Acids halides

Acid chlorides are prepared from carboxylic acids by reaction with thionyl chloride (SOCI2), as we saw in the previous section. Similar reaction of a carboxylic acid with phosphoms tribromide (PBr3) yields the acid bromide. 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compoimds 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, by NH2 to yield an amide, or by R to yield a ketone. 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 Add 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 to give the product carboxylic acid plus HCl. 

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Because HCl is formed during the hydrolysis, the reaction is often carried out in the presence of a hase such as pyridine or NaOH to remove the HCl and prevent it from causing side reactions. 

Acid halides are compounds structurally related to oxy-aeids by substitution of halogen atoms for OH groups. The acid chlorides are the most important  

Acid Halides, Carbonates, Anhydrides and Metallic Carbonyls 

Anhydrides (open-chain) Anhydrides Cyclic (5-ring) 

In esters, acids and ketones the substitution of a chlorine or bromine atom on an a-carbon atom to the carbonyl group results in a shift in the C=0 frequency to a higher value. With a direct attachment of the halogen to the carbonyl group, a considerably bigger shift in this direction is to be expected, and tliis is what is found in practice. 

Phosgene gas absorbs at 1828 cm , and acetyl chloride [1,2] and acetyl bromide at 1802 cm and 1812 cm respectively. An increase in the size of the remainder of the molecule does not appear to affect this frequency significantly, and phenylacetyl chloride absorbs at 1802cm [1,2], whilst we have found a value of 1790 cm for n-octoyl chloride. Similar results are given in Raman spectra for oxalyl chloride (1776 cm ) and. propionyl chloride (1786 cm ). 

Recently the carbonyl frequencies of some forty aromatic acid halides (benzoyl, naphthoyl and phthaloyl) have been given by Al Jallo et al [31]. Their values are in general agreement with the ranges listed above. 

As we have mentioned, acid hahdes are the most reactive of the carboxylic acid derivatives, becanse they produce the most stable leaving gronps. Therefore, we can prepare any of the other carboxylic acid derivatives from acid hahdes. So, it is critical that you know how to make an acid halide. It is very common to encounter a synthesis problem where you will need to make an acid hahde at some point in the synthesis. 

To make an acid halide, it wonld be nice if Cl would attack a carhoxyhc acid directly, expehing HO as a leaving group  

But this doesn t work, because HO is less stable than Cl , so this would be an uphill battle. CX is not going to expel HO . So, we must first convert the OH group into a different group that CAN be expelled by CH. So, here is our strategy  

Thionyl chloride, SOCI2, is a common reagent used to execute both steps of this strategy  

The carboxylic acid functions as a nucleophile and attacks the S=0 bond. The S==0 bond is then re-formed (by expelling a chloride ion), followed by a proton transfer step. The net resnlt of these three steps is the conversion of an OH gronp into a better leaving group, thereby achieving the first objective. 

The kinetics and mechanism of the dechlorination of N-aryl 2-oxo-2-phenylamino-cthanchydrazonyl chlorides (89) in triethylamine in aqueous dioxane at 25 °C giving the oxanilic hydrazidc (91) and 1,4-diaryl-1,2,4,5-tctrazinc (92) have been examined.80 The slow step of this interesting reaction is considered to be the breakup of the nitrilium imide (90). 

The NH acidities of some sterically hindered ureas, namely the ureido esters (93), have been reported.81 The kinetics and mechanism of the alkaline hydrolysis of urea and sodium cyanate, NaCNO, have been studied at a number of temperatures.82 Urea hydrolysis follows an irreversible first-order consecutive reaction path. Tetrahedral intermediates are not involved and an elimination-addition mechanism operates. Sodium cyanate follows irreversible pseudo-first-order kinetics. The decomposition of the carcinogen /V-mcthyl-/V-nitrosourea (19) was dealt with earlier.19 The pyrolysis of (V-acetylurea goes by a unimolecular first-order elimination reaction.83 

There are five papers on carbamate chemistry of interest.6,84-87 The mechanism of the reaction in MeCN of /V-mcthyl-Af-phenylcarbamoyl chlorides (94) with benzyl-amines is believed to be XN2 based on Hammett p values, a cross-interaction constant pxy of —0.14, ku/ko values for the (V-deuteriated benzylamines all 1, and low activation enthalpies.84 The aminolysis of /Miitrophenyl A -phenylcarbamates in acetonitrile involving the I 1 (7) was discussed earlier.6 Solvolysis-decomposition of Af-l-adamantyl-/V-/ -tolylcarbamoyl chloride (95) in hydroxylic solvents involves a facile slow ionization (SN1 mechanism) giving a cation which eliminates ArNCO to 

Two papers have appeared on hydroxylamines.88,89 Methylation of X -phenylhydr-oxylamine PhNHOH with methyl 4-methoxyphenylsulfonate (102) and related sulfonates in DMSO gave alkylation of the O atom rather than the N atom. The crucial role of the zwitterion (103) is examined.88 The fragmentation of the A -nitrosohydr-oxylamines (104) is stepwise and not concerted and NO is liberated in the reactions.89 These conclusions were reached from kinetic, millimetre-wave spectroscopy and 17 O NMR studies. 

