Acid chloride formation from carboxylic

Acid chloride formation from carboxylic acid, see under Carboxylic acid Addition, amine to acrylonitrile, 98, 118 bromine to methyl acrylate, 202 bromine to vinyl acetate, 102 chlorine to methyl acrylate, 202 chlorine to vinyl acetate, 147 HC1 to styrene, 77 HC1 and HBr to acrylonitrile, 82. ... 

Acid chloride—con l d esters from, 802-803 from carboxylic acids, 794-795 Grignard reaction of, 804-805 hydrolysis of, 802 IR spectroscopy of, 822-823 ketones from, 805 mechanism of formation from carboxylic acids, 795 naming, 786... 

Pyridones are easy to prepare (see Chapter 44) and can be alkylated on oxygen as predicted by their structure. A more important reaction is the direct conversion to chloropyridines with POCI3. The reaction starts by attack of the oxygen atom at phosphorus to create a leaving group, followed by aromatic nucleophilic substitution. The overall effect is very similar to acyl chloride formation from a carboxylic acid. 

Direct ester formation from carboxylic acids (R C02H) and alcohols (R OH) works in acid solution but not in basic solution. Why not By contrast, ester formation from alcohols (R OH) and acid anhydrides [(R CO)20)] or chlorides (R COCI) is commonly carried out in basic solution in the presence of bases such as pyridine. Why does this work ... 

Many carboxy derivatives are available by primary syntheses. Otherwise the best route to simple pyrimidinecarboxylic acid derivatives is oxidative. This statement is even more applicable to our present situation with readily available acyl-, alkenyl-, or alkynylpyrimidine substrates from the coupling procedures, which serve as excellent substrates for oxidative reactions. The normal carboxylic acid reactions are observed ester formation, ester hydrolysis, aminolysis, acid chloride formation and reactions. A carboxy group in an electrophilic position may readily be lost when the pyrimidine ring is further depleted of 7t-electrons by its substitution pattern selective decarboxylation can be effected in pyrimidinedicarboxylic acids. 

From the mechanism of the acid chloride formation, one can see that it is the C-OH bond of the carboxylic acid that is broken to form the C-Cl bond. Subsequently, the C-Cl bond is cleaved to form the C-OR bond with the alcohol oxygen. 

STRATEGY AND ANSWER An acid chloride results from treatment of A with B. Therefore, A is likely to be a carboxylic acid, a conclusion that is consistent with the oxidizing conditions that led to formation of A from methylbenzene (toluene). B must be a reagent that can lead to an acid chloride. Thionyl chloride or PCI5 would suffice. Overall, C, D, and E involve introduction of the nitrogen atom and loss of the carbonyl carbon. This sequence is consistent with preparation... 

This tertiary ester was developed to reduce aspartimide and piperidide formation during the Fmoc-based peptide synthesis by increasing the steric bulk around the carboxyl carbon. A twofold improvement was achieved over the the standard Fbutyl ester. The Mpe ester is prepared from the acid chloride and the alcohol and can be cleaved under conditions similar to those used for the r-butyl ester. ... 

The structure of this compound is confirmed by the preparation of the 1-acetyl derivative, acid degradation to 4-methylquinoxalin-3-one-2-carboxylic acid (12), and alternative synthesis from the acid chloride of (12) and AW -dimethyluread A most unusual cyclization occurs when AW-dimethyl-o-phenylenediamine (15) is treated with alloxan in ethanolic solution this apparently involves an A-methyl group and leads to the formation of the spirobarbituric acid (16). The struc-... 

Many procedures for the formation of carboxylic acid amides are known in the literature. The most widely practiced method employs carboxylic acid chlorides as the electrophiles which react with the amine in the presence of an acid scavenger. Despite its wide scope, this protocol suffers from several drawbacks. Most notable are the limited stability of many acid chlorides and the need for hazardous reagents for their preparation (thionyl chloride, oxalyl chloride, phosgene etc.) which release corrosive and volatile by-products. Moreover, almost any other functional group in either reaction partner needs to be protected to ensure chemoselective amide formation.2 The procedure outlined above presents a convenient and catalytic alternative to this standard protocol. 

