Inversion of Pyramidal Centers
The heteroatoms of silanes, quaternary ammonium and phosphonium salts, and amine-N- oxides and phosphine oxides are tetrahedral; therefore, they are structurally analogous to the carbon-based chiral centers of the type that we have been discussing in this chapter. As such, these compounds should be resolvable into configurationally stable enantiomeric forms, and they are.69 One particularly simple method for resolving quaternary ammonium salts is by means of their (S)-BINOL complexes (Example 2.35) if these can be crystallized.70 This involves simply partitioning the precipitated complex between dichloromethane and water separates the quaternary salt from the resolving agent.
N
CO2But
Me HO
Ar X
OH OH
CH2Cl2 N
CO2But
Me HO
Ar X
OH OH (2.35)
67. (a) Pirkle, W.H.; House, D.W. J. Org. Chem. 1979, 44, 1957. (b) Pirkle, W.H.; House, D.W. Finn, J.M. J.
Chromatogr. 1980, 192, 143. (c) Pirkle, W.H.; Finn, J.M. J. Org. Chem. 1981, 46, 2935. (d) Pirkle, W.H.; Schreiner, J.L. J. Org. Chem. 1981, 46, 4988.
68. (a) Dale, J.A.; Dull, D.L.; Mosher, H.S. J. Org. Chem. 1969, 34, 2543. (b) Dale, J.A.; Mosher, H.S. J. Am.
Chem. Soc. 1973, 95, 512.
69. (a) Barbachyn, M.R.; Johnson, C.R. In Morrison, J.D.; Scott, J.W., Eds. Asymmetric Synthesis (Academic:
New York, 1984), Ch. 2, p. 227. (b) Valentine, D., Jr.; In Morrison, J.D.; Scott, J.W., Eds. Asymmetric Synthesis (Academic: New York, 1984), Ch. 3, p. 263. (c) Davis, F.A.; Jenkins, R.H., Jr. In Morrison, J.D.; Scott, J.W., Eds.
Asymmetric Synthesis (Academic: New York, 1984), Ch. 4, p. 313. (d) Maryanoff, C.A.; Maryanoff, B.E.; In Morrison, J.D.; Scott, J.W., Eds. Asymmetric Synthesis (Academic: New York, 1984), Ch. 2, p. 355.
70. Tayama, E.; Otoyama, S.; Tanaka, H. Tetrahedron: Asymmetry 2009, 20, 2600.
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Like the heteroatoms in chiral ammonium and phosphonium salts, the heteroatoms in amines, phosphines, sulfoxides, and sulfonium salts may also be chiral. In these cases, the fourth group about the chiral center is the lone pair on the heteroatom. Potentially, therefore, such compounds ought to be resolvable into the two enantiomers. There is a mechanism for inversion of configuration available to these compounds that is not avail- able to chiral centers lacking a lone pair. In the absence of lone pairs, the inversion of configuration of the chiral center requires the cleavage and reformation of a covalent bond. In the case of a heteroatom carrying a lone pair, however, the inversion may occur by means of a rehybridization of the heteroatom from sp3 (chiral) to sp2 (not chiral) and back again (Example 2.36). This is the same hybridization change that occurs at carbon during the SN2 reaction, but the process generally has a lower activation energy than the SN2 process.
The barrier to inversion of open-chain amines is small71 (as measured by dynamic NMR,72 it is typically 5–7 kcal mol–1). This makes this inversion an especially facile pro- cess, because a barrier to inversion of at least 23 kcal mol–1 is needed for enantiomers to be configurationally stable at room temperature.73 Acyclic amines rapidly racemize at room temperature. The barrier to inversion of amine nitrogen atoms is raised substan- tially by (1) incorporating the nitrogen atom into a small ring (e.g., an aziridine, where attaining the sp2 hybridization results in increasing the already large angle strain in the three-membered ring) and by (2) attaching an electronegative substituent to the nitro- gen. Thus, although simple N-alkylaziridines themselves are not configurationally stable at room temperature, N-chloro-2,2-diphenylaziridine (Example 2.37) has been prepared in optically active form.74 Its barrier to inversion of 24.4 kcal mol–1 is modest, so it still racemizes completely in 4 days at 0°C. The effects of small ring size and electron-withdrawing substituents are even more pronounced in rings such as the oxaziridine ring system, which can fairly readily give stereochemically stable enantio- meric compounds.
