Neighboring-group participation—

SCHEME 6.2 Neighboring group participation mechanisms with esters. 

Further exploring the approach of nucleophiles to the carbonyl center, if the nucleophile is water, then orthoacids can be formed. However, orthoacids are very unstable and generally decompose to a mixture of two products. The first product is a derivative of the starting material with the tosylate displaced by hydroxide. In the second product, the acetate migrated from C-1 to C-2. With respect to mechanistic preferences, soft nucleophiles tend to favor ring opening, whereas hard nucleophiles tend to favor orthoester-type products. 

Unlike acyloxonium ions, oxazolinium ions bear a proton capable of being removed under basic conditions. If these conditions are applied to the oxazolinium ion, then the result is formation of a stable oxazoline. 

SCHEME 6.4 Neighboring group participation mechanism with nucleotides. 

When a molecule that is a substrate for nucleophilic substitution also contains a group that can act as a nucleophile, it is often observed that the kinetics and stereochemistry of nucleophilic substitution are strongly affected. The involvement of nearby nucleophihc substituents in a substitution process is called neighboring-group participation  

A classic example of neighboring-group participation involves the solvolysis of compoimds in which an acetoxy substituent is present next to a carbon that is imdergoing nucleophilic substitution. For example, the rates of solvolysis of the cis and trans isomers of 2-acetoxycyclohexyl jj-toluenesulfonate differ by a factor of about 670, the trans compound being the more reactive one  

Besides the pronoimced difference in rate, the products obtained fi om the isomeric compoimds reveal a marked difference in stereochemistry. The diacetate obtained from the cis isomer is the trans compoimd (inverted stereochemistry), whereas retention of configmation is observed for the trans isomer. 

When enantiomerically pure /rans-2-acetoxycyclohexyl tosylate is solvolyzed, the produet is racemie /rans-diacetate. This is consistent with the proposed mechanism, since the acetoxonium intermediate is achiral and can only give rise to racemic material. Additional evidence for this interpretation comes from the isolation of a cyclic ortho ester when the solvolysis is carried out in ethanol. In this solvent the acetoxonium ion is captured by the solvent. 

In basic solution, the alkoxide ions formed by deprotonation are even more effective nucleophiles. In ethanol containing sodium ethoxide, 2-chloroethanol reacts about 5000 times faster than ethyl chloride. The product is ethylene oxide, confirming the involvement of the oxygen atom as a nucleophile. 

The hydroxy group can act as an intramolecular nucleophile. Solvolysis of 4-chlorobutanol in water gives as the product the cyclic ether tetrahydrofuran. The reaction is much faster than solvolysis of 3-chloropropanol under similar conditions. 

These results are explained by the participation of the trans acetoxy group in the ionization process. The assistance provided by the acetoxy carbonyl group facilitates the ionization of the tosylate group, accounting for the rate enhancement. The 

Besides the pronounced difference in rate, the isomeric compounds reveal a marked 

45 (1964) B. Capon and S. P. McManus, Neighboring Group Participation, Plenum Press, New York, 1976. 

In a bimolecular reaction, each of the two reactant molecules can move about freely, having three degrees of translational freedom. When they unite to form the transition state, three degrees of freedom are lost since the molecules are now locked together. As a result there is a large decrease in the entropy, reflected by a negative contribution to AS the entropy of activation, and a corresponding decrease in rate. 

If now we had a similar reaction in which the reactant molecules were joined together, the reaction taking place between different parts of the same molecule rather than two different molecules, no translational entropy would be lost on forming the transition state. The entropy of activation should then be much more positive, and the rate consequently much greater, than for the corresponding bimolecular reaction. 

This effect is seen very clearly in the intramolecular reactions of co-chloro- 

The same effect is seen in chemical equilibria. Thus the reaction of two molecules of a carboxylic acid to form the anhydride. 

Cyclic anhydrides are therefore formed much more easily than acyclic anhydrides and are less easily hydrolyzed, particularly if the resulting anhydride has a five- or six-membered ring. Anhydrides of this kind are formed very easily just by heating the dicarboxylic acid, whereas acyclic anhydrides must usually be obtained by other procedures. 

