads away from the bridgehead. This rule no longer applies when the rings are large enough. In

determining whether a bicyclic system is large enough to accommodate a bridgehead double bond, the most reliable criterion is the size of the ring in which the double bond is located.⁵¹³ Bicyclo[3.3.1]non-1-ene⁵¹⁴ (138) and bicyclo[4.2.1]non-1(8)ene⁵¹⁵ (139) are stable compounds. Both can be looked upon as derivatives of trans-cyclooctene, which is of course a known compound. Compound 138 has been shown to have a strain

energy of the same order of magnitude as that of trans-cyclooctene.⁵¹⁶ On the other hand, in bicyclo[3.2.2]non-1-ene (140), the largest ring that contains the double bond is a trans-cycloheptene, which is as yet unknown. Compound 140 has been prepared, but dimerized before it could be isolated.⁵¹⁷ Even smaller systems ([3.2.1] and [2.2.2]), but with imine double bonds (141–143), have been obtained in matrixes at low temperatures.⁵¹⁸ These compounds are destroyed on warming. Compounds 141 and 142 are the first reported example of (E–Z) isomerism at a strained bridgehead double bond.⁵¹⁹

4.P.iv. Strain Due to Unavoidable Crowding⁵²⁰

In some molecules, large groups are so close to each other that they cannot fit into the available space in such a way that normal bond angles are maintained. It has proved possible to prepare compounds with a high degree of this type of strain. For example, success has been achieved in synthesizing benzene rings containing ortho tert-butyl groups. Two examples that have been prepared, of several, are 1,2,3-tri-tert-butyl compound 144⁵²¹ and the 1,2,3,4-tetra-tert-butyl compound 145.⁵²² That these molecules are strained is demonstrated by UV and IR spectra, which show that the ring is not planar in 1,2,4-tri-tert-butylbenzene, and by a comparison of the heats of reaction of this compound and its 1,3,5 isomer, which show that the 1,2,4 compound possesses ~22 kcal mol⁻¹ (92 kJ mol⁻¹) more strain energy than its isomer⁵²³ (see also Reaction 18-27). Although SiMe₃ groups are larger

than CMe₃ groups, it has proven possible to prepare C₆(SiMe₃)₆. This compound has a chair-shaped ring in the solid state, and a mixture of chair and boat forms in solution.⁵²⁴ Even smaller groups can sterically interfere in ortho positions. In hexaisopropylbenzene, the six isopropyl groups are so crowded that they cannot rotate, but are lined up around the benzene ring, all pointed in the same direction.⁵²⁵ This compound is an example of a geared molecule.⁵²⁶ The isopropyl groups fit into each other in the same manner as interlocked

gears. Another example is 146, which is a stable enol.⁵²⁷ In this case, each ring can rotate about its C–aryl bond only by forcing the other to rotate as well. In the case of triptycene derivatives (e.g., 147), a complete 360° rotation of the aryl group around the O–aryl bond requires the aryl group to pass over three rotational barriers; one of which is the C–X bond and the other two the “top” C–H bonds of the other two rings. As expected, the C–X barrier is the highest, ranging from 10.3 kcal mol⁻¹ (43.1 kJ mol⁻¹) for X = F to 17.6 kcal mol⁻¹ (73.6 kJ mol⁻¹) for X = tert-butyl.⁵²⁸ In another instance, it has proved possible to prepare cis and trans isomers of 5-amino-2,4,6-triiodo-N,N,N′,N′-tetramethylisophthalamide because there is no room for the CONMe₂ groups to rotate, caught as they are between two bulky iodine atoms.⁵²⁹ The trans isomer is chiral and has been resolved, while the cis isomer is a meso form. Another example of cis-trans isomerism resulting from restricted rotation about single bonds⁵³⁰ is found in 1,8-di-o-tolylnapthalene⁵³¹ (see also, Sec. 4.K.i).

There are many other cases of intramolecular crowding that result in the distortion of bond angles. Hexahelicene (Sec. 4.C, category 6) and bent benzene rings (Sec. 2.G) have been mentioned previously. The compounds tri-tert-butylamine, and tetra-tert-butylmethane are as yet unknown. In the latter, there is no way for the strain to be relieved and it is questionable whether this compound can ever be made. In tri-tert-butylamine, the crowding can be eased somewhat if the three bulky groups assume a planar instead of the normal pyramidal configuration. In tri-tert-butylcarbinol, coplanarity of the three tert-butyl groups is prevented by the presence of the OH group, and yet this compound has been prepared.⁵³² Tri-tert-butylamine should have less steric strain than tri-tert-butylcarbinol and it should be possible to prepare it.⁵³³ The tetra-tert-butylphosphonium cation (t-Bu)₄P⁺ has been prepared.⁵³⁴ Although steric effects are nonadditive in crowded molecules, a quantitative measure has been proposed by DeTar, based on molecular mechanics calculations. This is called formal steric enthalpy (FSE), and values have been calculated for alkanes, alkenes, alcohols, ethers, and methyl esters⁵³⁵ For example, some FSE values for alkanes are butane 0.00; 2,2,3,3-tetramethylbutane 7.27; 2,2,4,4,5-pentamethylhexane 11.30; and tri-tert-butylmethane 38.53.

