Chlorides, acyl chlorination

Acyl chlorides Although chlorine has unshared electron pairs it is a poor electron pair donor m resonance of the type... 

Mixed chloiide alkoxides aie prepared by reaction with acyl chlorides, metal chlorides, hydrogen chloride, or chlorine (64). 

Consider the case of an acyl chloride. The chlorine is an inductive electron with-drawer and a resonance electron donor. As we saw in Chapter 17, the inductive effect is stronger. (Recall that chlorine is not a very strong resonance electron donor because the long C—Cl bond and the size difference between the 3p AO on the Cl and the 2p AO on the C result in poor overlap of these orbitals.) In addition, chloride anion is a very weak base. Overall, acyl chlorides are the most reactive of the carboxylic acid derivatives discussed here and are the least favored at equilibrium. 

Acids can be reduced to aldehydes by first converting them to a functional group that is easier to reduce than an aldehyde the acid chloride. Acid chlorides (acyl chlorides) are reactive derivatives of carboxylic acids in which the acidic hydroxyl group is replaced by a chlorine atom. Acid chlorides are often synthesized by treatment of carboxylic acids with thionyl chloride, SOCl2. 

Several alkyl thiocyanates have insecticidal properties 4 an example is isobornyl thiocyanate (49) prepared from isoborneol (50) by sequential treatment with chloroacetyl chloride and sodium thiocyanate. In this reaction, the more reactive acyl chlorine atom reacts faster than the alkyl chlorine and is consequently preferentially substituted (Scheme 29). 

Bridged Sulfonamides. The most convenient syntheses of 3-bridged pyrazole sulfonamides utilizes either a mercapto group or amine functionality as a handle to prepare the requisite sulfonamide. For example, one can prepare a pyrazole sulfonamide with many of the required substituents by the scheme depicted below. Condensation of methyl hydrazine with chloroacrylonitrile yields N-methyl-3-aminopyrazole 58 (12-13). The amine is protected by acylation. Chlorination at the 4 position with sulfuryl chloride, followed by deprotection provides 3-amino-4-chloropyrazole 59. The sulfonamide 60 is prepared by decomposition of the diazonium salt of 59 in SO2/CUCI followed by amination of the resulting sulfonyl chloride. 

Now we can continue with the retrosynthetic analysis of TM 4.6. The hardness of aryl halides with similar electronic properties of the C atom in the benzene ring corresponds to the hardness of acyl chlorides with chlorine bound to the sp C-atom of the C=0 group. The hardness of bromobenzene TM 4.6a explains the inertness against the soft malonate anion, as indicated by questionable disconnection (a) in Scheme 4.22. 

The only acid-resistant protective group for carbonyl functions is the dicyanomethy-lene group formed by Knoevenagel condensation with malononitrile. Friedel-Crafts acylation conditions, treatment with hot mineral acids, and chlorination with sulfuryl chloride do not affect this group. They have, however, to be cleaved by rather drastic treatment with concentrated alkaline solutions (J.B. Basttis, 1963 H. Fischer, 1932 R.B. Woodward, 1960, 1961). 

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... 

Acylation. In chlorinated solvents, maleic anhydride reacts with aromatic hydrocarbons (ArH) in the presence of aluminum chloride... 

Uses. The largest usage of PCl is to produce phosphonic acid, H PO, which in reaction with iminodiacetic acid and formaldehyde forms a glyphosate intermediate that is decarboxymethylated to glyphosate, an effective nonselective herbicide (see Herbicides). Phosphoms trichloride is also a convenient chlorinating reagent for producing various acyl and alkyl chlorides. 

The original commercial source of E was extraction from bovine adrenal glands (5). This was replaced by a synthetic route for E and NE (Eig. 1) similar to the original pubHshed route of synthesis (6). Eriedel-Crafts acylation of catechol [120-80-9] with chloroacetyl chloride yields chloroacetocatechol [99-40-1]. Displacement of the chlorine by methylamine yields the methylamine derivative, adrenalone [99-45-6] which on catalytic reduction yields (+)-epinephrine [329-65-7]. Substitution of ammonia for methylamine in the sequence yields the amino derivative noradrenalone [499-61-6] which on reduction yields (+)-norepinephrine [138-65-8]. The racemic compounds were resolved with (+)-tartaric acid to give the physiologically active (—)-enantiomers. The commercial synthesis of E and related compounds has been reviewed (27). The synthetic route for L-3,4-dihydroxyphenylalanine [59-92-7] (l-DOPA) has been described (28). 

