Nucleophile carboxylic acids

Only carbonium ions and alkylating agents of similar high reactivity, such as trialkyloxonium cations133, will attack the very weakly nucleophilic carboxylic acid group at a useful rate under normal conditions. Ester formation by alkylation of the carboxyl oxygen atom normally involves the carboxylate anion, viz. 

Reaction of chlorimidium salts with nucleophiles Carboxylic acid amides and amidinium salts... 

Addition-elimination of the nucleophilic carboxylic acid to the chloroformate gives a mixed anhydride after expulsion of chloride. 

Intramolecular oxy palladation and amido palladation reactions onto alkynes provide a convenient way for preparing concise functionalized heterocyclic structures. As nucleophiles carboxylic acids, amines, and amides have been used. Also, further functionalization of the double bond might be achieved via cross-coupling with in situ-formed organopal-... 

Epoxides provide another useful a -synthon. Nucleophilic ring opening with dianions of carboxylic acids (P.L. Creger, 1972) leads to y-hydroxy carboxylic acids or y-lactones. Addition of imidoester anions to epoxides yields y-hydroxyaldehyde derivatives after reduction (H.W. Adickes, 1969). 

In his cephalosporin synthesis methyl levulinate was condensed with cysteine in acidic medium to give a bicyclic thiazolidine. One may rationalize the regioselective formation of this bicycle with the assumption that in the acidic reaction mixture the tMoI group is the only nucleophile present, which can add to the ketone. Intramolecular amide formation from the methyl ester and acid-catalyzed dehydration would then lead to the thiazolidine and y-lactam rings. The stereochemistry at the carboxylic acid a-... 

Typical nucleophiles known to react with coordinated alkenes are water, alcohols, carboxylic acids, ammonia, amines, enamines, and active methylene compounds 11.12]. The intramolecular version is particularly useful for syntheses of various heterocyclic compounds[l 3,14]. CO and aromatics also react with alkenes. The oxidation reactions of alkenes can be classified further based on these attacking species. Under certain conditions, especially in the presence of bases, the rr-alkene complex 4 is converted into the 7r-allylic complex 5. Various stoichiometric reactions of alkenes via 7r-allylic complex 5 are treated in Section 4. 

The reaction of alkenyl mercurials with alkenes forms 7r-allylpalladium intermediates by the rearrangement of Pd via the elimination of H—Pd—Cl and its reverse readdition. Further transformations such as trapping with nucleophiles or elimination form conjugated dienes[379]. The 7r-allylpalladium intermediate 418 formed from 3-butenoic acid reacts intramolecularly with carboxylic acid to yield the 7-vinyl-7-laCtone 4I9[380], The /i,7-titisaturated amide 421 is obtained by the reaction of 4-vinyl-2-azetidinone (420) with an organomercur-ial. Similarly homoallylic alcohols are obtained from vinylic oxetanes[381]. 

Formation of carboxylic acids ami their derivatives. Aryl and alkenyl halides undergo Pd-catalyzed carbonylation under mild conditions, offering useful synthetic methods for carbonyl compounds. The facile CO insertion into aryl- or alkenylpalladium complexes, followed by the nucleophilic attack of alcohol or water affords esters or carboxylic acids. Aromatic and a,/ -unsaturated carboxylic acids or esters are prepared by the carbonylation of aryl and alkenyl halides in water or alcohols[30l-305]. 

Another method for deallylation of ally esters is the transfer of the allyl group to reactive nucleophiles. Amines such as morpholine are used[415-417], Potassium salts of higher carboxylic acids are used as an accepter of the allyl group[418]. The method is applied to the protection and deprotection of the acid function in rather unstable /f-lactam 664[419,420]. 

Neutral Lewis bases such as water alcohols and carboxylic acids are much weaker nucleophiles than their conjugate bases When comparing species that have the same nucleophilic atom a negatively charged nucleophile is more reactive than a neutral one... 

Solvent Effects on the Rate of Substitution by the S 2 Mechanism Polar solvents are required m typical bimolecular substitutions because ionic substances such as the sodium and potassium salts cited earlier m Table 8 1 are not sufficiently soluble m nonpolar solvents to give a high enough concentration of the nucleophile to allow the reaction to occur at a rapid rate Other than the requirement that the solvent be polar enough to dis solve ionic compounds however the effect of solvent polarity on the rate of 8 2 reactions IS small What is most important is whether or not the polar solvent is protic or aprotic Water (HOH) alcohols (ROH) and carboxylic acids (RCO2H) are classified as polar protic solvents they all have OH groups that allow them to form hydrogen bonds... 

Although the present chapter includes the usual collection of topics designed to acquaint us with a particular class of compounds its central theme is a fundamental reaction type nucleophilic addition to carbonyl groups The principles of nucleophilic addition to aide hydes and ketones developed here will be seen to have broad applicability m later chap ters when transformations of various derivatives of carboxylic acids are discussed... 

Primary and secondary alkyl halides may be converted to the next higher carboxylic acid by a two step synthetic sequence involving the preparation and hydrolysis of nitriles Nitnles also known as alkyl cyanides are prepared by nucleophilic substitution... 

Esterification of carboxylic acids involves nucleophilic addition to the carbonyl group as a key step In this respect the carbonyl group of a carboxylic acid resembles that of an aldehyde or a ketone Do carboxylic acids resemble aldehydes and ketones m other ways Do they for example form enols and can they be halogenated at their a carbon atom via an enol m the way that aldehydes and ketones can ... 

A standard method for the preparation of an a ammo acid uses a bromo carboxylic acids as the substrate and aqueous ammonia as the nucleophile... 

CARBOXYLIC ACID DERIVATIVES NUCLEOPHILIC ACYL SUBSTITUTION... 

Carboxylic Acid Derivatives Nucleophilic Acyl Substitution... 

Both stages involve more than one step and these steps differ in detail among the various carboxylic acid derivatives and for different reaction conditions This chapter is organized to place the various nucleophilic acyl substitutions into a common mechanis tic framework and to point out the ways m which individual classes differ from the rest... 

What structural features are responsible for the reactivity order of carboxylic acid derivatives Like the other carbonyl containing compounds that we ve studied they all have a planar arrangement of bonds to the carbonyl group Thus all are about the same in offering relatively unhindered access to the approach of a nucleophile They differ m the degree to which the atom attached to the carbonyl group can stabilize the carbonyl group by electron donation... 

The order of reactivity of carboxylic acid derivatives toward nucleophilic acyl sub stitution can be explained on the basis of the electron donating properties of sub stituent X The greater the electron donating powers of X the slower the rate... 

The first stage of the mechanism is exactly the same as for nucleophilic addition to the carbonyl group of an aldehyde or ketone Many of the same nucleophiles that add to aldehydes and ketones—water (Section 17 6) alcohols (Section 17 8) amines (Sections 17 10-17 11)—add to the carbonyl groups of carboxylic acid derivatives... 

On treatment with the appropriate nucleophile an acyl chlonde may be converted to an acid anhydride an ester an amide or a carboxylic acid Examples are presented m Table 20 1... 

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