Derivatives Acids

Derivatives of carboxylic acids contain the acyl group. 

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

Acyl chlorides are Bronsted-Lowry acids, and, just like aldehydes, they donate an a-hydrogen. The electron withdrawing chlorine stabilizes the conjugate base more than the lone hydrogen of an aldehyde, making acyl chlorides significantly stronger acids than aldehydes. 

Acid chlorides are the most reactive of the carboxylic acid derivatives because of the stability of the Cl leaving group. 

Acid Derivatives.— 2,2 5,6-Di-0-isopropylidene-2-C-hydroxymethyl-L-gulono-1,4-lactone/ AT-(2-chloroethyl)-D-gluconamide (n.d.)/ 5-azido-5-deoxy-AriV-diethyl-l,2-0-isopropylidene-3-(9-methanesulphonyl-P-L-iodoruranuron-amide/ 3,6-anhydro-7-(4-bromobenzoyl)-2-deoxy-4,5-0-isopropylidene-D-ahro-heptononitrile/ sodium o-isoascorbate, and reductic acid (2,3-di-hydroxycycIopent-2-enone). . 

Cyclitols, Alditols, and otho Acyclic Derivatives.—epi-Inositol.SrClj/ dl-mannitol, ° l,3,4,6-tetra-0-acetyl-2,5-0-methylene-D-mannitol/ o-mannitol l,2 3,4 5,6-tris(phenylboronate)/ l-(l-S-ethyl-l-thio-D-arabinitol-l-yl)-5-fluorouracil and its 2, 3, 4, 5 -tetra-acetate/ 4,5,6-tri-0-benzoyl-2,3-di S-ethyl- 

Kirfel, G. Will, and G. Wulff, Acta Cryst., 1977, B33,637. 

3-dithio-D-allose diethyl dithioacetal/ 6-chloro-9-(l-S-ethyl-l-thio-D-gluc-itol-1 -yl)purine, 2,5-di-O-acetyl-1,4 3,6-dianhydro- 1,6-dithio-D-iditol R,R) disulphoxide/ and 4-0-p-D-galactopyranosyl-L-rhamnitol.  

NudeosideSy Nucleotides, and their Derivatives.—3, 5 -Di-0-acetyluridine/ 5-0-acetyl-l -(2-deoxy-a-D-cryt/iro-pentofuranosyl)uracil/° 2-thiouridine, 4-deoxy-3-deazauridine/° S-nitrouridine, 2, 3 -C -isopropylideneuridine, 2, 3 -0-(S)-methoxymethyleneuridme, ° the cyclonucleosides (653 R = H and Me), 0 3 2 -0-acetyluridine 3, 5 -(benzyl phosphate)/ (uridine 5 -phos-phate)(2,2 -dipyridylamine)copper(ii).  

Acid Derivatives.—Calcium DL-glycerate, potassium D-glucarate, calcium L-ascorbate (comparison of two analyses), 2,3 4,6-di-0-isopropylidene-L- 

Lopez-Castro, and R. M rquez, Acta Cryst., 1978, B34,2341. 

R Amino Acid Alkaloid a-Hydroxy-L-amino acid 1 L-amino acid 2 Reference 

CHj /CHj CHj Alanine Ergotamine Ergosine Alanine Alanine Phenylalanine Leucine Stoll (1918, 1945) Smith and Timmis (1937) 

CHjChC Leucine Ergostine a-Aminobutyric acid Phenylalanine Schlientz et ai (1964) 

Naturally Occurring Lysergic Acid Derivatives Other Than Peptides 

Ergonovine (ergobasine, ergometrine) CH3 1 —HN—Cm-H 1 CH2OH Dudley and Moir (1935) Stoll and Burckhardt (1935) Kharasch and Legault (1935) Thompson (1935) 

Carboxylic Acid Derivatives.—Calcium D-glucarate, D-glucaro-l,4-lactone, calcium sodium -D-galacturonate, methyl (l,2,3,4-tetra-0-acetyl-j8-i galacto-pyranosyl)uronate, calcium D-araW o-hexulopyranosonate, the 2-C-benzyl derivative (326) from L-ascorbic acid (prepared by treating L-ascorbic acid with benzyl chloride and then with methanol), and 2-(4-bromophenylhydrazono)-dehydro-L-ascorbic acid.  

