Page 244 - Advanced Organic Chemistry Part B - Reactions & Synthesis

216 reactions. Section 3.1 considers conversion of alcohols to reactive alkylating agents and
Section 3.2 discusses the use of S 2 reactions for various functional group transfor-
N
CHAPTER 3
mations. Substitution reactions can also be used to break bonds for synthetic purposes,
Functional Group and Section 3.3 deals with cleavage of C−O bonds in ethers and esters by S 2 and S 1
Interconversion N N
by Substitution, reactions. The carbonyl substitution reactions that interconvert the acyl halides, acid
Including Protection and anhydrides, esters, and carboxamides are discussed in Section 3.4. Often, manipulation
Deprotection
of protecting groups also involves nucleophilic substitution and carbonyl exchange
reactions. We discuss protection and deprotection of the most common functional
groups in Section 3.5.

3.1. Conversion of Alcohols to Alkylating Agents

3.1.1. Sulfonate Esters

Alcohols are a very important compounds for synthesis. However, because the
hydroxide ion is a very poor leaving group, alcohols are not reactive as alkylating
agents. They can be activated to substitution by O-protonation, but the acidity that
is required is incompatible with most nucleophiles except those, such as the halides,
that are anions of strong acids. The preparation of sulfonate esters from alcohols
is an effective way of installing a reactive leaving group on an alkyl chain. The
reaction is very general and complications arise only if the resulting sulfonate ester is
sufficiently reactive to require special precautions. p-Toluenesulfonate (tosylate) and
methanesulfonate (mesylate) esters are used most frequently for preparative work, but
the very reactive trifluoromethanesulfonates (triflates) are useful when an especially
good leaving group is required. The usual method for introducing tosyl or mesyl groups
1

is to allow the alcohol to react with the sulfonyl chloride in pyridine at 0 –25 C. An
alternative method is to convert the alcohol to a lithium salt, which is then allowed to
react with the sulfonyl chloride. 2
ROLi + ClSO 2 CH 3 ROSO 2 CH 3

Trifluoromethanesulfonates of alkyl and allylic alcohols can be prepared by reaction
with trifluoromethanesulfonic anhydride in halogenated solvents in the presence of
3
pyridine. Since the preparation of sulfonate esters does not disturb the C−O bond,
problems of rearrangement or racemization do not arise in the ester formation step.
However, sensitive sulfonate esters, such as allylic systems, may be subject to
reversible ionization reactions, so appropriate precautions must be taken to ensure
structural and stereochemical integrity. Tertiary alkyl sulfonates are neither as easily
prepared nor as stable as those from primary and secondary alcohols. Under the
standard preparative conditions, tertiary alcohols are likely to be converted to the
corresponding alkene.

1
R. S. Tipson, J. Org. Chem., 9, 235 (1944); G. W. Kabalka, M. Varma, R. S. Varma, P. C. Srivastava,
and F. F. Knapp, Jr., J. Org. Chem., 51, 2386 (1986).
2 H. C. Brown, R. Bernheimer, C. J. Kim, and S. E. Scheppele, J. Am. Chem. Soc., 89, 370 (1967).
3
C. D. Beard, K. Baum, and V. Grakauskas, J. Org. Chem., 38, 3673 (1973).