The two carbon atoms of a C=C double bond and the four groups attached to them are normally in a plane, but if the groups are large enough, significant deviation from planarity can result.⁵³⁶ The compound tetra-tert-butylethene (148) has not been prepared,⁵³⁷ but the tetraaldehyde (149), which should have about the same amount of strain, has been made. X-ray crystallography shows that 149 is twisted out of a planar shape by an angle of 28.6°.⁵³⁸ Also, the C=C double bond distance is 1.357 Å, significantly longer than normal C=C bond of 1.32 Å (Table 1.5). (Z)-1,2-Bis(tert-butyldimethylsilyl)-1,2-bis(trimethylsilyl)ethene (150) has an even greater twist, but could not be made to undergo conversion to the (E) isomer, probably because the groups are too large to slide past each other.⁵³⁹ A different kind of double-bond strain is found in tricyclo[4.2.2.2²,⁵]dodeca-1,5-diene (151),⁵⁴⁰ cubene (152),⁵⁴¹ and homocub-4(5)-ene (153).⁵⁴² In these molecules, the four groups on the

double bond are all forced to be on one side of the double-bond plane.⁵⁴³ In 151, the angle between the line C1–C2 (extended) and the plane defined by C2, C3, and C11 is 27°. An additional source of strain in this molecule is the fact that the two double bonds are pushed into close proximity by the four bridges. In an effort to alleviate this sort of strain, the bridge bond distances (C-3–C-4) are 1.595 Å, which is considerably longer than the 1.53 Å expected for a normal sp³–sp³ C–C bond (Table 1.5). Compounds 152 and 153 have not been isolated, but have been generated as intermediates that were trapped by reaction with other compounds.^541,542

Notes

1. See Eliel, E.L.; Wilen, S.H.; Mander, L.N. Stereochemistry of Organic Compounds, Wiley-Interscience, NY, 1994; Sokolov, V.I. Introduction to Theoretical Stereochemistry, Gordon and Breach, NY, 1991; Nógrádi, M. Sterochemistry, Pergamon, Elmsford, NY, 1981; Kagan, H. Organic Sterochemistry, Wiley, NY, 1979; Testa, B. Principles of Organic Stereochemistry, Marcel Dekker, NY, 1979; Izumi, Y.; Tai, A. Stereo-Differentiating Reactions, Academic Press, NY, Kodansha Ltd., Tokyo, 1977; Natta, G.; Farina, M. Stereochemistry, Harper and Row, NY, 1972; Eliel, E.L. Elements of Stereochemistry, Wiley, NY, 1969; Mislow, K. Introduction to Stereochemistry, W.A. Benjamin, NY, 1965. For a historical treatment, see Ramsay, O.B. Stereochemistry, Heyden & Son, Ltd., London, 1981.

2. See Pure Appl. Chem. 1976, 45, 13 and in Nomenclature of Organic Chemistry, Pergamon, Elmsford, NY, 1979 (the Blue Book).

3. See Cintas, P. Angew. Chem. Int. Ed. 2007, 46, 4016.

4. For a discussion of the conditions for optical activity in liquids and crystals, see O'Loane, J.K. Chem. Rev. 1980, 80, 41. For a discussion of chirality as applied to molecules, see Quack, M. Angew. Chem. Int. Ed. 1989, 28, 571.

5. Avalos, M.; Babiano, R.; Cintas, P.; Jiménez, J.L.; Palacios, J.C. Tetrahedron Asymm. 2000, 11, 2845.

6. Interactions among electrons, nucleons, and certain components of nucleons (e.g., bosons), called weak interactions, violate parity; that is, mirror image interactions do not have the same energy. It has been contended that interactions of this sort cause one of a pair of enantiomers to be (slightly) more stable than the other. See Tranter, G.E. J. Chem. Soc. Chem. Commun. 1986, 60, and references cited therein. See also, Barron, L.D. Chem. Soc. Rev.1986, 15, 189.

7. For a reported exception, see Hata, N. Chem. Lett. 1991, 155.

8. See Craig, D.P.; Mellor, D.P. Top. Curr. Chem. 1976, 63, 1.

9. Strictly speaking, the term racemic mixture applies only when the mixture of molecules is present as separate solid phases, but in this book this expression refers to any equimolar mixture of enantiomeric molecules, liquid, solid, gaseous, or in solution.

10. See Jacques, J.; Collet, A.; Wilen, S.H. Enantiomers, Racemates, and Resolutions, Wiley, NY, 1981.

11. See Wynberg, H.; Lorand, J.P. J. Org. Chem. 1981, 46, 2538 and references cited therein.

12. A good example is found in Kumata, Y.; Furukawa, J.; Fueno, T. Bull. Chem. Soc. Jpn. 1970, 43, 3920.

13. For a review of polarimetry see Lyle, G.G.; Lyle, R.E. in Morrison, J.D. Asymmetric Synthesis, Vol. 1, Academic Press, NY, 1983, pp. 13–27.

14. For examples, see Shriner, R.L.; Adams, R.; Marvel, C.S. in Gilman, H. Advanced Organic Chemistry, Vol. 1, 2nd ed. Wiley, NY, 1943, pp. 291–301.