Ru2ic-ToroS and B. Kojic-Prodic, Acta Cryst., 1976, B32, 2333. 

The compounds presented were, historically, actually derived from carboxylic acids. The concept of a derivative has stayed although many of these materials, prepared in other ways, are precursors to carboxylic acids. 

A common variant, used when the carbonyl group can best be considered a substituent (e.g., on a ring), is to simply append the word carbonyl to the name of the alkane for example, the unit cydohexanecarbonyl is 

Carboxylic acid chlorides are, generally, reactive compounds. However, they can be important intermediates between carboxyUc acids and other materials, and the conversion of an acid to this derivative is accompanied, in the IR, by loss of the -OH absorption of the carboxyhc acid (2500-3300 cm ) and a shift of the C=0 to shorter wavelength (for the carboxylic acid, the intense C=0 absorption is expected 

Cl (acid chloride) 0 X CHf a Ethanoyl chloride (acetyl chloride) 

0 y (acid anhydride) O- CHs 0 0 CH3- 0- CH3 Ethanoic anhydride (acetic anhydride) 

Acid chlorides, anhydrides, amides, esters, and ketoacids are some examples of acid derivatives. An acid derivative has an acyl group which is attached to a functional group. If the functional group attached to the acyl group is a hydroxyl group, then it is a carboxylic acid. 

Nitrile is also considered as a carboxylic acid derivative, even though it has no acyl group. 

An acid derivative can be converted to the corresponding carboxylic acid by hydrolysis. 

This hydrolysis reaction occurs by nucleophilic substitution 

The mechanisms associated with reactions of these compounds have already been introduced (Section 19-7), so this chapter mainly presents additional examples of reactions that follow familiar patterns. The most important new points involve (1) the relative reactivities of these derivatives and (2) how to convert each kind of derivative into any of the others, for synthetic purposes. 

20-1 Relative Reactivities, Structures, and Spectra of Carboxylic Acid Derivatives Comparisons of physical properties. 

Details of the chemistry of the four major carboxylic acid derivatives, plus nitriles, which are relatives of amides. 

Acyl halides are very useful in synthesis because (1) they are easily made from carboxylic acids (Section 

Copper mandelates react with pho ene and then pyridine to give 1,3-dioxoIan-2,4-diones, and application of this reaction to the pentafluoroKxnnpound [CeFe -C(0H)Me-C08]2Cu yields the substituted dioxolan (127) (62%). Compounds of this type give derivatives of the parent acid when they are treated with amines or alcohols, and may be polymerized to polyesters details of these reactions are awaited. Pentafluorobenzoic acid is converted into pentafluoroiodobenzene by treatment with iodine in the presence of a peroxide initiator, and certain penta-fluorobenzamido-derivatives of 4-fluorophenol, e.g. (128), prepared by conventional multistage syntheses from the parent phenol, are claimed to be useful as colour-formers in photographic emulsions. i 

Further cidnp studies of the intermediates involved in the decomposition of bispentafluorobenzoyl peroxide (see also p. 369) have been made, but a fair assessment of the value of the work remains difficult in view of the authors continued failure to relate it adequately to the abundance of chemical studies of this 

21-1 lUPAC name first then common name 

21-2 An aldehyde has a C—H absorption (usually 2 peaks) at 2700-2800 cm A carboxylic acid has a strong, broad absorption between 2400-3400 cm The spectrum of methyl benzoate has no peaks in this region. 

21-3 The C—O single bond stretch in ethyl octanoate appears at 1170 cm while methyl benzoate shows this absorption at 1120 and 1280 cm  

The HNMR corroborates the assignment. The IH multiplet at 6 5.8 is the vinyl H next to the carbonyl. The 2H multiplet at 5 6.3 is the vinyl hydrogen pair on carbon-3. The 2H singlet at 5 4.8 is the amide hydrogens. 

The CNMR confirms the structure two vinyl carbons and a carbonyl. 

