None
The action of ethylamine, diethylamine and triethylamine on chloracetic acid produces ethyl glycocoll, diethyl glycocoll, and triethyl glycocoll, triethyl betaine, (CaH5)3NCH2COO. Similarly to betaine itself, the latter compound is converted by destructive distillation into diethylamine acetic ethyl ester, b.p. 177°, the iodo- ethyloxide of which is reconverted by silver oxide into triethyl betaine. Similar changes have been observed with dimethyl ethyl betaines and methyl diethyl betaine 388 ORGANIC CHEMISTRY (B. 35, 584), The homologous betaines can also be prepared by the addition of iodo-alkyls to dialkylamine acetonitriles and the subsequent saponification of the iodo-alkylate formed. The dialkylamino-acetonitriles just referred to can be synthesized from formaldehyde, hydrocyanic acid, and dialkylamines (B. 36, 4188). CH3I | | (C2H6)2NCH2CN > (C2H5)2N(CH3I)CH2CN > (C2H6)2N(CH3)CH2COO. Formyl Glycocoll, Formamine Acetic Acid, HCONH.CH2COOH, m.p. 151- 152°, is prepared by heating glycocoll with formic acid to 100° ; and from glyoxylic acid and ammonia (B. 36, 2525 ; 38, 3999). 2CHO.COOH+NH3=HCO.NH.CH2COOH+CO2+H2O. Glyoxylic Acid. Formyl Glycine. Acetyl Glycocoll, A cetamine Acetic Acid, Aceturic ^a^,CH3CONH.CH2COOH, m.p. 206°, results from the action of acetyl chloride on silver glycocoll ; from acetamide and monochloracetic acid ; from ammonia and a mixture of glyoxylic and pyroracemic acids (B. 36, 2526). It is readily soluble in water and alcohol, and behaves like a monobasic acid (B. 17, 1664). More important are hippuric acid or benzoyl glycocoll (q.v.) and glycocholic acid (q.v.) which have already been referred to in connection with glycocoll, and which will be dealt with later. They are similarly constituted to aceturic acid. Naphthalene Sulpho glycine, C10H7Sp2NH.CH2COOH, m.p. 156° (B. 35, 3779). Iminodiacetic acid and nitrilotriacetic acid bear the same relation to glycocoll that di- and trihydroxy-ethylamine sustain to hydroxy-ethylamine : NH2CH2CO2H NH(CH2.CO2H)2 N(CH2.CO2H)3 NH2CH2CH2OH NH(CH2CH2OH)2 N(CH2CH2OH)3. These compounds are formed on boiling monochloracetic acid with concen- trated aqueous ammonia (A. 122, 269 ; 145, 49 ; 149, 88). Iminodiacetic Acid, NH(CH2CO2H)2, m.p. 225°, forms salts both with acids and bases, whilst Nitrilotriacetic Acid, N(CH2CO2H)3, cannot unite with acids. Imino-acetonitrile, NH(CH2CN)2, m.p. 75°, and Nitrilo-acetonitrile, N(CH2CN)3, m.p. 126°, are obtained from methylene cyanhydrin and ammonia (A. 278, 229 ; 279, 39). Dimethyl Dicyano-methyl Ammonium Bromide, (CH3)2NBr(CH2CN)2, is prepared from dimethylamino-acetonitrile and bromacetonitrile (B. 41, 2123). Alanine, a-Aminopropionic Acid, CH3CH(NH2)CO2H, or CH3CH- (NH3)COO, m.p 293° with decomposition on being rapidly heated, is derived from a-chloro- and a-bromo-propionic acid by means of ammonia ; also from aldehyde-ammonia, hydrocyanic acid, and hydro- chloric acid ; or aldehyde, ammonium cyanide, and hydrochloric acid (B. 41, 2061), by hydrolysis of the intermediate a-amino-propioni- trile, CH3CH(NH2)CN. This can be precipitated as sulphate from an alcoholic solution of aldehyde-ammonia and hydrocyanic acid by sulphuric acid, and may be resolved into its optically active components by formation of the tartrates (p. 384) (C. 1904, I. 360). Synthetic