N Ph Ph
Cl
∆G‡ = 24.4 kcal mol–1 N Ph Ph Cl
(2.37)
Unlike tricoordinate nitrogen, the barrier to inversion of tricoordinate sulfur and phosphorus is large enough that chiral sulfoxides and phosphines are configurationally stable at room temperature and may be resolved and used. The barriers to inversion in simple diaryl sulfoxides and aryl methyl sulfoxides are typically in the range of 35 to 42 kcal mol–1, which means that the racemization of these compounds typically has a half- life of 6 hours at 200°C.75 The activation parameters of this inversion are consistent with its being the “umbrella” inversion at sulfur, rather than some other mechanism.
The corresponding barrier to inversion of phosphines is dependent on the substituents on phosphorus. For simple trialkylphosphines not bearing electronegative substituents or having the phosphorus in a small ring, the barrier to inversion is typically in the
71. Reviews: (a) Rauk, A.; Allen, L.C.; Mislow, K. Angew. Chem. Int. Ed. Engl. 1970, 9, 400. (b) Lambert, J.B.
Top. Stereochem. 1971, 6, 19. (c) Jennings, W.B.; Boyd, D.R. In lambert, J.B.; Takechi, Y., Eds. Cyclic Organoni- trogen Stereodynamics (VCH: Cambridge, 1992), 105.
72. (a) Stevenson, P.E.; Burkey, D.L. J. Am. Chem. Soc. 1974, 96, 3061. (b) Bushweller, C.H.; Anderson, W.G.;
Stevenson, P.E.; Burkey, D.L.; O’Neil, J.W. J. Am. Chem. Soc. 1974, 96, 3892. (c) Bushweller, C.H.; Lourandos, M.Z.; Brunelle, J.A. J. Am. Chem. Soc. 1974, 96, 1591.
73. Kessler, H. Angew. Chem. Int. Ed. Engl. 1970, 9, 219.
74. Annunziata, R.; Fornasier, R.; Montanari, F. J. Chem. Soc., Chem. Commun. 1972, 1133.
75. Rayner, D.R.; Gordon, A.J.; Mislow, K. J. Am. Chem. Soc. 1968, 90, 4854.
R1 X R3 R2
R1 X R3 R2 X R1
R3 R2
sp3 chiral
sp2 not chiral
sp3 chiral
(2.36)
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range of 29 to 36 kcal mol–1.76 The incorporation of an electronegative substituent on phosphorus raises the barriers to inversion significantly (as happens with the corre- sponding amines).77
O S O
MeO
MgBr
O S O Me Me
MeO
(2.38)
N S O (2.39)
Chiral sulfoxides are readily available by the reaction between optically active men- thyl p-toluenesulfinate with alkyllithium nucleophiles; the reaction occurs with inver- sion at sulfur. Indeed, chiral sulfoxides have been used as chiral directing groups in a variety of reactions, including conjugate addition (e.g., Example 2.38)78 and reduction.79 In both these reactions, chelation by a metal ion involving the sulfoxide oxygen restricts the conformation of the reactant and thus facilitates chirality transfer from sulfur to carbon. Nitrogen bound to sulfur makes these sulfur derivatives especially configura- tionally stable. For this reason, chiral sulfinylamines such as the tert-butylsulfinylimine (Example 2.39), which carries a chiral sulfur atom, have become widely used chiral auxiliaries in asymmetric synthesis.
Chapter Summary
This chapter has considered organic stereochemistry—the shape of molecules in three dimensions. The discussion has ranged from enantiomers (molecules that are non- superimposable mirror images) to diastereoisomers (molecules that are stereoisomers but not enantiomers), including considerations of geometric isomers and meso com- pounds. The symmetry requirements compatible with chirality (axes of symmetry) and those incompatible with chirality (mirror plane, inversion center, improper axis of ro- tation) have been discussed. The protocenter model for the basis of stereoisomerism has been introduced. The difference between configuration and conformation has been discussed, and the Cahn-Ingold-Prelog method for assigning configurations to chiral molecules and to geometric isomers has been introduced. The conformations of open- chain and cyclic molecules have been discussed. The measurement of optical purity and the determination of enantiomeric excess (e.e.) or enantiomer ratio (e.r.) have been discussed in the light of methods to achieve asymmetric synthesis. The three concep- tually different methods for obtaining asymmetric induction in a reaction (chiral auxiliaries, chiral reagents, and chiral catalysts) have been introduced. The Cram and Felkin-Anh models for predicting the stereochemistry of additions to chiral aldehydes
