Alcohols reaction with carboxylic acids under acid

It is for this reason that alcohols will react with carboxylic acids under acid catalysis. The acid (usually HCl or H2SO4) reversibly protonates a small percentage of the carboxylic acid molecules, and the protonated carboxylic acids are extremely susceptible to attack by even a weak nucleophile such as an alcohol. This is the first half of the reaction ... 

Esters can be prepared by reaction of alcohols with carboxylic acids under acidic catalysis but can be hydrolyzed in either acid or basic solution. They can also be prepared by reaction of alcohols with acid chlorides or anhydrides. 

Kaminski has noted that partial substitution of chlorine atoms in TCT 3 by methoxy or phenoxy groups changes the course of the reaction with carboxylic acids <1985TL2901>. In fact, instead of the expected acyl chlorides, the reaction between 2-chloro-4,6-dialkoxy-[l,3,5]-triazine 295 and carboxylic acids gave highly reactive 2-acyloxy-4,6-dialkoxy-[l,3,5]-triazine 296, which, under further treatment with amines, alcohols, and carboxylic acid anions, afforded amides, esters, and anhydrides, respectively (Scheme 57). 

In the previous section, an alcohol was used as the nucleophile that leads to replacement of the OH of a carboxylic acid under acid-catalyzed conditions to give an ester. This reaction is acid-catalyzed acyl substitution. Acyl substitution is also possible for an ester, and it is possible for one alcohol unit to replace another. This means that replacing one OR group in an ester with a new group (OR ) will give a different ester. This reaction is known as transesterification. Transesterification is a very specific term that means exchanging the alcohol unit of one ester with a different alcohol unit to make a new ester. 

A sulfonate ester can also be prepared by the reaction of an alcohol and a sulfonic acid under acidic conditions, exactly analogous to the same reaction with a carboxylic acid. In the presence of an acid catalyst, 2-methylpropane-sulfonic acid (181) reacts with ethanol to give ethyl 2-methylpropanesulfonate (187). The mechanism of this reaction is remarkably similar to that for the reaction of a carboxylic acid and an alcohol in the presence of an acid catalyst (see Section 20.5.2). The reaction proceeds by initial reaction of 181 with H+ to give 182. The oxygen of ethanol is the electron-donating species in this reaction, and the most electrophilic atom is sulfur, so reaction of 182 and ethanol generates a new S-O bond in 183. 

The Fischer-Tropsch synthesis, which may be broadly defined as the reductive polymerization of carbon monoxide, can be schematically represented as shown in Eq. (1). The CHO products in Eq. (1) are any organic molecules containing carbon, hydrogen, and oxygen which are stable under the reaction conditions employed in the synthesis. With most heterogeneous catalysts the primary products of the reaction are straight-chain alkanes, while the secondary products include branched-chain hydrocarbons, alkenes, alcohols, aldehydes, and carboxylic acids. The distribution of the various products depends on both the type of catalyst and the reaction conditions employed (4). 

A well-known reaction of carboxylic acids is that they react with alcohols under acidic conditions to yield esters. 

Two types of esterification reaction that can be studied with water as solvent are lactone formation, in which the alcohol is part of the same molecule as the acid, and the lsO-exchange reaction of carboxylic acids, which makes it possible to examine A-2 reactions of carboxylic acids under the conditions used for ester hydrolysis. Work in both these fields confirms the similarities between ester hydrolysis and formation. The hydrolysis and formation of y-butyrolactone have already been discussed (p. 109). We deal here with the lsO-exchange reactions of carboxylic acids. 

Esters of 4-oxoacids, such as ethyl levulinate, can also be cyclized in the cold by treatment with hydrogen sulfide under acid conditions. An early report (39JCS1116) described the conversion of diethyl 2-acetylsuccinate (168) to ethyl 2-methyl-5-ethoxythiophene-3-carboxylate (169), by treatment with hydrogen sulfide in alcoholic HC1 at 0 °C. The reaction was reviewed in 1977 <77PS(3)377) a large number of 4-oxoesters (170) were subjected to the hydrogen sulfide treatment, and the products were carefully isolated and characterized. 