alanine, of which the name refers to its connection with aldehyde- ammonia, is the racemic or [d+f] form of a-amino-propionic acid. It crystallizes from water in aggregates of hard needles ; it is soluble in 3 parts of water, less easily in alcohol, and not at all in ether. On being quickly heated, it melts with partial decomposition, partially into ethylamine and CO2, and partially into aldehyde, CO, and ammonia (B. 25, 3502 ; 32, 245). Alanine Ethyl Ester, CH3CH(NH2)COOC2H6, b.p.u 48° ; hydrochloride is easily soluble in alcohol, contrary to glycine ester hydrochloride (B. 34, 442). Alanine Chloride Hydro- chloride, CH3CH(NH3C1)COC1, is a white crystalline powder (B. 38, 2917). ^-Naphthalene Sulpho-alanine, C10H7SO2.NHCH(CH3)COOH, m.p. 152°. Benzoyl Alanine, C6H5CO.NHCH(CH3)COOH, m.p. 165°, is resolved by means of brucine into the components [d- and I]- benzoyl alanine, which, on hydrolysis, yield /- and d- alanine. d-Alanin also occurs as a product of hydrolytic decomposition of many proteins ; from fibroin of silk it is obtained by means of its ester. It forms NITROGEN DERIVATIVES OF THE HYDROXY-ACIDS 389 rhombic crystals, which decompose at 297°. In aqueous solution its rotatory power is small, [aff=+2'7° ; in hydrochloric acid solution it is much greater, [a]^= + io-4° (B. 39, 462 ; 40, 3721). Nitrous acid converts ^-alanine into the ordinary ^-lactic acid (p. 364) ; on the other hand, nitrosyl bromide (p. 384) changes ^-alanine into /-bromopro- pionic acid, which with ammonia yields /-alanine. This, with nitrosyl bromide, gives rf-bromopropionic acid, which ammonia converts into ^-alanine (Walden's inversion, p. 364 ; B. 40, 3704). ^-Alanine is also obtained by the reduction, with sodium amalgam, of /-fl-chloralanine, C1H2CH(NH2)COOH. The ester of this acid is obtained from /-serine ester (/3-hydroxy-a-aminopropionic ester) and PC15 ; since /-serine can be converted into rf-glyceric acid and this into /-tartaric COOH acid, the formula of tf-alanine must be NH2 — C — CH3 (B. 40, 3717) (see also H the considerations on the configuration of the carbohydrates). lodomethane and sodium hydroxide solution convert if-alanine into l-Trimethyl Propionic Betaine, (CH3)3NCH(CH3)COO, which also results from the interaction of rf-a-bromopropionic acid and trimethylamine (B. 40, 5000). Triethyl Propionic Betaine is formed by hydrolysis of the iodo-ethylate of Diethylaminopropionitrile, (C2H6)2NCH(CH3)CN, b.p.27 81°, the reaction product of lactic acid nitrile and diethylamine (B. 36, 4188). CTT CH Iminodipropionic Acid, HOCcP^11 — NH — CH^-COOH' contains two asymmetric carbon atoms, giving rise to two optically inactive forms, m.p. 255°, corresponding with meso tartaric acid, and m.p. 235°, corresponding with racemic acid. The monamides, m.ps. 332° and 210°, are formed by the prolonged inter- action of dilute hydrocyanic acid and aldehyde-ammonia at ordinary tempera- tures, together with iminodipropionimide, NH[CH(CH3)CO]2NH, m.p. 186°, alanine, and other substances (B. 39, 3942). Higher homologues of a-amino-aeids are prepared mainly by the general methods (i) from a-halogen-fatty acids and (5) from the nitriles of a-hydroxy- acids and ammonia. » a-Amino-n-butyric Acid, CH3CN2CH(NH2)COOH, m.p. 307° with decomposi- tion, is resolved by means of the morphine salt of the