76. Baechler, R.D.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 3090.
77. Baechler, R.D.; Andose, J.D.; Stackhouse, J.; Mislow, K. J. Am. Chem. Soc. 1972, 94, 8060.
78. Posner, G.H. Acc. Chem. Res. 1987, 20, 72.
79. Bode, M.L.; Gates, P.J.; Gebretnsae, S.Y.; Vleggaar, R. Tetrahedron 2010, 66, 2026.
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and ketones have been introduced. Chirality at atoms other than carbon has been briefly discussed, and the configurational stability of chiral compounds carrying a lone pair on the chiral atom has been briefly addressed. The concepts of topism and prochi- rality have been discussed.
Key Terms
absolute configuration anomers
anti, gauche
asymm etric induction atropisomers
axial, equatorial axis of chirality boat, chair
Cahn-Ingold-Prelog systems
center of chirality center of inversion center of pseudochirality
chiral auxiliary chirality
circular dichroism conformation Cram's rule diastereoisomers eclipsed, staggered conformational preference enantiomeric excess enantiomers epimers
Felkin-Anh rule geometric isomers
improper axis of rotation meso isomers
mirror plane of symmetry Newman projection optical activity
optical rotatory dispersion plane of chirality
prochiral center proper axis of rotation protocenters of
stereochemistry racemate
topism
Additional Problems
2-22 Draw the Newman projection of the most stable conformation about the indi- cated bond of each of the following compounds.
(a) meso-3,4-dimethylhexane (the 3–4 bond)
(b) (3R,4R)-3-chloro-4-methylheptane (the 3–4 bond) (c) S-1,2-dicyclopentylpropane (the 1–2 bond) (d) meso-2,3-dicyclohexylbutane (the 2-3 bond)
(e) (1S,2S)-1,2-dichlorocyclohexane (the 1-2 bond) (f) meso-1,2-divinylcyclopropane (the 1–2 bond)
2-23 Each of the following reactions gives a product in which at least one new chiral center has been formed. The stereochemistry of the final product has not been given explicitly in any of these reactions, but it can be deduced from the reactants and the reagents used. Draw all the products in each of the reactions (including pairs of en- antiomers, if appropriate). Are the products formed in equal amounts? Draw the lowest energy and highest energy conformations about the bond to the new chiral center in each product (use the Newman projection for acyclic compounds).
(d) HBr/ROOR Br
(a) CHOH EtMgBr
OH
(b) H2/PtO2
H
(c) Me2CuLi
O O
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(e)
O
CN
NaBH4/EtOH
OH
CN
(f) CHO
Me3SiCN/Zn(CN)2
NC
OSiMe3
2-24 What is the major product of each of the following reactions?
(c) O CHO
CH3MgBr/Et2O
(d) CHO CH3MgBr/Et2O
OCH3
(e) C6H5C≡CLi (f) CHO
O CHO
C6H5C≡CLi
(a) CHO
CH3MgBr/Et2O
(b) CHO CH3MgBr/Et2O
(g)
CHO
N O
O O BBu2
+ 1) THF
2) H2O
(h) O
CHO
N O
O O Li
+ 1) THF
2) H2O
(i) O
CHO
N O
O O BBu2
+ 1) THF
2) H2O
(j)
CHO
N O
O O BBu2
+ 1) THF
2) H2O
2-25 Using dynamic NMR spectroscopy to study the inversion of aziridines, it has been shown that the inversion of the aziridine nitrogen in the upper compound at left (a 1,4-benzoquinone) is more than 50 times as fast as the inversion of its re- duction product (a 1,4-hydroquinone derivative, shown as the lower example).
Provide a rationalization of these observations. Based on your answer, how could you slow down the inversion of the quinone?
N Ph
H H Ph
O
N Ph
H H
Ph O
O
O
N Ph
H H Ph
N Ph
H H
Ph HO
OH fast
slow
HO OH
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2-26 In carbon tetrachloride solution, cis-cyclohexane-1,3-diol exists mainly in the conformer with two axial OH groups, but in methanol solution, the major con- former has both OH groups equatorial. Why?
2-27 Calculate the populations of the two chair conformers of each of the following cyclohexane derivatives using the Corey-Feiner parameters.
