Acid chlorides nucleophilic substitution

Inorganic acid chlorides like SOCK, PC1V and PCI each react with carboxylic acids by nucleophilic substitution to form acyl chlorides (also called acid chlorides). 

Acid chlorides can be converted to acid anhydrides, esters, or amides. These reactions are possible because acid chlorides are the most reactive of the four carboxylic acid derivatives. Nucleophilic substitutions of the other acid derivatives are more limited because they are less reactive. For example, acid anhydrides can be used to synthesise esters and amides, but cannot be used to synthesise acid chlorides. 

The foregoing transacylation method was later employed in the synthesis of other highly bioactive cephamycin derivatives including CS1170 (Nakao et al., 1976 Shimizu et al., 1976). N-BOC-protected esters (425) were diacylated (426) with chloroacetyl chloride (or faster with bromo-acetyl bromide) and bis(trimethylsilyl)trifluoroacetamide in methylene chloride (40°C). Trifluoroacetic acid treatment afforded the transacylated acid (427). Nucleophilic substitution of 427 by a variety of heterocyclic mercapto compounds in the presence of 2 equiv of sodium hydroxide gave a series of semisynthetic cephamycins for which antibacterial data were given vide infra). 

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

Step 1 The Boc protected amino acid is anchored to the resin Nucleophilic substitution of the benzylic chloride by the carboxylate anion gives an ester... 

The second most important nucleophilic substitution in pyridazine A-oxides is the replacement of a nitro group. Nitro groups at the 3-, 4-, 5- and 6-position are easily substituted thermally with a chlorine or bromine atom, using acetyl chloride or hydrobromic acid respectively. Phosphorus oxychloride and benzoyl chloride are used less frequently for this purpose. Nitro groups in nitropyridazine A-oxides are easily replaced by alkoxide. The... 

Replacement of one of the benzene rings in a fenamic acid by pyridine interestingly leads to a compound which exhibits antiliypertensive rather than antiinflammatory activity. Preparation of this agent starts with nucleophilic aroniatic substitution of anthranilic acid (8) on 4-chloropyri-dine. The product (9) is converted to its acid chloride (10), and this is condensed with piperidine. There is thus obtained ofornine (11) f31. 

The net effect of nucleophilic acyl substitution is the replacement of the leaving group by the entering nucleophile. We ll see in Chapter 21, for instance, that acid chlorides are rapidly converted into esters by treatment with alkoxide ions (Figure 4). 

A nucleophilic acyl substitution reaction involves the substitution of a nucleophile for a leaving group in a carboxylic acid derivative. Identify the leaving group (Cl- in the case of an acid chloride) and the nucleophile (an alcohol in this case), and replace one by the other. The product is isopropyl benzoate. 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

Conversion of Acid Halides into Acids Hydrolysis Acid chlorides react with water to yield carboxylic acids. This hydrolysis reaction is a typical nucleophilic acyl substitution process and is initiated by attack of water on the acid chloride carbonyl group. The tetrahedral intermediate undergoes elimination of Cl and loss of H+ fo give the product carboxylic acid plus HC1. 

Conversion of Acid Halides into Anhydrides Nucleophilic acyl substitution reaction of an acid chloride with a carboxylate anion gives an acid anhydride. Both symmetrical and unsymmetrical acid anhydrides can be prepared in this way. 

Problem 21.9 How might you prepare the following esters using a nucleophilic acyl substitution reaction of an acid chloride ... 

Conversion of Acid Chlorides into Alcohols Reduction Acid chlorides are reduced by LiAJH4 to yield primary alcohols. The reaction is of little practical value, however, because the parent carboxylic acids are generally more readily available and can themselves be reduced by L1AIH4 to yield alcohols. Reduction occurs via a typical nucleophilic acyl substitution mechanism in which a hydride ion (H -) adds to the carbonyl group, yielding a tetrahedral intermediate that expels Cl-. The net effect is a substitution of -Cl by -H to yield an aldehyde, which is then immediately reduced by UAIH4 in a second step to yield the primary alcohol. 

Notice in both of the previous reactions that only "half" of the anhydride molecule is used the other half acts as the leaving group during the nucleophilic acyl substitution step and produces acetate ion as a by-product. Thus, anhydrides are inefficient to use, and acid chlorides are normally preferred for introducing acyl substituents other than acetyl groups. 

The Curtius rearrangement, like the Hofmann rearrangement, involve migration of an -R group from the G-O carbon atom to the neighboring nitro gen with simultaneous loss of a leaving group. The reaction takes place on heat ing an acyl azide that is itself prepared by nucleophilic acyl substitution of m acid chloride. 

We ve already studied the two most general reactions of amines—alkylation and acylation. As we saw earlier in this chapter, primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to control and often give mixtures of products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution reaction with an acid chloride or an acid anhydride to yield an amide (Sections 21.4 and 21.5). Note that overacylation of the nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the starting amine. 

Many of the reactions of amines are familiar from past chapters. Thus, amines react with alkyl halides in S 2 reactions and with acid chlorides in nucleophilic acyl substitution reactions. Amines also undergo E2 elimination to yield alkenes if they are first qualernized by treatment with iodomethane and then heated with silver oxide, a process called the Hofmann elimination. 

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