benzoyl-deriva.tive, d-acid [0^=4-8°, /-acid [a]^=-7-9°; ethyl ester, b.p.n 61° (B. 33, 2387; 34, 443); nitrile (B. 41,2062). a-Amino-isobutyric Acid, (CH3)2C(NH2)CO2H, sublimes at 280° without melting, and is formed also by oxidation of diacetonamine sulphate ; nitrile, b.p.12 50°, is prepared from acetone and ammonium cyanide (B. 33, 1900 ; 39, 1181, 1726). a-Amino-valeric Acid, CH3[CH2]2CH(NH2)COOH, is formed also by oxidation of benzoyl coniine (B. 19, 500) ; ethyl ester, b.p.8 68° (B. 35, 1004). » a-Amino-isovaleric Acid, V aline, Butalanine, (CH3)2CHCH(NH2)COOH, decomposes 298°. The inactive acid results from a-bromisovaleric acid and ammonia; ethyl ester, b.p.8 63°. Formyl Valine, HCONHCH(C3H7)COOH, m.p. 140-145°, is produced by heating valine and formic acid together. It is resolved by means of its brucine salts, the /- and d-formyl valine, yielding l-V aline and d-V 'aline. The latter, m.p. 315°, [a]^=-f-6'42°, in aqueous solution and +28-8° in hydrochloric acid, is a decomposition product of protein bodies — in the germs of the lupin, horn, casein, from protamines, and from the pancreas of oxen. /-Valine has a much sweeter taste than d- valine (B. 39, 2320). a-A mino Methyl Ethyl Acetic Acid, (C2H5)(CH3)C(NH2)COOH, is prepared from methyl ethyl ketone, etc. ; ethyl ester, b.p.20 66° (B. 35, 400 ; 39, 1189). a-Aminocaproie Acids. a-Amino-n-caproic Acid, CH3[CH2]3CH(NHa)COOH, is prepared from a-bromo-n-caproic acid and ammonia. It is resolved into its optical component by means of its benzoyl-derivative (B. 33, 2381 ; 34, 3764). * a-Amino-isocaproic Acids. Leucine. — (CHs^CHCH^CH^NEyCOOH, optically active leucine. Leucine (from ACVKOS, glistening white, referring to the appearance of the scaly crystals) occurs in different animal fluids, in the pancreas, in the spleen, in the lymph-glands, and 3QO ORGANIC CHEMISTRY is physiologically very important. It is formed by the decay of pro- teins, or when they are boiled with alkalis and acids. It is prepared by heating horn, the dried cervical ligament of oxen, or from casein with dilute sulphuric acid. Its purification is best effected byconver- sion into the ester (B. 34, 446 ; C. 1908, I. 1633). Leucine is also obtained from vegetable proteins such as that of the lupin. Strecker (1848) showed that when it was treated with nitrous acid it passed into a hydroxycaproic acid, leucic acid, m. p. 73°, p. 366. The naturally occurring leucjjie, m.p. 270°, sublimes unaltered when carefully heated, but decomposes on rapid rise of temperature into amylamine and CO2. It forms shining leaflets, which feel greasy to the touch. It is soluble in 48 parts of water and 800 parts of hot alcohol. It is optically active, the free acid rotating the plane of polarization to the left, whilst its hydrochloride rotates it to the right. When heated with alkalis it becomes inactive and is then identical with that synthesized from isovaleraldehyde, ammonium cyanide, and hydrochloric acid ; or by decomposing the condensation product of isobutyraldehyde and hippuric acid (A. 316, 145) : NH4NC /NH, NHS C,H6C:N v (CHS),CHCH2CHO > (CH8)2CHCH8CH< •< >C XCOOH O.CCK || (CH8)2CHCH The resolution of the rac .