An interesting preparation of alkyl carboxylates in high yield (Table 3.14) from the sodium salt of the carboxylic acids under mild phase-transfer catalytic conditions involves their reaction with alkyl chlorosulphate [50] and has been used with success in the preparation of alkyl esters derived from p-lactam antibiotics. The procedure is also excellent for the production of chloromethyl esters, particularly where the carboxylic acids will not withstand the classical Lewis acid-catalysed procedure using an acid chloride and formaldehyde, or where the use of iodochloromethane [51] results in the formation of the bis(acyloxy)methane. The procedure has been applied with some success to the synthesis of chloromethyl A-protected a-amino carboxylates [52],... 

The use of DMF to accelerate the formation of acid chlorides from carboxylic acids has been reviewed previously,4 and is believed to occur via an imidoyl chloride intermediate.5... 

Dinitrocubane (28) has been synthesized by Eaton and co-workers via two routes both starting from cubane-l,4-dicarboxylic acid (25). The first of these routes uses diphenylphos-phoryl azide in the presence of a base and tert-butyl alcohol to effect direct conversion of the carboxylic acid (25) to the tert-butylcarbamate (26). Hydrolysis of (26) with mineral acid, followed by direct oxidation of the diamine (27) with m-CPBA, yields 1,4-diiutrocubane (28). Initial attempts to convert cubane-l,4-dicarboxylic acid (25) to 1,4-diaminocubane (27) via a Curtins rearrangement of the corresponding diacylazide (29) were abandoned due to the extremely explosive nature of the latter. However, subsequent experiments showed that treatment of the acid chloride of cubane-l,4-dicarboxylic acid with trimethylsilyl azide allows the formation of the diisocyanate (30) without prior isolation of the dangerous diacylazide (29) from solution. Oxidation of the diisocyanate (30) to 1,4-dinitrocubane (28) was achieved with dimethyldioxirane in wet acetone. Dimethyldioxirane is also reported to oxidize both the diamine (27) and its hydrochloride salt to 1,4-dinitrocubane (28) in excellent yield. ... 

The usual procedure of preparing acid azides, which involves treating an acid chloride with sodium azide,8,9 suffers from the disadvantage that it is often difficult to obtain pure acid chlorides in good yields from acids which either decompose or undergo isomerization in the presence of mineral acids.7 Synthesis of the azide by way of the ester and hydrazide10 has been used to circumvent this difficulty but is much less convenient. The present procedure permits ready formation of acid azides in excellent yields from mixed carboxylic-carbonic anhydrides and sodium azide under very mild conditions. 

When solid-phase peptide synthesis was initially being developed, the question of whether or not a separate neutralization step is necessary was considered. Since it was known from the work of others that the chloride ion promotes racemization during the coupling step in classical peptide synthesis, and since we were deprotecting the Boc group with HC1, it seemed advisable to neutralize the hydrochloride by treatment with TEA and to remove chloride by filtration and washing. This short, additional step was simple and convenient and became the standard protocol. Subsequently, we became aware of three other reasons why neutralization was desirable (1) to avoid weak acid catalysis of piperazine-2,5-dione formation, 49 (2) to avoid acid-catalyzed formation of pyroglutamic acid (5-oxopyr-rolidine-2-carboxylic acid), 50 and (3) to avoid amidine formation between DCC and pro-tonated peptide-resin. The latter does not occur with the free amine. 

The problem in the above example is to perform an enantiocontrolled electrophilic substitution in the a-position of a carboxylic acid derivative 1. To this end, chiral auxiliary 2, readily available in both (R) and (5) form from phenylalanine, is attached to the acid chloride 1 by amide formation. The amide 3 is converted into the (T )-enolatc 4, with the chelate ring forming... 

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