The Cannizzaro reaction, that is, the base-catalysed disproportionation of a carbonyl compound to an alcohol and a carboxylic acid, has gained some importance as an economically viable alternative to the reduction with borohydrides. However, the reaction is restricted to carbonyl compounds without any a-hydrogen, which do not undergo competing aldol reactions. Thus, mainly aromatic aldehydes are used for this kind of transformation. The protocols developed for microwave applications typically involve solvent-free conditions using alumina as the solid support. Under these conditions, a significant acceleration of the reaction was achieved. 

In this case TPAP is used lor oxidation of the alcohol to a carboxylic acid. Use of TPAP is more common for oxidation to the aldehyde stage (see Chapter 5). but with a longer reaction time it is also possible to cause more complete oxidation to an acid. Since this oxidation takes place under almost neutral conditions, the nsk of racemi/ation is minimi/al relative to that with the alternative chromium-containing oxidizing agents.I<5 5 mo hr fPr)4NRu04 (TPAP), C H,CN. NMO. 65 . 

In the synthesis of specially substituted methylene diphosphines, made from secondary phosphines and carbonyl derivatives (7), a carbenium ion adjacent to trivalent phosphorus as the transition state has been discussed. The transfer of this reaction principle to primary phosphines and suitable carbonyl compound revealed a further pathway to derivatives of dicoordinated phosphorus (8). Aromatic phosphines react with carboxylic acid amide acetals under elimination of alcohol giving dialkylamino-alkylidene phosphines (Scheme 5). A modification of the synthesis... 

Unfortunately, such selective oxidations were not possible because primary alcohols form small amounts of carboxylic acid under the reaction conditions these acids efficiently inhibit oxidation, thereby accounting for the apparent Inertness of primary alcohols. When a secondary alcohol was mixed with a primary alcohol, neither was oxidized by the solid reagent in good yield. An oxidation of a secondary alcohol over crystalline KMnO would immediately cease when octanolc acid was added in tiny amounts to the benzene. The octanolc acid presumably binds to "active sites" at the crystal surface and Impedes the reaction by an unknown mechanism. 

O-tert-Butyl trichloroacetimidate, prepared in 70% yield by reacting potassium rerr-butoxide with trichloroacetonitrile, reacts with carboxylic acids and alcohols in the presence of a catalytic amount of boron trifluoride etherate at room temperature in cyclohexane-dichloromethane [Scheme 6.35], 7 The method also converts alcohols to ferr-butyl ethers (see section 4.3.2). A very similar reaction that allows /erf-butylation under essentially neutral conditions on a large scale involves reaction of a carboxylic acid with 3-4 equivalents of JV,N -di-isopropyl-Orerf-butylisourea88 [Scheme 6,36].56S9 The reaction proceeds via a tertiary carbocation ion intermediate and since capture of the cation is inefficient, excess isourea is required. The presence of alcohols is tolerated but not thiols or unhindered amines. The reaction conditions are compatible with a range of acid sensitive groups such as AMrityl derivatives and cydopentylidene acetals.90... 

The alkene reduction reactions most frequently observed are of a,3-unsaturated aldehydes, ketones, acids and esters. Examples of stereospecific reductions of acyclic substrates are given in Scheme 50.148.157-159 (j, (, e formation of (123), the double bond of (122) is reduced prior to the aldehyde function. The conversion of (124) to (125) involves oxidation of the intermediate alcohol to the carboxylic acid by bubbling air into the fermentation medium. Stereospecific reductions of a, 3-unsaturated ketones may be similarly effected (Scheme 61). The reduction of the chloro ketone (126) gives (127) initially. This epimerizes under the reaction conditions, and each enantiomer is then reduced further to (128) and (129), with the predominance of the (128) stereoisomer increasing with the size of the R-group. Reduction of ( )-(130) leads to (131) and (132). ... 