Archibald etal, US Patent 6,329,362 (December 11, 2001) Assignee Celltech Therapeutics Limited Utility Treatment of Immune or Inflammatory Disorders 

A suspension of 4-hydroxybezaldehyde (157.5 mmol), 2,6-dichlorobenzylbromide (150 mmol) and K2CO3 in 150 ml DME was stirred overnight at ambient temperature. The mixture was filtered, evaporated, and the residue dissolved in 500 ml diether ether. It was washed with 100 ml apiece water and brine, dried, and evaporated under reduced pressure. The solid was re-crystallized in diisopropylether to give the product in 85% yield, mp = 70-71 °C. H-NMR and elemental analysis data supplied. 

N-Acetyl-D-thioproline-0-(2,6-dichlorobenzyl)-(Z)-didehydotyrosine methyl ester 

The product from Step 2 (2.06 mmol) was dissolved in 10 ml THE and added drop wise to a stirred suspension of NaH (2.27 mmol) in 5 ml THE at ambient temperature. After 15 minutes, the product from Step 1 (2.1 mmol) dissolved in 5 ml THE was added, the mixture stirred for several hours and was then quenched with 1 ml water. The organic phase was evaporated and the residue purified by column chromatography on silica with CH2Cl2/methyl alcohol, 95 5, yielding a Z/E geometric isomer ratio of 76 24, respectively. The desired Z-isomer was isolated by re-crystallization, mp = 189-190 °C. H-NMR and mass spectrum data supplied. 

Both for primary and secondary a-lluorocstcrs, the a-protons absorb slightly downfield of analogous aliphatic ketones and somewhat upheld of analogous aromatic ketones. 

The only structure with an ester, four CH2 groups, and a ring, is 8-valerolactone  

Functional Group Transformation by Nucleophilic Acyl Substitution Reactions 

Detailed hydrolysis studies of the carboxylic acid derivatives by Bender (1960) and others (Samuel and Silver, 1965) provided the initial evidence for formation of the tetrahedral intermediate. These investigators found that when hydrolysis studies were conducted in 0-labeled water, incorporation of 0 into unhydrolyzed substrate occurred. 

The exchange of label could be rationalized through the tetrahedral intermediate if expulsion of water is competitive with expulsion of the leaving group, X . The 

The base-catalyzed mechanism (Bac2) proceeds via the direct nucleophilic addition of OH to the carbonyl group. Base catalysis occurs because hydroxide ion is a stronger nucleophile than water. 

Although neutral hydrolysis of carboxylic acid esters does occur, the base-catalyzed reaction will be the dominant pathway in most natural waters. Generally, acid hydrolysis will dominate in acidic waters with pHs below 4. 

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White crystals, m.p. 191°C. A barbituric acid derivative. The sodium salt is administered orally as a sedative. 

Lecithins are fatty acid esters of glycero-phosphoric acid derivatives. Commercially glycerophosphoric acid is used to prepare the medicinal glycerophosphate salts, c.g. the calcium salt. 

MCPB, 4-(4-chloro-2-methylphenoxy)-butyric acid, CiiHisClOj. A compound in itself harmless to plants, but when absorbed and translocated in the cells, CnHuClOs is converted to a powerful herbicide, and results in the death of the plant. Acts as a selective weedkiller. Other butyric acid derivatives used commercially are 2,4-Dg and 2,4,5-Tb, the butyric acid analogues of 2,4-D and 2,4,5-T. ... 

By oxidation with permanganate it forms pinonic acid, C,oH,<503, a monobasic acid derived from cyclobutane. With strong sulphuric acid it forms a mixture of limonene, dipentene, terpinolene, terpinene, camphene and p-cymene. Hydrogen chloride reacts with turpentine oil to give CioHijCl, bomyl chloride, artificial camphor . 

It is now applied more widely to include malonic acid derivatives, such as diethyl monoethyl-malonate, ethyl cyanacetate, etc. Various amines may be used as catalysts, and usually the most effective is piperidine (hexahydro-pyridine) a mixture of piperidine and pyridine, or pyridine alone, is also often used. 

Lassaigne s test is obviously a test also for carbon in the presence of nitrogen. It can be used therefore to detect nitrogen in carbon-free inorganic compounds, e.g., complex nitrites, amino-sulphonic acid derivatives, etc., but such compounds must before fusion with sodium be mixed with some non-volatile nitrogen-free organic compound such as starch... 