The submitters have shown that these reactions proceed by dehydro-chlorination of the acid chloride to the ketene, which is then trapped by reaction with the phosphorane. The resulting betaine decomposes to the allenic ester via an oxaphosphetane. In contrast, the reaction of acid chlorides with 2 equivalents of phosphoranes involves initial acylation of the phosphorane followed by proton elimination from the phosphonium salt. ... 

The high reactivity of the acyl chlorides also reflects the polar electron-withdrawing effect of the chlorine, which more than outweighs the small 7t-donor effect. 

Acyl radicals can fragment with toss of carbon monoxide. Decarbonylation is slower than decarboxylation, but the rate also depends on the stability of the radical that is formed. For example, when reaction of isobutyraldehyde with carbon tetrachloride is initiated by t-butyl peroxide, both isopropyl chloride and isobutyroyl chloride are formed. Decarbonylation is competitive with the chlorine-atom abstraction. 

Replacement of chlorine on the pendant benzoyl group by azide is apparently consistent with antiinflammatory activity. Acylation of indomethacin intermediate with p-nitrobenzoyl chloride leads to the corresponding amide (7). Saponification ( ) followed by reduction of the nitro group gives the amine 9. The diazonium salt (10) obtained on treatment with nitrous acid is then reacted with sodium azide there is thus obtained zidomethacin (11). 

Pi peridinobenzimidazole also serves as starting material for the antipsychotic agent halopemide (69). In the absence of a specific reference, one may speculate that the first step involves alkylation with bromochloro-ethane to give halide The chlorine may then be converted to the primary amine by any of several methods such as reaction with phthalimide anion followed by hydrazinolysis. Acylation with j -fluorobenzoyl chloride then gives the desired product. 

In a similar vein, acylation of the corticoid 50 with furoyl chloride gives the diacyl derivative 51. Reduction with sodium borohydride serves to convert the 11-ketone to the alcohol 52. Hydrolysis under mild acid conditions preferentially removes the acyl group at the less hindered 21 position. The hydroxyl group in that derivative (53) is then converted to the mesylate 54. Replacement by chlorine affords mometasone (55) [12]. 

Electronically, we find that strongly polarized acyl compounds react more readily than less polar ones. Thus, acid chlorides are the most reactive because the electronegative chlorine atom withdraws electrons from the carbonyl carbon, whereas amides are the least reactive. Although subtle, electrostatic potential maps of various carboxylic add derivatives indicate the differences by the relative blueness on the C-O carbons. Acyl phosphates are hard to place on this scale because they are not used in the laboratory, but in biological systems they appear to be somewhat more reactive than thioesters. 

A number of other methods exist for the a halogenation of carboxylic acids or their derivatives. Acyl halides can be a brominated or chlorinated by use of NBS or NCS and HBr or HCl. The latter is an ionic, not a free-radical halogenation (see 14-2). Direct iodination of carboxylic acids has been achieved with I2—Cu acetate in HOAc. " ° Acyl chlorides can be a iodinated with I2 and a trace of HI. Carboxylic esters can be a halogenated by conversion to their enolate ions with lithium A-isopropylcyclohexylamide in THF and treatment of this solution at -78°C with... 

Aldehydes can be directly converted to acyl chlorides by treatment with chlorine however, the reaction operates only when the aldehyde does not contain an a hydrogen and even then it is not very useful. When there is an a hydrogen, a halogenation (12-4) occurs instead. Other sources of chlorine have also been used, among them S02Cl2 and r-BuOCl. The mechanisms are probably of the free-radical type. V-Bromosuccinimide, with AIBN (p. 912) as a catalyst, has been used to convert aldehydes to acyl bromides. 

---