15. Krow, G.; Hill, R.K. Chem. Commun. 1968, 430.

16. Wiberg, K. B.; Vaccaro, P. H.; Cheeseman, J.R. J. Am. Chem. Soc. 2003, 125, 1888.

17. See Barron L.D. Chem. Soc. Rev. 1986, 15, 189.

18. The definitions of plane, center, and alternating axis of symmetry are taken from Eliel, E.L. Elements of Stereochemistry, Wiley, NY, 1969, pp. 6,7. See also, Lemière, G.L.; Alderweireldt, F.C. J. Org. Chem. 1980, 45, 4175.

19. McCasland, G.E.; Proskow, S. J. Am. Chem. Soc. 1955, 77, 4688.

20. For discussions of the relationship between a chiral carbon and chirality, see Mislow, K.; Siegel, J. J. Am. Chem. Soc. 1984, 106, 3319; Brand, D.J.; Fisher, J. J. Chem. Educ. 1987, 64, 1035.

21. For a review of such molecules, see Nakazaki, M. Top. Stereochem. 1984, 15, 199.

22. See Barth, G.; Djerassi, C. Tetrahedron 1981, 24, 4123; Verbit, L. Prog. Phys. Org. Chem. 1970, 7, 51; Floss, H.G.; Tsai, M.; Woodard, R.W. Top. Stereochem. 1984, 15, 253.

23. Streitwieser, Jr., A.; Schaeffer, W.D. J. Am. Chem. Soc. 1956, 78, 5597.

24. For a discussion of optical activity in paraffins, see Brewster, J.H. Tetrahedron 1974, 30, 1807.

25. Ten Hoeve, W.; Wynberg, H. J. Org. Chem. 1980, 45, 2754.

26. For compounds with asymmetric atoms other than carbon, see Aylett, B.J. Prog. Stereochem. 1969, 4, 213; Belloli, R. J. Chem. Educ. 1969, 46, 640; Sokolov, V.I.; Reutov, O.A. Russ. Chem. Rev. 1965, 34, 1.

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118. Eliel, E.L.; Wilen, S.H.; Mander, L.N. Stereochemistry of Organic Compounds, Wiley, NY, 1994, pp. 1007–1071; Nakanishi, K.; Berova, N.; Woody, R.W. Circular Dichroism: Principles and Applications, VCH, NY, 1994; Purdie, N.; Brittain, H.G. Analytical Applications of Circular Dichroism, Elsevier, Amsterdam, The Netherlands, 1994.

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140. Leitereg, T.J.; Cram, D.J. J. Am. Chem. Soc. 1968, 90, 4019. For discussions, see Anh, N.T. Top. Curr. Chem, 1980, 88, 145, pp. 151–161; Eliel, E.L. in Morrison, J.D. Asymmetric Synthesis, Vol. 2, Academic Press, NY, 1983, pp. 125–155. See Smith, R.J.; Trzoss, M; Bühl, M.; Bienz, S. Eur. J. Org. Chem. 2002, 2770.

141. See Eliel, E.L. The Stereochemistry of Carbon Compounds, McGraw-Hill, NY, 1962, pp. 68–74; Bartlett, P.A. Tetrahedron 1980, 36, 2, pp. 22–28; Ashby, E.C.; Laemmle, J.T. Chem. Rev. 1975, 75, 521; Goller, E.J. J. Chem. Educ. 1974, 51, 182; Toromanoff, E. Top. Stereochem. 1967, 2, 157.

142. Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199; Chérest, M.; Felkin, H. Tetrahedron Lett. 1968, 2205; Anh, N.T.; Eisenstein, O. Nov. J. Chem. 1977, 1, 61. For experiments that show explanations for certain systems based on the Felkin–Anh model to be weak, see Yadav, V.K.; Gupta, A.; Balamurugan, R.; Sriramurthy, V.; Kumar, N.V. J. Org. Chem. 2006, 71, 4178.

143. Cornforth, J.W.; Cornforth, R.H.; Mathew, K.K. J. Chem. Soc. 1959, 112; Evans, D.A.; Siska, S.J.; Cee, V.J. Angew. Chem. Int. Ed. 2003, 42, 1761.

144. See Eliel, E.L. in Morrison, J.D. Asymmetric Synthesis, Vol. 2, Academic Press, NY, 1983, pp. 125–155; Eliel, E.L.; Koskimies, J.K.; Lohri, B. J. Am. Chem. Soc. 1978, 100, 1614; Still, W.C.; McDonald, J.H. Tetrahedron Lett. 1980, 21, 1031; Still, W.C.; Schneider, J.A. Tetrahedron Lett. 1980, 21, 1035.

145. Cee, V.J.; Cramer, C.J.; Evans, D.A. J. Am. Chem. Soc. 2006, 128, 2920.

146. Evans, S.V.; Garcia-Garibay, M.; Omkaram, N.; Scheffer, J.R.; Trotter, J.; Wireko, F. J. Am. Chem. Soc. 1986, 108, 5648; Garcia-Garibay, M.; Scheffer, J.R.; Trotter, J.; Wireko, F. Tetrahedron Lett. 1987, 28, 4789. For an earlier example, see Penzien, K.; Schmidt, G.M.J. Angew. Chem. Int. Ed. 1969, 8, 608.