-benzoyl leucine, (CH ,) 2CHCH 2CH (NHCOC.H 5 )COOH, by means of cinchonine produces benzoyl d-leucine (laevo-rotatory) and benzoyl l-leucine (dextro-rotatory), from which hydrolysis liberates d-leucine (dextro- rotatory), and l-leucine (laevo-rotatory) identical with the naturally occurring substance. It is more convenient to resolve by means of \d-\-l\-formyl leucine, HCO.NHCH(C4H9).COOH (B. 38, 3997). ^-Leucine is also obtainable from /-leucine by Penicillium glaucum ; its hydrochloride is laevo-rotatory (B. 24, 669 ; 26, 56 ; 33, 2370). Leucine Ethyl Ester, b.p. 196°. Acetyl Leucine, m.p. 160° (B. 34, 433). Leucine Chloride Hydrochloride, C4H,CH(NH3C1)COC1 (B. 38, 615). a-Amino-sec.-butyl Acetic Acid, Isoleucine, C^8>CH.CH(NH2)COOH, con- tains 2 asymmetric carbon atoms, and therefore gives rise to 4 optically active components and 2 racemic forms. A d-isoleucine, m.p. 280°, with decomposition, [a]^=-f-9'7 in water, +36*8 in hydrochloric acid, occurs together with leucine in beet-root melasse, and as a decomposition product of proteins. Synthetically, rac.-isoleucine is produced by reduction of a-hydroximino-isobutyl acetic acid (p. 410), and from a-bromo-sec.-butyl acetic acid and ammonia. ^-Isoleucine is prepared from ^-valeric aldehyde by the cyanhydrin synthesis (B. 40, 2538 ; 41, 1453). a-Amino-csnanthic Acid, CH8[CH2]4CH(NH2)CO2H (B. 8, 1168). a-Amino caprylic Acid. CH8[CH2]5CH(NH2)CO2H (A. 176, 344). a-Aminopalmitic Acid, CH8[CH2]1SCH(NH2)CO2H (B. 24, 941). a-Aminostearic Acid, CH8[CHa]16CH- (NH2).C02H, m.p. 221° (B. 24, 2395). DIPEPTIDES AND POLYPEPTIDES As has repeatedly been mentioned, the simple a-amino-acids, such as glycocoll, alanine, valine, and leucine, occur together, and also with such complicated substances as serine, proline, cystine, asparagine, lysine, arginine, histidine, and tyrosine, as products of the hydrolytic decomposition of proteins. It is probable that these breakdown bodies are united with one another in the protein molecule through their amide groups. This question has been attacked both synthetically and analytically (E. Fischer : Untersuchung iiber Amino-sauren, Polypeptide und Pro- teine, Berlin, 1906 ; Th. Curtius : Verkettung von Amino-sauren) (J. pr. Ch. [2] 70, 57). In synthesis, the esters, chlorides, and azides of NITROGEN DERIVATIVES OF THE HYDROXY-ACIDS 391 the aminocarboxylic acids themselves or of the substances which go to produce them, have been employed ; and by their means the aminacyl residue has been substituted into the amino-group of other ammo -acids, and the process has been successively repeated. The aminacyl aminocarboxylic acids produced have been named by E. Fischer, peptides because of their comparability with the natural pep- tones (protein products of digestion). They are classified according to the number of the connected amino-acids — di-, tri-, tetra-peptides, etc. i. Dipeptides and their inner anhydrides, cyclic double amides, ay- Dioxopiperazines. a-Amino-esters, when heated or even on standing in aqueous solution, part with alcohol and form dimolecular cyclic amides, corresponding with the lactides (p. 385) : The fundamental substance, to which such compounds can be referred as being oxygen substitution products, is diethylene diamine or piper azine (p. 336), whence the names ay-diketo-, diaci-, or dioxo- piperazine : Diglycollide. ay-Dioxopiperazine. Piperazine. When warmed for a short time with hydrochloric or hydrobromic acid, or when shaken with dilute alkalis, the dioxopiperazine is split up into the dipeptide, which when melted, or when its ester is heated, easily changes into the dioxo- piperazine : •KTTTX'CO CHa«w .»JTT _._ — ^. HOCO — CH2v. -vru NH<CH2— CO>NH ^^ H2NCH2— CO>NH* ay-Dioxopiperazine. Glycyl Glycine (the simplest dipeptide). Unsymmetrically substituted dioxopiperazines, such as leucyl glycine anhydride, can be split into two different dipeptides, from which the same anhydride can be reformed. 