Hydroxamic acids have been the subject of six papers.4 9 94 Earlier the operation of the x-effect in the reaction of/ -nitrophcnyl acetate with benzohydroxamates in aqueous MeCN was discussed.43 The conformational behaviour of series of mono- (105) and di-hydroxamic acids (106) in MeOH, DMSO, and chloroform and in the solid state has been examined with IR and NMR spectroscopy.90 X-ray crystal structure determinations of (105 X = Me, R = Me) and the monohydrate of glutarodihydroxamic acid (106 n = 3, R = H) together with ab initio MO calculations for several hydrated and non-hydrated acids have been performed. The cis-Z conformation of the hydroxamate groups is preferentially stabilized by H-bonding with water. 

A kinetic smdy of the acylation of ethylenediamine with benzoyl chloride (110) in water-dioxane mixtures at pH 5-7 showed that the reaction involves mainly benzoylation of the monoprotonated form of ethylenediamine. Stopped-flow FT-IR spectroscopy has been used to study the amine-catalysed reactions of benzoyl chloride (110) with either butanol or phenol in dichloromethane at 0 °C. A large isotope effect was observed for butanol versus butanol-O-d, which is consistent with a general-base-catalysed mechanism. An overall reaction order of three and a negligible isotope effect for phenol versus phenol- /6 were observed and are consistent with either a base- or nucleophilic-catalysed mechanism. Mechanistic studies of the aminolysis of substituted phenylacetyl chlorides (111) in acetonitrile at —15 °C have revealed that reactions with anilines point to an associative iSN2 pathway.  

The proposed formation of 2,5-benzothiazocine-l,6-diones (114 R = Pr) from the reaction of phthaloyl chloride (112) and amidino thioamides (113 R = Pr, Ar = 4-O2NC6H4, 4-MeOC6H4) in pyridine has been disproved. Instead, supported by an X-ray structure, the products have been shown to be spiro[4,4]lactones (116 R = Pr, Ar = 4-O2NC6H4, 4-MeOCeH4). The proposed mechanism of formation of 

The extended (two-term) Grunwald-Winstein equation has been applied to the solvolyses of ethyl chloroformate (117) and ethyl chlorothioformate (118). For each substrate, there is evidence for two competing reaction channels. Solvolysis 

A bicyclic urea (123) was an unexpected product of the reaction between pyrrolidine and the phenyl ester of 2-cyano-l,4,5,6-tetrahydro-l-pyridinecarboxylic acid (124 R = Ph) the corresponding methyl ester (124 R = Me) reacted, as expected, to give the product of Michael addition (125). ° The better leaving ability of phenoxide vs methoxide presumably tilted the reaction towards the substitution rather than the addition product, although thiols (e.g. PhSH) underwent only the addition reaction. 

Solvolyses of the A(A -diphenylcarbamoylpyridinium ion (126) were found to be subject to specific and/or general base catalysis, which could be eliminated by addition of perchloric acid or increased, especially in fluoroalcohol-containing solvents, by addition of pyridine. The uncatalysed solvolyses in aqueous methanol and aqueous ethanol involve a weakly nucleophilically assisted (/ = 0.22) heterolysis and the solvolyses in the pure alcohols are anomalously slow.  

In unsaturated lactones, when the double bond is adjacent to the —O—, a strong C=C absorption is observed in the 1685-1660 cm 1 region. 

1 C=0 Stretching Vibrations Anhydrides display two stretching bands in the carbonyl region. The two bands result from asymmetrical and symmetrical C=0 stretching modes. Saturated acyclic anhydrides absorb near 1818 and 1750 cm-1. Conjugated acyclic anhydrides show absorption near 1775 and 1720 cm-1 the decrease in the frequency of absorption is caused by resonance. The higher frequency band is the more intense. 

C=Ost 1820-1750 Chlorides, strong in Raman, weak to medium. Of narrow or medium width, for bromides and iodides at lower wavenumber 

C-CO St 1000-800 1000-900 aliphatic, assignment uncertain 900-800 aromatic, assignment uncertain 

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Chloral hydrate Acid halides Halogeno-hydrocarbons Ammonium salts )... 

In a generalized sense, acids are electron pair acceptors. They include both protic (Bronsted) acids and Lewis acids such as AlCb and BF3 that have an electron-deficient central metal atom. Consequently, there is a priori no difference between Bronsted (protic) and Lewis acids. In extending the concept of superacidity to Lewis acid halides, those stronger than anhydrous aluminum chloride (the most commonly used Friedel-Crafts acid) are considered super Lewis acids. These superacidic Lewis acids include such higher-valence fluorides as antimony, arsenic, tantalum, niobium, and bismuth pentafluorides. Superacidity encompasses both very strong Bronsted and Lewis acids and their conjugate acid systems. 