147. Enders, D.; Eichenauer, H.; Baus, U.; Schubert, H.; Kremer, K.A.M. Tetrahedron 1984, 40, 1345.

148. See Brockmann, Jr., H.; Risch, N. Angew. Chem. Int. Ed. 1974, 13, 664; Potapov, V.M.; Gracheva, R.A.; Okulova, V.F. J. Org. Chem. USSR 1989, 25, 311.

149. Meyers, A.I.; Oppenlaender, T. J. Am. Chem. Soc. 1986, 108, 1989. For reviews of asymmetric reduction, see Morrison, J.D. Surv. Prog. Chem. 1966, 3, 147; Yamada, S.; Koga, K. Sel. Org. Transform., 1970, 1, 1. See also, Morrison, J.D. Asymmetric Synthesis, Vol. 2, Academic Press, NY, 1983.

150. See, in Morrison, J.D. Asymmetric Synthesis, Vol. 5, Academic Press, NY, 1985, the reviews by Halpern, J. pp. 41–69, Koenig, K.E. pp. 71–101, Harada, K. pp. 345–383; Ojima, I.; Clos, N.; Bastos, C. Tetrahedron 1989, 45, 6901, pp. 6902–6916; Jardine, F.H. in Hartley, F.R. The Chemistry of the Metal–Carbon Bond, Vol. 4, Wiley, NY, 1987, pp. 751–775; Nógrádi, M. Stereoselective Synthesis, VCH, NY, 1986, pp. 53–87; Knowles, W.S. Acc. Chem. Res. 1983, 16, 106; Brunner, H. Angew. Chem. Int. Ed. 1983, 22, 897; Sathyanarayana, B.K.; Stevens, E.S. J. Org. Chem. 1987, 52, 3170; Wroblewski, A.E.; Applequist, J.; Takaya, A.; Honzatko, R.; Kim, S.; Jacobson, R.A.; Reitsma, B.H.; Yeung, E.S.; Verkade, J.G. J. Am. Chem. Soc. 1988, 110, 4144.

151. Goering, H.L.; Kantner, S.S.; Tseng, C.C. J. Org. Chem. 1983, 48, 715.

152. For a review, see Masamune, S.; Choy, W.; Petersen, J.S.; Sita, L.R. Angew. Chem. Int. Ed. 1985, 24, 1.

153. For a monograph, see Morrison, J.D. Asymmetric Synthesis, Vol. 5, Academic Press, NY, 1985. For reviews, see Tomioka, K. Synthesis 1990, 541; Consiglio, G.; Waymouth, R.M. Chem. Rev. 1989, 89, 257; Brunner, H. in Hartley, F.R. The Chemistry of the Metal–Carbon Bond, Vol. 5, Wiley, NY, 1989, pp. 109–146; Noyori, R.; Kitamura, M. Mod. Synth. Methods 1989, 5, 115; Pfaltz, A. Mod. Synth. Methods 1989, 5, 199; Kagan, H.B. Bull. Soc. Chim. Fr. 1988, 846; Brunner, H. Synthesis 1988, 645; Wynberg, H. Top. Stereochem. 1986, 16, 87.

154. For reviews of these and related topics, see Zief, M.; Crane, L.J. Chromatographic Separations, Marcel Dekker, NY, 1988; Brunner, H. J. Organomet. Chem. 1986, 300, 39; Bosnich, B.; Fryzuk, M.D. Top. Stereochem. 1981, 12, 119.

155. See Eliel, E.L.; Wilen, S.H.; Mander, L.N. Stereochemistry of Organic Compounds, Wiley–Interscience, NY, 1994. Also see, Smith, M.B. Organic Synthesis, 3rd ed., Wavefunction Inc./Elsevier, Irvine, CA/London, England, 2010. For random examples, see Wu, Q.-F.; He, H.; Liu, W.-B.; You, S.-L. J. Am. Chem. Soc. 2010, 132, 11418; Berhal, F.; Wu, Z.; Genet, J.-P.; Ayad, T.; Ratovelomanana-Vidal, V. J. Org. Chem. 2011, 76, 6320; He, P.; Liu, X.; Shi, J.; Lin, L.; Feng, X. Org. Lett. 2011, 13, 936; Yang, H.-M.; Li, L.; Li, F.; Jiang, K.-Z.; Shang, J.-Y.; Lai, G.-Q.; Xu, L.-W. Org. Lett. 2011, 13, 6508.

156. Findeis, M.A.; Whitesides, G.M. J. Org. Chem. 1987, 52, 2838; Réty, J.; Robinson, J.A. Stereospecificity in Organic Chemistry and Enzymology, Verlag Chemie, Deerfield Beach, FL, 1982. For reviews, see Klibanov, A.M. Acc. Chem. Res. 1990, 23, 114; Jones, J.B. Tetrahedron 1986, 42, 3351; Jones, J.B. in Morrison, J.D. Asymmetric Synthesis, Vol. 5, Academic Press, NY, 1985, pp. 309–344.