2. Dipeptides and polypeptides are obtained in the following manner : — (a) Chlorides of the a-halogen fatty acids react with a-amino-acids to form a-halogen acylamino-acids, which with am- monia give dipeptides. These by further treatment with a-halogen acyl chlorides and ammonia yield tripeptides, and these tetrapeptides, pentapeptides, and so on : NH3 ClCH2CaNHCH2COOH - > NH2CH2CO.NHCH2COOH - > Chloracetyl Glycine. Glycyl Glycine. NH3 C1CH2CO.NHCH8CO.NHCH8COOH - > Chloracetyl Glycyl Glycine. NH8CH2CO.NHCH2CO.NHCH2COOH. . Diglycyl Glycine. The esters of the halogen acylamino-acids are easily converted by ammonia into dipeptide anhydrides, dioxopiperazines (see above). (&) Again, the halogen-acyl-amino acids can be converted into their chlorides, united with other amino-acids and then be acted on by ammonia : C4H9CHBrCO.NHCH2COCl - > Bromisocaproyl Glycine Chloride. NH3 C4H,CHBrCO.NHCH2CO.NHCH2COOH - >• Bromisocaproyl Glycyl Glycine. C4H,CH(NH2)CO.NHCH,COOH. Leucyl Glycyl Glycine. 392 ORGANIC CHEMISTRY (c) Finally, the chlorides of the amino-carboxylic acid hydrochlorides can be employed with advantage (p. 383). The azides, also, of the acyl amino-acids such a's hippuryl azide, C6H6.CONHCH2CON3, unite with amino-acids, splitting off N3H, and easily forming acyl derivatives of the di- and polypeptides. 3. Higher polypeptides result from heating the methyl esters of lower peptides : 2NH2CH2CO.NHCH2CO.NHCH2CO2CH3 - >• Diglycyl Glycine Ester. NH 2CH 2CO. [NHCH 2CO] 4NHCH 2CO 2CH 3. Pentaglycyl Glycine Ester. 4. Analytically, some di- and polypeptides have been produced by the partial hydrolysis of proteins, such as silk fibroin, elastin, gliadine, gelatin, by means of cold fuming hydrochloric acid ; or by tryptic digestion, as, for instance, glycyl alanine, alanyl leucine, alanyl diglycyl tyrosine (?) (B. 40, 3544). Properties. — Di- and polypeptides are mostly soluble in water ; less soluble are, for instance, the penta- and ^exa-peptides of glycocoll, which are, however, soluble in acids and alkalis, showing that the amino-acid character is preserved. The peptides are mostly insoluble in alcohol. They decompose, with or without melting, above 200°, the dipeptides forming mostly dioxo-piperazine. The " biuret reaction " — a red or violet coloration with an alkaline solution of copper sulphate — which is characteristic for the naturally occurring proteins, is given by many of the higher artificial peptides, such as Curtius' biuret base (triglycyl glycine ester). The behaviour of di- and poly-peptides with pancreatic juice is of importance, since some are hydrolyzed by it and some are not, e.g. [d+/]-alanyl glycine is split up, yielding rf-alanine and glycine, whilst glycyl alanine is not. All peptides" are completely hydrolyzed by hydrochloric acid. Glycyl Glycine, NH2CH2CO.NHCH2COOH, decomposes 