Protons anti conformation

The large sulfur atom is a preferred reaction site in synthetic intermediates to introduce chirality into a carbon compound. Thermal equilibrations of chiral sulfoxides are slow, and parbanions with lithium or sodium as counterions on a chiral carbon atom adjacent to a sulfoxide group maintain their chirality. The benzylic proton of chiral sulfoxides is removed stereoselectively by strong bases. The largest groups prefer the anti conformation, e.g. phenyl and oxygen in the first example, phenyl and rert-butyl in the second. Deprotonation occurs at the methylene group on the least hindered site adjacent to the unshared electron pair of the sulfur atom (R.R. Fraser, 1972 F. Montanari, 1975). 

The iH—NMR spectra of the recently prepared [2.2](l,4)anthraceno-phanes 36 63> resemble those of the isomeric naphthalenophanes 34. In the anti conformer A, the Ha proton, which lies directly above an anthracene ring, absorbs at much higher field strength than the syn Ha proton. 

Elimination reactions often compete with substitution. They involve elimination of the halogen and a hydrogen from adjacent carbons to form an alkene. Like substitution, they occur by two main mechanisms. The E2 mechanism is a one-step process. The nucleophile acts as a base to remove the adjacent proton. The preferred form of the transition state is planar, with the hydrogen and the leaving group in an anti conformation. The E1 mechanism has the same first step as the SN1 mechanism. The resulting carbocation then loses a proton from a carbon atom adjacent to the positive carbon to form the alkene. 

Although all proteinogenic amino acids form predominantly anti peptide bonds, a search in the Brookhaven Protein Database revealed that approximately 6-7% of all X-prolyl peptide bonds are found in the syn conformation in the native state of proteins [8]. The reason for this relatively frequent occurrence of syn-prolyl peptide bonds lies in steric repulsion of the proline 3 protons and the adjacent N-terminal amino acid in the anti conformation, resulting in a low barrier of rotation and energetically similar syn and anti isomers (Figure 1.2.3). 

Related work in our group led to the synthesis of the cyclophanes 21-23 (Scheme 7) [20]. It was found that 21 adopted the syn conformation exclusively and 23 adopted the anti conformation exclusively. However, cyclophane 22 was observed to exist in a ca. 6 1 antv.syn ratio at equilibrium. The two conformers can be separated by flash chromatography and the return to the equilibrium ratio monitored by H NMR. Noteworthy here is the direct observation of an anti to syn flip of a [2.2]metacyclophane. There have been only two other reports of such anti to syn flips [21], Also noteworthy is the chemical shift of the internal proton of the inner ring of anti-22, which appears at S 3.03. 

Another type of substitution, and one which is likely to have a stronger effect, is the replacement of one of the H atoms of water by a more electronegative atom like Cl. This substitution enhances the proton-donating ability of the water, so that HOCl is the donor when combined with a water molecule. Unlike the water dimer itself, for which the anti conformer is the only stable minimum, both syn and anti arrangements represent minima on the surface of ClOH-OHj as illustrated in Fig. 2.10. There are no minima corresponding to a reversal in which HOCl acts as proton acceptor. However, the reader should be cautioned that HOH OHCl may appear to be a minimum, even at fairly high levels of theory. It required MP2/6-311 + +G(d,p) to demonstrate it not to be a true minimum. 

In summary, there is little distinction between the syn and anti lone pairs of the car-boxylate oxygen atom with regard to forming H-bonds with proton donors. When a proton has approached closely enough to form a covalent bond, the syn position is favored, but only in the gas phase. The syn and anti conformers of the carboxylic acid are close in energy in aqueous solution. Even in the gas phase, the preference for the syn configuration of the isolated carboxylic acid can be eliminated when it forms a H-bond, due to more favorable electrostatic interactions between the partner and the anti geometry of the carboxyl. 

In contrast to this equal propensity toward formation of a H-bond, there is a definite preference for a proton to locate on the syn side when coming much closer and forming a covalent bond. That is, the syn conformer of RCOOH is more stable than the anti structure by about 5 kcal/mol in the gas phase. If this is the case, why then is there so little apparent pK difference between the syn and anti structures The answer to this question resides in solvation phenomena. The presence of the polarizable medium preferentially stabilizes the anti conformer of the carboxylic acid due to its higher dipole moment. 

The conformational preferences of 9-O-carbamoyl cinchona free bases reflect in general those of the native cinchona alkaloids. 6 -Neopentoxy-9-0-tert-butylcarba-moylcinchonidine exists as a mixture of two major anti-closed and anti-open conformers in a 65 35 ratio, whereas upon protonation anti-open conformation has been observed exclusively [62]. 

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