157. Heathcock, C.H.; White, C.T. J. Am. Chem. Soc. 1979, 101, 7076.

158. For a review, See Buchardt, O. Angew. Chem. Int. Ed. 1974, 13, 179. For a discussion, see Barron L.D. J. Am. Chem. Soc. 1986, 108, 5539.

159. See Bernstein, W.J.; Calvin, M.; Buchardt, O. J. Am. Chem. Soc. 1973, 95, 527; Nicoud, J.F.; Kagan, J.F. Isr. J. Chem. 1977, 15, 78. See also, Zandomeneghi, M.; Cavazza, M.; Pietra, F. J. Am. Chem. Soc. 1984, 106, 7261.

160. Faigl, F.; Fogassy, E.; Nógrádi, M.; Pálovics, E.; Schindler, J. Tetrahedron Asymm. 2008, 19, 519. See Wilen, S.H.; Collet, A.; Jacques, J. Tetrahedron 1977, 33, 2725; Boyle, P.H. Q. Rev. Chem. Soc. 1971, 25, 323; Eliel, E.L.; Wilen, S.H.; Mander, L.N. Stereochemistry of Organic Compounds, Wiley–Interscience, NY, 1994, pp. 297–424; Jacques, J.; Collet, A.; Wilen, S.H. Enantiomers, Racemates, aand Resolutions, Wiley, NY, 1981.

161. Schiffers, I.; Rantanen, T.; Schmidt, F.; Bergmans, W.; Zani, L.; Bolm, C. J. Org. Chem. 2006, 71, 2320.

162. See Boyle, P.H. Q. Rev. Chem. Soc. 1971, 25, 323; Eliel, E.L.; Wilen, S.H.; Mander, L.N. Stereochemistry of Organic Compounds, Wiley–Interscience, NY, 1994, pp. 322–424.

163. For an extensive list of reagents that have been used for this purpose and of compounds resolved, see Wilen, S.H. Tables of Resolving Agents and Optical Resolutions, University of Notre Dame Press, Notre Dame, IN, 1972.

164. See Klyashchitskii, B.A.; Shvets, V.I. Russ. Chem. Rev. 1972, 41, 592.

165. Periasamy, M.; Kumar, N.S.; Sivakumar, S.; Rao, V.D.; Ramanathan, C.R.; Venkatraman, L. J. Org. Chem. 2001, 66, 3828.

166. Andersen, N.G.; Ramsden, P.D.; Che, D.; Parvez, M.; Keay, B.A. J. Org. Chem. 2001, 66, 7478.

167. Caccamese, S.; Bottino, A.; Cunsolo, F.; Parlato, S.; Neri, P. Tetrahedron Asymm. 2000, 11, 3103.

168. See Slingenfelter, D.S.; Helgeson, R.C.; Cram, D.J. J. Org. Chem. 1981, 46, 393; Davidson, R.B.; Bradshaw, J.S.; Jones, B.A.; Dalley, N.K.; Christensen, J.J.; Izatt, R.M.; Morin, F.G.; Grant, D.M. J. Org. Chem. 1984, 49, 353.

169. See Prelog, V.; Kovaevi, M.; Egli, M. Angew. Chem. Int. Ed. 1989, 28, 1147; Worsch, D.; Vögtle, F. Top. Curr. Chem. 1987, 140, 21; Toda, F. Top. Curr. Chem. 1987, 140, 43; Stoddart, J.F. Top. Stereochem. 1987, 17, 207; Arad-Yellin, R.; Green, B.S.; Knossow, M.; Tsoucaris, G. in Atwood, J.L.; Davies, J.E.D.; MacNicol, D.D. Inclusion Compounds, Vol. 3, Academic Press, NY, 1984, pp. 263–295.

170. See Schlenk, Jr., W. Liebigs Ann. Chem. 1973, 1145, 1156, 1179, 1195. See Arad-Yellin, R.; Green, B.S.; Knossow, M.; Tsoucaris, G. J. Am. Chem. Soc. 1983, 105, 4561.

171. Miyamoto, H.; Sakamoto, M.; Yoskioka, K.; Takaoka, R.; Toda, F. Tetrahedron Asymm. 2000, 11, 3045.

172. For a review, see Tsuji, J. Adv. Org. Chem. 1969, 6, 109, see p. 220.

173. Amos, R.D.; Handy, N.C.; Jones, P.G.; Kirby, A.J.; Parker, J.K.; Percy, J.M.; Su, M.D. J. Chem. Soc. Perkin Trans. 2 1992, 549.

174. See Westley, J.W.; Halpern, B.; Karger, B.L. Anal. Chem. 1968, 40, 2046; Kawa, H.; Yamaguchi, F.; Ishikawa, N. Chem. Lett. 1982, 745.

175. See Meyers, A.I.; Slade, J.; Smith, R.K.; Mihelich, E.D.; Hershenson, F.M.; Liang, C.D. J. Org. Chem. 1979, 44, 2247; Goldman, M.; Kustanovich, Z.; Weinstein, S.; Tishbee, A.; Gil-Av, E. J. Am. Chem. Soc. 1982, 104, 1093.

176. See Lough, W.J. Chiral Liquid Chromatography; Blackie and Sons: London, 1989; Krstulovi, A.M. Chiral Separations by HPLC, Ellis Horwood, Chichester, 1989; Zief, M.; Crane, L.J. Chromatographic Separations, Marcel Dekker, NY, 1988. For a review, see Karger, B.L. Anal. Chem. 1967, 39(8), 24A.