215-220°; ethyl ester, m.p. 89°, easily parts with alcohol, yielding Glycine Anhydride, Diglycolyl Diamide, ay-Dioxopiperazine, ay-Diacipipera- xine, NHCH2CO.NHCH2CO, m.p. 275°, is also easily prepared from glycocoll ester in aqueous solution. By boiling for a short time with strong hydro- chloric acid or by shaking with «/x sodium hydroxide, it is easily split up into glycyl glycine (B. 38, 607). Sarcosine Anhydride, CH3NCH2CON(CH3)CH2CO, m.p. 150°, b.p. 350°, is obtained by heating sarcosine (B. 17, 286). Glycyl [d +/]- Alanine, NH2CH2CO.NHCH(CH3)COOH, m.p. 227° with decom- position, is prepared from chloracetyl alanine and ammonia ; anhydride, m.p. 245° with decomposition, is formed from chloracetyl alanine ester and ammonia. Glycyl d- Alanine and its anhydride are obtained by the hydrolysis of silk fibroin (B. 40, 3546). d-A lanyl Glycine, CH3CH(NH2)CO.NHCH2COOH, m.p. 235° with decomposition, is produced from rf-alanyl chloride hydrochloride and glycocoll ester (B. 38, 2914). Alanyl Alanine. CH3CH(NH2)CO.NHCH(CH3)COOH, m.p. 276° with decom- position, is obtained by the decomposition by alkali of its anhydride. Di-lactyl Di-amide, Lactimide, NH<cO CH(CH)^>NH' m'p- 275°' The anhydride is best obtained from alanine ester at 180°. It is reduced by sodium and alcohol to jB8-dimethyl piperazine (B. 38, 2376; C. 1902, I. 631). I- Alanyl ^-Alanine is produced from /-bromopropionyl d-alanine and ammonia, [a]^=— 68-5° ; its ester on parting with alcohol is converted into the optically inactive meso- anhydride (see Introduction, p. 32). a-Aminobutyryl a-Aminobutyric Acid, NH2CH(C3H7)CO.NHCH(C3H7)COOH, 2 stereoisomeric forms, m.p. 273° with decomposition, and m.p. 257° with decom- position, is prepared from bromobutyryl aminobutyric acid ; anhydride, m.p. 267° (A. 340, 187). Leucyl Leucine, NH2CH(C4H9)CONHCH(C4H9)COOH, m.p. 270° with decom- position, is formed from bromisocaproyl leucine and ammonia ; anhydride leu- cinimide, m.p. 271°, is prepared from leucine ester (B. 37, 2491). Diglycyl Glycine, NH2CH2CO.NHCH2CO.NHCH2COOH, m.p. 246° with decomposition, is prepared from chloracetyl glycyl glycine and ammonia ; methyl ester, m.p. 111°, when heated passes into pentaglycyl glycine ester, slightly soluble in water (B. 39 472). tilTROGEN DERIVATIVES OF THE CARBOXYLIC ACIDS 393 Triglycyl Glycine is prepared from chloracetyl diglycyl glycine ; ester, NH2CH2CO.NHCH2CO.NHCH2C9.NHCH2COOC2H8, the " biuret base," is formed together with a little glycine anhydride, when glycocoll is left to stand in solution in absolute ether. Benzoyl Triglycyl Glycine, m.p. 217°, is formed also from hippuryl glycine azide and glycyl glycine (B. 37, 1284 ; 2486). Leucyl Pentaglycyl Glycine, C4H,CH("NH2)CO[NHCH2COJ6NHCH2COOH, is prepared from bromisocaproyl pentaglycyl glycine and ammonia (B. 39, 461). j8-AMINOCARBOXYLIC ACIDS Of this group of substances little is known. They form neither cyclic double amides, as do the a-amino-acids, nor cyclic simple amides or lactams like the higher amino-acids, except beta'ine. fi-Aminopropionic Acid, fi-Alanine, CH2(NH2)CH2.COOH, m.p. 196° with decomposition into ammonia and acrylic acid. It is isomeric with alanine (p. 388), and is prepared from j8-iodopropionic acid and ammonia, from jS-nitro- propionic acid, from isoserine (a-hydroxy- /?