The position of this equilibrium will depend upon the nucleophilicity of the carbonyl oxygen which varies with the electronics of substituent R. A trichloroacetate, for example, cannot participate whereas a monochloroacetate does, but with lower efficiency than a simple acetate [33]. 

Although it is possible that the observed improvement in stereoselectivity originates from potential alteration of the steric profile of the lactosamine donor as a result of changing the protecting groups, a completely acetylated lactosamine donor [37] gave identical selectivity to 9. 

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Neighboring group participation (a term introduced by Winstein) with the vacant p-orbital of a carbenium ion center contributes to its stabilization via delocalization, which can involve atoms with unshared electron pairs (w-donors), 7r-electron systems (direct conjugate or allylic stabilization), bent rr-bonds (as in cyclopropylcarbinyl cations), and C-H and C-C [Pg.150]

In some cases where there is a neighboring group participation effect, aldehydes are formed. The a-vinyl group in the / -lactam 29 is mainly oxidized to aldehyde 30[83],... 

The pify of the leaving group and the hydrophobe chain length can dramatically affect the efficiency of the perhydrolysis reaction. Additionally, the stmcture of the acid portion of the precursor can affect the yield and sensitivity of the reaction to pH. The mono-4-hydroxybenzenesulfonic acid ester of a-decylsuccinic acid (13) undergoes extremely efficient perhydrolysis at much lower pHs than other peracid precursors, eg, decanoyloxybenzene sulfonate (14). This may be because of the neighboring group participation of the adjacent carboxylate as shown in Table 2 (115). 

In contrast to the usual behavior, replacement of the mesyl group in 2 O mesyl-3-diallylaminodeoxy-a-D-altropyranoside by treatment with triethylamine trihydrofluonde leads to, because of neighboring-group participation, the fluori-nated product with retention of configuration [45] (equation 33)... 

Series 7 gives a linear plot with p = —5.27, consistent with the S l mechanism. Series 8, however, shows a discontinuity, which Gassmann and Fentiman interpreted as a change in mechanism. Compounds in series 8 are capable of intramolecular assistance (neighboring group participation) by electron donation from the double bond to stabilize the cation, as in 9. 

This is consistent with neighboring group participation by the oxygen atom in the separation of the chloride ion. ... 

Somewhat milder oxidative conditions lead to loss of but one carbon. Periodic acid cleavage of the side chain in 65, leads to the so-called etio acid (66). Reaction with propionic anhydride leads to acylation of the 17-hydroxyl group (67). Possibilities for neighboring group participation severely limit the methods available for activating the acid for esterification. Best results seemed to have been obtained by use of a mixed anhydride from treatment with diphenyl chloro-... 

Cyclization of hydrazone 38 with mercuric oxide and EDTA gave dihy-drotriazine 39 (87AP198). On the other hand, methyl hydrazone 38, under 4-electron withdrawal and neighboring group participation reacts with the same reagent to give lactam 40, a useful precursor for the synthesis of the pyrrolo[2,l-c]triazinium salt 41 by cyclization with perchloric acid (87AP258) (Scheme 12). 

There is a special interest in the role of neighboring group participation by sulfinyl groups in nucleophilic aliphatic substitution. Thus Martin and Uebel218 found that trans-4-chlorothiane-S-oxide 36 is solvolyzed (50% v/v aqueous ethanol, 140 °C) 630 times faster than the cis isomer 37. This was attributed to the intervention of 38 for the former. 

For a review of neighboring group participation by sulfinyl oxygen, see Montanari221. This special influence of sulfinyl groups on reactivity is, of course, due to the high polarity... 

In discussing nonclassical carbocations we must be careful to make the distinction between neighboring-group participation and the existence of nonclassical carbocations. ° If a nonclassical carbocation exists in any reaction, then an ion with electron delocalization, as shown in the above examples, is a discrete reaction intermediate. If a carbon-carbon double or single bond participates in the departure of the leaving group to form a carbocation, it may be that a nonclassical carbocation is involved, but there is no necessary relation. In any particular case, either or both of these possibilities can be taking place. 

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