177. Weinstein, S. Tetrahedron Lett. 1984, 25, 985.

178. See Allenmark, S.G. Chromatographic Enantioseparation, Ellis Horwood, Chichester, 1988; König, W.A. The Practice of Enantiomer Separation by Capillary Gas Chromatography, Hüthig, Heidelberg, 1987. For reviews, see Schurig, V.; Nowotny, H. Angew. Chem. Int. Ed. 1990, 29, 939; Pirkle, W.H.; Pochapsky, T.C. Chem. Rev. 1989, 89, 347; Blaschke, G. Angew. Chem. Int. Ed. 1980, 19, 13; Rogozhin, S.V.; Davankov, V.A. Russ. Chem. Rev.1968, 37, 565. See also, many articles in the journal Chirality.

179. Ohara, M.; Ohta, K.; Kwan, T. Bull. Chem. Soc. Jpn. 1964, 37, 76. See also, Blaschke, G.; Donow, F. Chem. Ber. 1975, 108, 2792; Hess, H.; Burger, G.; Musso, H. Angew. Chem. Int. Ed. 1978, 17, 612.

180. See Schurig, V.; Nowotny, H.; Schmalzing, D. Angew. Chem. Int. Ed. 1989, 28, 736; Ôi, S.; Shijo, M.; Miyano, S. Chem. Lett. 1990, 59; Erlandsson, P.; Marle, I.; Hansson, L.; Isaksson, R.; Pettersson, C.; Pettersson, G. J. Am. Chem. Soc. 1990, 112, 4573.

181. See, for example, Pirkle, W.H.; Welch, C.J. J. Org. Chem. 1984, 49, 138.

182. Kanoh, S.; Hongoh, Y.; Katoh, S.; Motoi, M.; Suda, H. J. Chem. Soc. Chem. Commun. 1988, 405; Bradshaw, J.S.; Huszthy, P.; McDaniel, C.W.; Zhu, C.Y.; Dalley, N.K.; Izatt, R.M.; Lifson, S. J. Org. Chem. 1990, 55, 3129.

183. See, for example, Hamilton, J.A.; Chen, L. J. Am. Chem. Soc. 1988, 110, 5833.

184. See Miyata, M.; Shibakana, M.; Takemoto, K. J. Chem. Soc. Chem. Commun. 1988, 655.

185. For a review, see Sih, C.J.; Wu, S. Top. Stereochem. 1989, 19, 63.

186. See Nakamura, K.; Inoue, Y.; Ohno, A. Tetrahedron Lett. 1994, 35, 4375; Kazlauskas, R.J. J. Am. Chem. Soc. 1989, 111, 4953; Schwartz, A.; Madan, P.; Whitesell, J.K.; Lawrence, R.M. Org. Synth. 69, 1. For resolution with Subtilisin, see Savile, C.K.; Magloire, V.P.; Kazlauskas, R.J. J. Am. Chem. Soc. 2005, 127, 2104. For the chemoenzymatic kinetic resolution of primary amines, see Paetzold, J.; Bäckvall, J.E. J. Am. Chem. Soc. 2005, 127, 17620.

187. For an example, see Gais, H.-J.; Jungen, M.; Jadhav, V. J. Org. Chem. 2001, 66, 3384.

188. For an example of the resolution of acyloins, see Ödman, P.; Wessjohann, L.A.; Bornscheuer, U.T. J. Org. Chem. 2005, 70, 9551.

189. For reviews, see Collet, A.; Brienne, M.; Jacques, J. Chem. Rev. 1980, 80, 215; Bull. Soc. Chim. Fr. 1972, 127; 1977, 494. For a discussion, see Curtin, D.Y.; Paul, I.C. Chem. Rev. 1981, 81, 525 pp. 535–536.

190. Besides discovering this method of resolution, Pasteur also discovered the method of conversion to diastereomers and separation by fractional crystallization and the method of biochemical separation (and, by extension, kinetic resolution).

191. This is a case of optically active materials arising from inactive materials. However, it may be argued that an optically active investigator is required to use the tweezers. Perhaps a hypothetical human being constructed entirely of inactive molecules would be unable to tell the difference between left- and right-handed crystals.

192. For a review of the seeding method, see Secor, R.M. Chem. Rev. 1963, 63, 297.

193. Martin, R.H; Baes, M. Tetrahedron 1975, 31, 2135. See also, Wynberg, H.; Groen, M.B. J. Am. Chem. Soc. 1968, 90, 5339; McBride, J.M.; Carter, R.L. Angew. Chem. Int. Ed. 1991, 30, 293.

194. Kress, R.B.; Duesler, E.N.; Etter, M.C.; Paul, I.C.; Curtin, D.Y. J. Am. Chem. Soc. 1980, 102, 7709. See also, Gottarelli, G.; Spada, G.P. J. Org. Chem. 1991, 56, 2096. For a discussion and other examples, see Agranat, I.; Perlmutter-Hayman, B.; Tapuhi, Y. Nouv. J. Chem. 1978, 2, 183.

