Amide acyl chlorides

Many compounds contain more than one functional group Prostaglandin Ei a hormone that regulates the relaxation of smooth muscles con tains two different kinds of carbonyl groups Classify each one (aldehyde ketone carboxylic acid ester amide acyl chloride or acid anhydride) Identify the most acidic proton in prostaglandin Ei and use Table 1 7 to estimate its pK ... 

Acylation (Section 12 7 and Chapter 20) Reaction in which an acyl group becomes attached to some structural unit in a molecule Examples include the Fnedel-Crafts acylation and the conversion of amines to amides Acyl chloride (Sections 4 1 and 20 1) Compound of the type... 

The inductive effects shall now be discussed specifically with regard to the various functional moieties such as amides, acyl chlorides, alkyl esters and aryl esters ... 

Primary amides Acyl chlorides react with hexamethyldisilazane in CH2C12 at room temperature to give, after acid hydrolysis, primary amides in 60-90% yield from the carboxylic acid. 

In synthetic target molecules esters, lactones, amides, and lactams are the most common carboxylic acid derivatives. In order to synthesize them from carboxylic acids one has generally to produce an activated acid derivative, and an enormous variety of activating reagents is known, mostly developed for peptide syntheses (M. Bodanszky, 1976). In actual syntheses of complex esters and amides, however, only a small selection of these remedies is used, and we shall mention only generally applicable methods. The classic means of activating carboxyl groups arc the acyl azide method of Curtius and the acyl chloride method of Emil Fischer. 

In these cases the acyl azides formed have been used to prepare amines via Curtius rearrangement. The acyl chloride or azide intermediates can. however, also be reacted with amines or alcohols to form amides or esters. 

As a catalyst for ester and amide formation from acyl chlorides or anhydrides, 4-(di-methylamino)pyridine has been recommended (DMAP G. Hdfle, 1978). In the presence of this agent highly hindered hydroxyl groups, e.g. of steroids and carbohydrates, are acylated under mild conditions, which is difficult to achieve with other catalysts. 

Regioselectivity becomes important, if unsymmetric difunctional nitrogen components are used. In such cases two different reactions of the nitrogen nucleophile with the open-chain educt may be possible, one of which must be faster than the other. Hydrazone formation, for example, occurs more readily than hydrazinoLysis of an ester. In the second example, on the other hand, the amide is formed very rapidly from the acyl chloride, and only one cyclization product is observed. 

The chemistry of the carbonyl group is probably the single most important aspect of organic chemical reactivity Classes of compounds that contain the carbonyl group include many derived from carboxylic acids (acyl chlorides acid anhydrides esters and amides) as well as the two related classes discussed m this chapter aldehydes and ketones... 

The chemistry of carboxylic acids is the central theme of this chapter The impor tance of carboxylic acids is magnified when we realize that they are the parent com pounds of a large group of derivatives that includes acyl chlorides acid anhydrides esters and amides Those classes of compounds will be discussed m Chapter 20 Together this chapter and the next tell the story of some of the most fundamental struc tural types and functional group transformations m organic and biological chemistry... 

IS general for nucleophilic acyl substitution and well worth remembering The range of reactivities is quite large a factor of about 10 m relative rate separates acyl chlorides from amides... 

The negatively charged oxygen substituent is a powerful electron donor to the carbonyl group Resonance m carboxylate anions is more effective than resonance m carboxylic acids acyl chlorides anhydrides thioesters esters and amides... 

Reaction with ammonia and amines (Sec tion 20 14) Acyl chlorides react with am monia and amines to form amides A base such as sodium hydroxide is normally added to react with the hydrogen chio ride produced... 

Conversions of acid anhydrides to other carboxylic acid derivatives are illustrated m Table 20 2 Because a more highly stabilized carbonyl group must result m order for nucleophilic acyl substitution to be effective acid anhydrides are readily converted to carboxylic acids esters and amides but not to acyl chlorides... 

The first example in Table 20 2 mlroduces a new aspecl of nucleophilic acyl sub slilulion lhal applies nol only lo acid anhydrides bul also lo acyl chlorides Ihioeslers esters and amides Nucleophilic acyl subslilulions can be calalyzed by acids... 

Amides are readily prepared by acylation of ammonia and amines with acyl chlorides acid anhydrides or esters... 

These thermal methods for preparing amides are limited m their generality Most often amides are prepared m the laboratory from acyl chlorides acid anhydrides or esters and these are the methods that you should apply to solving synthetic problems... 

This chapter concerns the preparation and reactions of acyl chlorides acid anhydrides thioesters esters amides and nitriles These com pounds are generally classified as carboxylic acid derivatives and their nomenclature is based on that of carboxylic acids... 

Nitrogen is a better electron parr donor than oxygen and amides have a more stabilized carbonyl group than esters and anhydrides Chlorine is the poorest electron pair donor and acyl chlorides have the least stabi lized carbonyl group and are the most reactive... 

The characteristic reaction of acyl chlorides acid anhydrides esters and amides is nucleophilic acyl substitution Addition of a nucleophilic reagent Nu—H to the carbonyl group leads to a tetrahedral mtermedi ate that dissociates to give the product of substitution... 

Section 20 4 Acyl chlorides are converted to acid anhydrides esters and amides by nucleophilic acyl substitution... 

Acyl chloride Amine Amide Ammonium chlonde salt ... 

Section 20 6 Acid anhydrides are less reactive toward nucleophilic acyl substitution than acyl chlorides but are useful reagents for preparing esters and amides... 

Section 20 21 Acyl chlorides anhydrides esters and amides all show a strong band for C=0 stretching m the infrared The range extends from about 1820 cm (acyl chlorides) to 1690 cm (amides) Their NMR spectra are characterized by a peak near 8 180 for the carbonyl carbon H NMR spectroscopy is useful for distinguishing between the groups R and R m esters (RCO2R ) The protons on the carbon bonded to O m R appear at lower field (less shielded) than those on the carbon bonded to C=0... 

Amines are convert ed to amides on reaction with acyl chlorides Other acylating agents such as carboxylic acid anhydrides and esters may also be used but are less reactive... 

As a dibasic acid, malic acid forms the usual salts, esters, amides, and acyl chlorides. Monoesters can be prepared easily by refluxing malic acid, an alcohol, and boron trifluoride as a catalyst (9). With polyhydric alcohols and polycarboxyUc aromatic acids, malic acid yields alkyd polyester resins (10) (see Alcohols, polyhydric Alkyd resins). Complete esterification results from the reaction of the diester of maUc acid with an acid chloride, eg, acetyl or stearoyl chloride (11). 

H-Bond Acceptor (HBA) Acyl chlorides Acyl fluorides Hetero nitrogen aromatics Hetero oj gen aromatics Tertiary amides Tertiary amines Other nitriles Other nitros Isocyanates Peroxides Aldehydes Anhydrides Cyclo ketones Ahphatic ketones Esters Ethers Aromatic esters Aromatic nitriles Aromatic ethers Sulfones Sulfolanes... 

There are large differences in reactivity among the various carboxylic acid derivatives, such as amides, esters, and acyl chlorides. One important factor is the resonance stabilization provided by the heteroatom. This decreases in the order N > O > Cl. Electron donation reduces the electrophilicity of the carbonyl group, and the corresponding stabilization is lost in the tetrahedral intermediate. 

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