Substitution at tertiary carbon

If the molecule contains both the primary and secondary carbons carrying hydrogens in a-positions, as CHg-CHKTl-CL -Cl, then a secondary position is substituted more readily than the primary, some allylic substitution at tertiary carbon has also been reported. In case the molecule contains both the double and triple bonds, the preferred position of substitution is a to the triple bond. 

The essential features of the mechanism for aliphatic nucleophilic substitution at tertiary carbon were established in studies by Hughes and Ingold." ° However, as chemists probed more deeply, the problems associated with the characterization of borderline reaction mechanisms were encountered, and controversy remains to this day about whether these problems have been entirely solved." What is generally accepted is that ferf-butyl derivatives undergo borderline solvolysis reactions through a ferf-butyl carbocation intermediate that is too unstable to diffuse freely through nucleophilic solvents such as methanol and water. The borderline nature of substitution reactions at tertiary carbon is exemplihed by the following observations. 

An important question is whether nucleophilic substitution at tertiary carbon proceeds though a carbocation intermediate that shows a significant chemical barrier to the addition of solvent and other nucleophiles. The yield of the azide ion substitution product from the reaction of 5-Cl is similar to that observed for the reactions of X-2-Y when this product forms exclusively by conversion of the preassociation complex to product. Therefore the carbocation 5 is too unstable to escape from an aqueous solvation shell and undergo diffusion-controlled trapping by azide ion. This result sets a lower limit of w fcj > -d 1.6 x 10 ° s (Scheme 2.4) " for addition of solvent to the ion pair intermediate 5" C1 . 

J. P. Richard, T. L. Amyes, and T. Vontor, Absence of Nucleophibc Assistance by Solvent and Azide Ion to the Reaction of Cumyl Derivatives Mechanism of Nucleophibc Substitution at Tertiary Carbon, J. Am. Chem. Soc. 1991, 113, 5871. 

Alcohols (X = OH) and alkyl halides (X = F Cl Br or I) are classified as primary secondary or tertiary according to the degree of substitution at the carbon that bears the functional group... 

Alkyl halides can be hydrolyzed to alcohols. Hydroxide ion is usually required, except that especially active substrates such as allylic or benzylic types can be hydrolyzed by water. Ordinary halides can also be hydrolyzed by water, if the solvent is HMPA or A-methyl-2-pyrrolidinone." In contrast to most nucleophilic substitutions at saturated carbons, this reaction can be performed on tertiary substrates without significant interference from elimination side reactions. Tertiary alkyl a-halocarbonyl compounds can be converted to the corresponding alcohol with silver oxide in aqueous acetonitrile." The reaction is not frequently used for synthetic purposes, because alkyl halides are usually obtained from alcohols. 

Only low yields of the azide ion adduct are obtained from the reaction of simple tertiary derivatives in the presence of azide ion 2145 46 and it is not possible to rigorously determine the kinetic order of the reaction of azide ion, owing to uncertainties in the magnitude of specific salt effects on the rate constants for the solvolysis and elimination reactions. Therefore, these experiments do not distinguish between stepwise and concerted mechanisms for substitution reactions at tertiary carbon. 

As we have just seen, SnI reactions are highly favoured at tertiary carbon, and very much disfavoured at primary carbon. This is in marked contrast to Sn2 reactions, which are highly favoured at primary carbon and not at tertiary carbon. With Sn2 reactions, consideration of steric hindrance rationalized the results observed. This leads to the generalizations for nucleophilic substitutions shown in Table 6.8, with secondary substrates being able to participate in either type of process. 

There is an ongoing controversy about whether there is any stabilization of the transition state for nucleophilic substitution at tertiary aliphatic carbon from interaction with nucleophilic solvent." ° This controversy has developed with the increasing sophistication of experiments to characterize solvent effects on the rate constants for solvolysis reactions. Grunwald and Winstein determined rate constants for solvolysis of tert-butyl chloride in a wide variety of solvents and used these data to define the solvent ionizing parameter T (Eq. 3). They next found that rate constants for solvolysis of primary and secondary aliphatic carbon show a smaller sensitivity (m) to changes in Y than those for the parent solvolysis reaction of tert-butyl chloride (for which m = 1 by definition). A second term was added ( N) to account for the effect of changes in solvent nucleophilicity on obsd that result from transition state stabilization by a nucleophilic interaction between solvent and substrate. It was first assumed that there is no significant stabilization of the transition state for solvolysis of tert-butyl chloride from such a nucleophilic interaction. However, a close examination of extensive rate data revealed, in some cases, a correlation between rate constants for solvolysis of fert-butyl derivatives and solvent nucleophicity. " ... 

Their approach in looking into the problem further was to find structures in which specific covalent bonding to the back side of the carbon undergoing substitution is difficult or impossible. As models for reactions at tertiary carbon they chose bridgehead substitutions. We have seen in Section 5.2 that rates in these systems are retarded, in some cases by many powers of ten, because of the increase in strain upon ionization. But the important point in the present context is that it is impossible for a solvent molecule to approach from the back side of a bridgehead carbon the only possibilities are frontside attack, known to be strongly disfavored (Section 4.2), or limiting SW1 solvolysis with nonspecific solvation. 

Komblum, N. Stuchal, F. W. New and fatile substitution reactions at tertiary carbon. The reactions of amines with p-nitrocumyl chloride and a,p-dinitrocumene. J. Am. Chem. Soc. 

The acetylide ion is a strongly basic and nucleophilic species which can induce nucleophilic substitution at positive carbon centres. Acetylene is readily converted by sodium amide in liquid ammonia to sodium acetylide. In the past alkylations were predominantly carried out in liquid ammonia. The alkylation of alkylacetylenes and arylacetylenes is carried out in similar fashion to that of acetylene. Nucleophilic substitution reactions of the alkali metal acetylides are limited to primary halides which are not branched in the -position. Primary halides branched in the P-position as well as secondary and tertiary halides undergo elimination to olefins by the NaNH2. The rate of reaction with halides is in the order I > Br > Cl, but bromides are generally preferred. In the case of a,o)-chloroiodoalkanes and a,to-bromoiodoalkanes. 

A remarkable feature of reaction (19) is the substitution of the nitro group attached at tertiary carbon of the p nitrocumenyl system. The reaction of the displacement of a nitro group from a saturated carbon atom througlt an anion has been described for the first time [SRc]. 

Dauben, H. J., Jr., McCoy, L. L. N-Bromosuccinimide. II. Allylic bromination of tertiary hydrogens. J. Org. Chem. 1959, 24,1577-1579. Russell, G. A., DeBoer, C. Directive effects in aliphatic substitutions. XVIII. Substitutions at saturated carbon-hydrogen bonds utilizing molecular bromine or bromotrichloromethane. J. Am. Chem. Soc. 1963, 85, 3136-3139. 

Tertiary phosphines substituted at the -carbon by electronegative groups, e.g. (56), react with boron trihalides to give products derived from carbon-phosphorus bond cleavage. Phosphines containing only hydrocarbon groups do not react. 

---