195. Addadi, L.; Weinstein, S.; Gati, E.; Weissbuch, I.; Lahav, M. J. Am. Chem. Soc. 1982, 104, 4610. See also, Weissbuch, I.; Addadi, L.; Berkovitch-Yellin, Z.; Gati, E.; Weinstein, S.; Lahav, M.; Leiserowitz, L. J. Am. Chem. Soc. 1983, 105, 6615.

196. Paquette, L.A.; Lau, C.J. J. Org. Chem. 1987, 52, 1634.

197. For reviews, see Pellissier, H. Tetrahedron 2008, 64, 1563; Ward, R.S. Tetrahedron Asymm. 1995, 6, 1475; Pellissier, H. Tetrahedron 2003, 59, 8291.

198. Lu, Y.; Zhao, X.; Chen, Z.-N. Tetrahedron Asymm. 1995, 6, 1093.

199. Brown, H.C.; Ayyangar, N.R.; Zweifel, G. J. Am. Chem. Soc. 1964, 86, 397.

200. Carlier, P.R.; Mungall, W.S.; Schröder, G.; Sharpless, K.B. J. Am. Chem. Soc. 1988, 110, 2978; Discordia, R.P.; Dittmer, D.C. J. Org. Chem. 1990, 55, 1414. For other examples, see Katamura, M.; Ohkuma, T.; Tokunaga, M.; Noyori, R. Tetrahedron Asymm. 1990, 1, 1; Hayashi, M.; Miwata, H.; Oguni, N. J. Chem. Soc. Perkin Trans. 2 1991, 1167.

201. Lohray, B.B.; Bhushan, V. Tetrahedron Lett. 1993, 34, 3911.

202. Kubota, H.; Kubo, A.; Nunami, K. Tetrahedron Lett. 1994, 35, 3107.

203. Tomooka, K.; Komine, N.; Fujiki, D.; Nakai, T.; Yanagitsuru, S. J. Am. Chem. Soc. 2005, 127, 12182.

204. Pirkle, W.H.; Reno, D.S. J. Am. Chem. Soc. 1987, 109, 7189. For another example, see Reider, P.J.; Davis, P.; Hughes, D.L.; Grabowski, E.J.J. J. Org. Chem. 1987, 52, 955.

205. Stecher, H.; Faber, K. Synthesis 1997, 1.

206. Allan, G. R.; Carnell, A. J. J. Org. Chem. 2001, 66, 6495.

207. For a review, see Raban, M.; Mislow, K. Top. Stereochem. 1967, 2, 199.

208. If a sample contains 80% (+) and 20% (−) isomer, the (−) isomer cancels an equal amount of (+) isomer and the mixture behaves as if 60% of it were (+) and the other 40% inactive. Therefore the rotation is 60% of 80° or 48°. This type of calculation, however, is not valid for cases in which [α] is dependent on concentration (Sec. 4.B); see Horeau, A. Tetrahedron Lett. 1969, 3121.

209. For a method to measure %ee using electrooptics, see Walba, D.M.; Eshdat, L.; Korblova, E.; Shao, R.; Clark, N.A. Angew. Chem. Int. Ed. 2007, 46, 1473.

210. Raban, M.; Mislow, K. Tetrahedron Lett. 1965, 4249, 1966, 3961; Jacobus, J.; Raban, M. J. Chem. Educ. 1969, 46, 351; Tokles, M.; Snyder, J.K. Tetrahedron Lett. 1988, 29, 6063. For a review, see Yamaguchi, S. in Morrison, J.D. Asymmetric Synthesis, Vol. 1, Academic Press, NY, 1983, pp. 125–152. See also, Raban, M.; Mislow, K. Top. Stereochem. 1967, 2, 199.

211. Though enantiomers give identical NMR spectra, the spectrum of a single enantiomer may be different from that of the racemic mixture, even in solution. See Williams, T.; Pitcher, R.G.; Bommer, P.; Gutzwiller, J.; Uskokovi, M. J. Am. Chem. Soc. 1969, 91, 1871.

212. Raban, M.; Mislow, K. Top. Stereochem. 1967, 2, 199, see pp. 216–218.

213. For a method that relies on diastereomer formation without a chiral reagent, see Feringa, B.L.; Strijtveen, B.; Kellogg, R.M. J. Org. Chem. 1986, 51, 5484. See also, Pasquier, M.L.; Marty, W. Angew. Chem. Int. Ed. 1985, 24, 315; Luchinat, C.; Roelens, S. J. Am. Chem. Soc. 1986, 108, 4873.

214. See Trost, B.M.; Belletire, J.L.; Godleski, S.; McDougal, P.G.; Balkovec, J.M.; Baldwin, J.J.; Christy, M.E.; Ponticello, G.S.; Varga, S.L.; Springer, J.P. J. Org. Chem. 1986, 51, 2370.

215. For reviews of NMR chiral solvating agents, see Weisman, G.R. in Morrison, J.D. Asymmetric Synthesis, Vol. 1, Academic Press, NY, 1983, pp. 153–171; Pirkle, W.H.; Hoover, D.J. Top. Stereochem. 1982, 13, 263. Sweeting, L.M.; Anet, F.A.L. Org. Magn. Reson. 1984, 22, 539. See also, Pirkle, W.H.; Tsipouras, A. Tetrahedron Lett. 1985, 26, 2989; Parker, D.; Taylor, R.J. Tetrahedron 1987, 43, 5451.