(a) HO C
N
(b)
OH
(c) (d)
2-28 The diketone in the figure is a meso compound, with a plane of symmetry through the molecule, and therefore it cannot be resolved into two enantio- mers. Reduction of the diketone with a metal hydride reducing agent leads to the formation of two diastereoisomeric diol products. The diol in the figure has a mirror plane of symmetry like the starting diketone, and is therefore a meso compound incapable of optical resolution. The diastereoisomeric diol shown does not have a mirror plane of symmetry (nor, in fact, does it have a simple axis of rotation). Can it be resolved into enantiomers? Give your reasons.
O O
H H
H H
OH HO
H H
H H
OH HO
H H
H H
+
2-29 The following synthesis of acetate anion with a chiral methyl group was com- pleted by the research group of Sir John Cornforth in 1969. Analyze the stereo- chemistry of each step of the sequence. Then deduce both the regiochemistry and the stereochemistry of each reaction used in the sequence.
Br H Ph
H 1) BuLi/THF/-78°C 2) T2O
T H Ph
H PhCO3H/CHCl3
T H Ph
H O
T H Ph
H O
LiAlD4/Et2O
T H Ph
H
HO D
T H Ph
H
HO D
T H Ph
H
HO D
T H Ph
H
HO D
1) H2CrO4 2) CF3CO3H 3) KOH/H2O 1) H2CrO4 2) CF3CO3H 3) KOH/H2O
T H O O
D
T H O O
D O
O
O 1)
2) brucine; crystallize 3) KOH/H2O
2-30 The barrier to inversion at sulfur in benzylic sulfoxides is much less than for sim- ilar simple dialkyl or diaryl sulfoxides. In addition, sulfoxides such as the one at right, which is chiral at both sulfur and carbon, racemize at both carbon at sulfur. Suggest a mechanism for the racemization that is consistent with these observations.
2-31 Trửger's base is a fascinating molecule that has a rigid skeleton containing two chiral nitrogen atoms. In dilute acid, Trửger's base racemizes. Two mechanisms, shown below as mechanisms A and B, have been proposed for this reaction.
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Mechanism A
N N H N N H H2C N NH N N H N N
Mechanism B
N N H N N H N N N N H N N
H
Where bonds are broken, the racemization involves inversion of configuration as the bonds are reformed. Consider the racemization of the Trửger's base derivative at left and suggest the outcome of its racemization by both mechanisms. (As part of your answer, it may be useful to analyze the topism of the various groups on the Trửger's base molecule.)
2-32 The polynactins are a class of ionophore antibiotics based on the same ring system. They differ in the substitution pattern on the ring. Analyze each of the five polynactins below for their symmetry elements. Which is (are) the most sym- metrical (i.e., has [have] the highest order symmetry element)?
R1 R2 R3 R4 Nonactin Me Me Me Me Monactin Et Me Me Me Dinactin Et Me Et Me Trinactin Et Et Et Me Tetranactin Et Et Et Et
Does this give any hints about how the synthesis of any of these compounds might be approached?
2-33 All the l-amino acids have the same general structure and the same Fischer projection. What is the absolute configuration of each of the amino acids shown in the R/S system?
H2N CO2H R
H
Trp Ser Cys Phe Val Ala
NH H2C
R = R = HO CH2 R = HS CH2R = CH2 R = R = Me
Does this suggest any caveats when using the R/S protocol in biochemical systems?
O O
R4 O
O
O O
O R1
R3 O
H H H H
O O R2 O
O H H H
H
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2-34 The synthesis of 8-phenylmenthol (or phenmenthol) from pulegone is carried out using the sequence of reactions shown.
1) PhMgBr/CuBr 2) HCl/H2O
3) Na/EtOH HO
+ O
Ph
Ph OH
Analyze the stereochemistry of the reactions that give these two products. What fixes the stereochemistry of the carbinol carbon? The minor product of the reac- tion is epi-ent-phenmenthol. Which of the two structures above is most likely to be this minor product? Why?
2-35 Deduce the stereochemical course of each of the following reactions. Where more than one organic reactant is involved, deduce the reaction stereochemistry with respect to each reactant.
HO OH
(a) AgOAc/I2/H2O/HOAc
H Br OH
(b) NBS/H2O/MeCN
(c)
O
O
OMe
OMe +
O
O H OMe
OMe
∆
(d)
O
NH 1) Me3SiN3/CCl4 O
2) H2O
(e) CO2H I2/KOH/H2O
O O
H I
2-36 Why is the 400 MHz 1H NMR signal from the methylene group indicated in the compound shown much more complex than the simple quartet that would be expected by splitting by the three protons of the adjacent methyl group?
O MeO
Me
O H
H
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