Most of the known acylations have been described for 2-aminothiazoles, the activity of the acylating agent being in the order, acid halides > anhydrides > esters > acids — amides. 

Thiazolecarboxylic acid hydrazides are prepared by the same general methods used to prepare amides, that is, by treating acids, esters, amides, anhydrides, or acid halides with hydrazine or substitued hydrazines. For example, see Scheme 21 (92). The dihydrazides are obtained in the same way (88). With diethyl 2-chloro-4,5-thiazoledicarboxylate this reaction gives the mono hydr azide monoester of 2-hydrazine-4,5-... 

Acid halides —CO—halogen Haloformyl -carbonyl halide... 

Acid Halides (Lewis Acids). AH metal haUde-type Lewis catalysts, generally known as Friedel-Crafts catalysts, have an electron-deficient central metal atom capable of electron acceptance from the basic reagents. The most frequendy used are aluminum chloride and bromide, followed by... 

Solid Superacids. Most large-scale petrochemical and chemical industrial processes ate preferably done, whenever possible, over soHd catalysts. SoHd acid systems have been developed with considerably higher acidity than those of acidic oxides. Graphite-intercalated AlCl is an effective sohd Friedel-Crafts catalyst but loses catalytic activity because of partial hydrolysis and leaching of the Lewis acid halide from the graphite. Aluminum chloride can also be complexed to sulfonate polystyrene resins but again the stabiUty of the catalyst is limited. 

Mote stable catalysts ate obtained by using fluorinated graphite or fluorinated alumina as backbones, and Lewis acid halides, such as SbF, TaF, and NbF, which have a relatively low vapor pressure. These Lewis acids ate attached to the fluorinated soHd supports through fluorine bridging. They show high reactivity in Friedel-Crafts type reactions including the isomerization of straight-chain alkanes such as / -hexane. 

Naphthenyl alcohols are formed by reduction of the acids or their simple esters. They are valuable as surfactants, solvents, and components of lubricants. The acid halides are of value mainly as chemical intermediates (1). 

Substituted Amides. Monosubstituted and disubstituted amides can be synthesized with or without solvents from fatty acids and aLkylamines. Fatty acids, their esters, and acid halides can be converted to substituted amides by reaction with primary or secondary aLkylamines, arylamines, polyamines, or hydroxyaLkylamines (30). Di- -butylamine reacts with oleic acid (2 1 mole ratio) at 200—230°C and 1380 kPa (200 psi) to produce di-A/-butyloleamide. Entrained water with excess -butylamine is separated for recycling later (31). 

Esterification. Esters are formed by the reaction of ethanol with inorganic and organic acids, acid anhydrides, and acid halides. If the inorganic acid is oxygenated, eg, sulfuric acid, nitric acid, the ester has a carbon—oxygen linkage that is easily hydrolyzed (24—26). 

Ethyl alcohol also reacts with acid anhydrides or acid halides to give the corresponding esters. 

In most other reactions the azolecarboxylic acids and their derivatives behave as expected (cf. Scheme 52) (37CB2309), although some acid chlorides can be obtained only as hydrochlorides. Thus imidazolecarboxylic acids show the normal reactions they can be converted into hydrazides, acid halides, amides and esters, and reduced by lithium aluminum hydride to alcohols (70AHC(12)103). Again, thiazole- and isothiazole-carboxylic acid derivatives show the normal range of reactions. 

Properly substituted isoxazolecarboxylic acids can be converted into esters, acid halides, amides and hydrazides, and reduced by lithium aluminum hydride to alcohols. For example, 3-methoxyisoxazole-5-carboxylic acid (212) reacted with thionyl chloride in DMF to give the acid chloride (213) (74ACS(B)636). Ethyl 3-ethyl-5-methylisoxazole-4-carboxylate (214) was reduced with LAH to give 3-ethyl-4-hydroxymethyl-5-methylisoxazole (215) (7308(53)70). 

The second general method is the aluminum halide-catalyzed reaction of acid halides with ethylene to give g-halo ketones which are subsequently converted to ketals. ... 

Organic halides, organic acid halides, esters and salts... 

Perfluoroalkyl or -aryl halides undergo oxidative addition with metal vapors to form nonsolvated fluonnated organometallic halides and this topic has been die subject of a review [289] Pentafluorophenyl halides react with Rieke nickel, cobalt, and iron to give bispentafluorophenylmetal compounds, which can be isolated in good yields as liquid complexes [290] Rieke nickel can also be used to promote the reaction of pentafluorophenyl halides with acid halides [297] (equation 193)... 

The treatment of enamines with acid halides which possess no a hydrogens results in the simple acylation of the enamine (7,12,62-67). If the acid halide possesses an a hydrogen, however, ketenes are produced in situ through base-catalyzed elimination of hydrogen chloride from the acid halide. The base catalyst for this reaction may be the enamine itself or some other base introduced into the reaction mixture such as triethylamine. However, if the ketene is produced in situ instead of externally, there still remains the possibility of a side reaction between the acid halide and the enamine other than the production of ketene (67,84). 

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