The procedure is not usually applicable to aminosulphonic acids owing to the interaction between the amino group and the phosphorus pentachloride. If, however, the chlorosulphonic acid is prepared by diazotisation and treatment with a solution of cuprous chloride in hydrochloric acid, the crystalline chlorosulphonamide and chlorosulphonanilide may be obtained in the usual way. With some compounds, the amino group may be protected by acetylation. Sulphonic acids derived from a phenol or naphthol cannot be converted into the sulphonyl chlorides by the phosphorus pentachloride method. 

If the benzoyl derivative is soluble in alkali, precipitate it together with the benzoic acid derived from the reagent by the addition of hydrochloric acid filter and extract the product with cold ether or light petroleum (b.p. 40-60°) to remove the benzoic acid. 

Derivatives with 3-nitrophthalic anhydride. 3-Nitrophthalic anhydride reacts with primary and secondary amines to yield nitro-phthalamic acids it does not react with tertiary amines. The phthalamic acid derived from a primary amine undergoes dehydration when heated to 145° to give a neutral A -substituted 3-nitrophthalimide. The phthalamic acid from a secondary amine is stable to heat and is, of course, soluble in alkali. The reagent therefore provides a method for distinguishing and separating a mixture of primary and secondary amines. 

Acrylic acid derivatives. Acrylic esters polymerise readily under the influence of oxygen, peroxides, light or heat to give colourless, glass-Uke plastics. 

The residue in the flask is either a solution or a suspension of the potassium salt of the acid derived from the ester in diethylene glycol. Add 10 ml. of water and 10 ml. of ethyl alcohol to the residue and shake until thoroughly mixed. Then add a drop or two of phenolphthalein and dilute sulphuric acid, dropwise, until just acid. Allow the mixture to stand for about 5 minutes and then Alter the potassium sulphate. Use the clear filtrate for the preparation of a sohd derivative or two of the acid (see Section 111,85,4). 

The derivative selected in any particular instance should be one which clearly singles out one compound from among all the possibilities and thus enables an unequivocal choice to be made. The melting points of the derivatives to be compared should differ by at least 5-10°. Whenever possible, a derivative should be selected which has a neutralisation equivalent as well as a melting point (e.g., an aryloxyacetic acid derivative of a phenol. Section IV,114,4, or a hydrogen S nitrophthalate of an alcohol. Section 111,25,5). 

Activated Adds Chern. Soc. Rev. 1983, 12, 129 Angew. Chern. fnt. Ed. Engl. 1978, 17, 569. RC02F4 "activated acid" carboxylic acid derivative (ester, amide, etc.)... 

Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

Acid derivatives are made directly from acids or by conversion from other acid derivatives depending on their stabihty. The most important are esters (RCOiEt), amides (RCO2NR2), anhydrides (RCOO COR) and add clilorides (RCOCI). Arrange these in an order of stabilily, the most reactive at the top of the list, the most stable at the bottom. 

This gives us a complete chart for acid derivatives. 

Carboxyl and nitrile groups are usually introduced in synthesis with commercial carboxylic acid derivatives, nitriles, or cyanide anion. Carbanions can be carboxylated with carbon dioxide (H.F. Ebel, 1970) or dialkyl carbonate (J. Schmidlin, 1957). 

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

The conversion of carboxylic acid derivatives (halides, esters and lactones, tertiary amides and lactams, nitriles) into aldehydes can be achieved with bulky aluminum hydrides (e.g. DIBAL = diisobutylaluminum hydride, lithium trialkoxyalanates). Simple addition of three equivalents of an alcohol to LiAlH, in THF solution produces those deactivated and selective reagents, e.g. lithium triisopropoxyalanate, LiAlH(OPr )j (J. Malek, 1972). 

Reduction of Aldehydes, Ketones, and Carboxylic Acid Derivatives... 

Several structures of the transition state have been proposed (I. D. Williams, 1984 K. A. Jorgensen, 1987 E.J. Corey, 1990 C S. Takano, 1991). They are compatible with most data, such as the observed stereoselectivity, NMR measuiements (M.O. Finn, 1983), and X-ray structures of titanium complexes with tartaric acid derivatives (I.D. Williams, 1984). The models, e. g., Jorgensen s and Corey s, are, however, not compatible with each other. One may predict that there is no single dominant Sharpless transition state (as has been found in the similar case of the Wittig reaction see p. 29f.). 

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. 

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