216. Sweeting, L.M.; Crans, D.C.; Whitesides, G.M. J. Org. Chem. 1987, 52, 2273; Morrill, T.C. Lanthanide Shift Reagents in Stereochemical Analysis, VCH, NY, 1986; Fraser, R.R. in Morrison, J.D. Asymmetric Synthesis, Vol. 1, Academic Press, NY, 1983, pp. 173–196; Sullivan, G.R. Top. Stereochem. 1978, 10, 287.

217. See Westley, J.W.; Halpern, B. J. Org. Chem. 1968, 33, 3978.

218. For a review, see Pirkle, W.H.; Finn, J. in Morrison, J.D. Asymmetric Synthesis, Vol. 1, Academic Press, NY, 1983, pp. 87–124.

219. For reviews, see in Morrison, J.D. Asymmetric Synthesis, Vol. 1, Academic Press, NY, 1983, the articles by Schurig, V. pp. 59–86 and Pirkle, W.H.; Finn, J. pp. 87–124.

220. See Hill, H.W.; Zens, A.P.; Jacobus, J. J. Am. Chem. Soc. 1979, 101, 7090; Matsumoto, M.; Yajima, H.; Endo, R. Bull. Chem. Soc. Jpn. 1987, 60, 4139.

221. Berson, J.A.; Ben-Efraim, D.A. J. Am. Chem. Soc. 1959, 81, 4083; Andersen, K.K.; Gash, D.M.; Robertson, J.D. in Morrison, J.D. Asymmetric Synthesis, Vol. 1, Academic Press, NY, 1983, pp. 45–57.

222. Horeau, A.; Guetté, J.; Weidmann, R. Bull. Soc. Chim. Fr. 1966, 3513. For a review, see Schoofs, A.R.; Guetté, J. in Morrison, J.D. Asymmetric Synthesis, Vol. 1, Academic Press, NY, 1983, pp. 29–44.

223. Hofer, E.; Keuper, R. Tetrahedron Lett. 1984, 25, 5631.

224. Schippers, P.H.; Dekkers, H.P.J.M. Tetrahedron 1982, 38, 2089.

225. cis-trans isomerism was formerly called geometrical isomerism.

226. For a complete description of the system, see Pure Appl. Chem. 1976, 45, 13; Nomenclature of Organic Chemistry, Pergamon, Elmsford, NY, 1979 (the Blue Book).

227. See in Patai, S. The Chemistry of the Carbon–Nitrogen Double Bond, Wiley, NY, 1970, the articles by McCarty, C.G. pp. 363–464 (pp. 364–408), and Wettermark, G. pp. 565–596 (pp. 574–582).

228. Wang, Y.-N.; Bohle, D.S.; Bonifant, C.L.; Chmurny, G.N.; Collins, J.R.; Davies, K.M.; Deschamps, J.; Flippen-Anderson, J.L.; Keefer, L.K.; Klose, J.R.; Saavedra, J.E.; Waterhouse, D.J.; Ivanic, J. J. Am. Chem. Soc. 2005, 127, 5388.

229. King, J.F.; Durst, T. Can. J. Chem. 1966, 44, 819.

230. A mechanism has been reported for the acid-catalyzed Z/E isomerization of imines. See Johnson, J.E.; Morales, N.M.; Gorczyca, A.M.; Dolliver, D.D.; McAllister, M.A. J. Org. Chem. 2001, 66, 7979.

231. This rule does not apply to allenes, which do not show cis--trans isomerism (see Sec. 4.C, category 5).

232. Cope, A.C.; Moore, P.T.; Moore, W.R. J. Am. Chem. Soc. 1959, 81, 3153.

233. Öki, M. Applications of Dynamic NMR Spectroscopy to Organic Chemistry, VCH, NY, 1985, pp. 41–71.

234. Mannschreck, A. Angew. Chem. Int. Ed. 1965, 4, 985. See also, Völter, H.; Helmchen, G. Tetrahedron Lett. 1978, 1251; Walter, W.; Hühnerfuss, H. Tetrahedron Lett. 1981, 22, 2147.

235. This is another example of atropisomerism (Sec. 4.C, category 5).

236. For reviews, see Sandström, J. Top. Stereochem. 1983, 14, 83; Öki, M. Applications of Dynamic NMR Spectroscopy to Organic Chemistry, VCH, NY, 1985, pp. 111–125.

237. Sandström, J.; Wennerbeck, I. Acta Chem. Scand. Ser. B, 1978, 32, 421.

238. Yamamoto, T.; Tomoda, S. Chem. Lett. 1997, 1069.

239. See Leonard, J.E.; Hammond, G.S.; Simmons, H.E. J. Am. Chem. Soc. 1975, 97, 5052.

240. Sorensen, T.S.; Sun, F. J. Chem. Soc. Perkin Trans. 2 1998, 1053.

241. Meinwald, J.; Tufariello, J.J.; Hurst, J.J. J. Org. Chem. 1964, 29, 2914.

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