In this reaction the carboxylic acid is heated together with formamidacetals (50) in an inert solvent (benzene, etc.). The products are the ester, DMF and alcohol RK)H. Only Sn2 active groups like methyl, ethyl, benzyl etc. can be transferred. Mechanistic studies have shown that the HGA species (52) is generated from (50) via elimination of R OH under proton donation from the carboxylic acid. The carboxylate in turn undergoes an 5n2 displacement with (52) to form the ester and DMF (equation 21). 

Synthesis of trifluoromethylated compounds 152 has been achieved via ester-enolate [2,3]-Wittig and [3,3]-lreland-Claisen rearrangements. Perfluorocyclo-butane phosphonium ylides, e.g. 153, have been used as a masked fluoride anion source in their reactions with alcohols and carboxylic acids which lead to alkyl-and acyl-fluorides. Ylides 153 are also reported to cleave Si-C and Si-O bonds, cause dimerisation of fluoro-olefins, and also react with acid chlorides or other activated aromatic compounds under halogen exchange. ... 

Ester formation is a standard organic reaction between an alcohol and a carboxylic acid, which is an equilibrium reaction that has been shown to occur under catalysis by either acid or base. In polyesterification involving an organic acid, the substrate is itself the catalyst. It has been noted (Pilati, 1989) that, among the many reaction mechanisms, Scheme 1.1 is the most likely for acid-catalysed esterification, with the second reaction being the rate-determining step. 

Reaction of the C-0 and O-H Bonds Primary alcohols oxidize to carboxylic acids secondary alcohols oxidize to ketones with chromium trioxide or sodium dichromate. Tertiary alcohols do not oxidize under mild conditions. With pyridinium chlorochromate (PCC) the oxidation of primary alcohols can be stopped at aldehydes. 

Trichloro[l,3,5]triazine has also been attached to the Wang resin. Reaction of the resulting supported dichlorinated triazine with 2-(2-aminoethoxy)ethanol and further treatment again with an excess of 2,4,6-trichIoro[l,3,5]triazine afforded resin 65, which has been shown to be effective in the conversion of carboxylic acids into acid chlorides, using triethylamine as base in dichloromethane or acetone as solvent [78]. The obtained acid chlorides can be easily transformed into ester or amides after removal of the resin by filtration and addition of an alcohol or an amine. From the isolated yields of the esters or amides it could be deduced that the yields of the obtained acid chlorides are around 70-90%. However, a chiral amino acid was completely racemized under this resin treatment. 

Primary, secondary, and tertiary amines yield N-substituted oximes, hydroxy-lamines, and N-oxides, respectively [93-94]. Secondary alcohols are selectively oxidised to corresponding ketones. From primary alcohols, aldehydes or carboxylic acids are produced, under low or high conversion conditions, respectively. It is noteworthy that the oxidation of methanol is sufficiently slow, to allow its use as the solvent of choice for most reactions. The rate of oxidation of primary and secondary alcohols decreases with increasing chain length and number of substituents. The OH group position is important as well. 2-Pentanol reacts 13 times faster than 3-isomer [93]. 

Methylation of Heteroatoms. The most widely used feature of the chemistry of diazomethane is the methylation of carboxylic acids. Carboxylic acids are good substrates for reaction with diazomethane because the acid is capable of protonating the dia-zomethane on carbon to form a diazonium carboxylate. The car-boxylate can then attack the diazonium salt in what is most likely an Sn2 reaction to provide the ester. Species which are not acidic enough to protonate diazomethane, such as alcohols, require an additional catalyst, such as Boron Trifluoride Etherate, to increase their acidity and facilitate the reaction. The methylation reaction proceeds under mild conditions and is highly reliable and very selective for carboxylic acids. A typical procedure is to add a yellow solution of diazomethane to the carhoxylic acid in portions. When the yellow color persists and no more gas is evolved, the reaction is deemed complete. Excess reagent can be destroyed by the addition of a few drops of acetic acid and the entire solution concentrated to provide the methyl ester. 

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