-aminopropionic acid) by reduction with hydriodic acid and phosphorus (B. 35, 3796) ; but most conveniently from CH2.CCX succimide, I >NH, by the Hofmann inversion (p. 159) by means of bromine CH2.CCX and alkali (B. 26, R. 96 ; C. 1905, I. 155 ; 1906, I. 818) » methyl ester, b.p.15 58° ; amide, m.p. 40° ; j$-Dimethylamine Propionic Methyl Ester, (CH3)2NCH2- CH2COOCH3, b.p. 154°, is prepared from j8-iodopropionic ester and dimethyl- amine. Heat partially transforms it into its isomer fi-Trimethyl Propiobetaine, (CH3)3NCH2CH2COO, which in its turn undergoes transformation on melting into trimethylamine acrylate, CH2:CHCOONH(CH3)3 (B. 35, 584). fi-Aminobutyric Acid, CH3CH(NH2)CH2CO2H, m.p. 156° (approx.), is prepared by heating crotonic acid with ammonia. It is a very hygroscopic crystalline mass (J. pr. Ch. [2] 70, 204). fi-Amino-isovaleric Acid, (CH3)2C(NH2)CH2COOH, is produced by the reduction of the corresponding nitro-acid (p. 382.). y-, 8-, €-, and £-Aminocarboxylic Acids. The most important characteristic of the y- and S-amino-carboxylic acids as well as of some of the higher acids is that when heated they part with water and yield cyclic, simple acid amides or lactams (p. 395). (i) Piperidine derivatives, when oxidized, have yielded some of these acids (Schotten). (2) Potassium phthalimide affords a general synthetic method : ethylene bromide or trimethylene bromide, acted on by it, changes to w-brom- ethyl phthalimide and o>-brompropyl phthalimide (Gabriel). These bodies, as is known, have also been utilized in the preparation of hydroxalkylamines (p. 328). In order to get y- and S-amino-carboxylic acids by their aid they are caused to react with sodium malonic ester and sodium alkyl malonic ester. The conden- sation product resulting in this manner is decomposed on heating it with hydro- chloric acid, into phthalic acid, y-, or 8-amino-carboxylic hydrochloride, carbon dioxide and alcohol (B. 24, 2450) : C.H4{M£g>NCH2CH2CH2Br w-Bromethyl Phthalimide. I w-Brompropyl Phthalimide. 2H5)a C. 2H C6 y-Aminobutyric Acid. fi-Aminovaleric Acid. Similarly, €-bromo-amyl phthalimide can be made to yield e-phthalimido- amyl malonic ester, and this converted into £-aminoheptylic acid (B. 35, 1367). 394 ORGANIC CHEMISTRY Or, benzoyl amino-amyl iodide (p. 365) may easily be made to react with potassium cyanide or sodium malonic ester, the product from which is hydrolyzed. (3) A general method for the preparation of 8-, e-, and £-amino-acids and their lactams, is the transformation of the oximes of cyclic ketones, such as penta-, hexa-, and hepta-methylene ketoximes (Vol. II.). These are converted by con- centrated sulphuric acid into isoximes or lactams (comp. Beckmann's inversion, p. 227) which can be decomposed into their respective amino-acids (Wallach, A. 312, 171): CH2.CH2V CHo.CH2.NH | >C:NOH > | | ; CH2.CH/ CH2.CII2.CO CH2.CH2.C:NOH CH2.CH2.CH2 v I I > I >NH CH2.CH2.CH2 CH2.CH2.CO < CHa.CH2.CH2\ CH2.CH2.CH2.NH | >C:NOH > | | CH2.CH2.CH/ CH2.CH2.CH2.CO For considerations on the course of these transformations and on the Becnmann inversion generally, see A. 346, 27. y-Aminobutyrie Acid, Piperidic Acid, m.p. 183-184°. It is formed (i) when piperidyl urethane, 'CH2<^2^2>N.CO2C2H6, is oxidized with nitric acid (B. 16, 644) ; (2) by means of potassium phthalimide ; either — (a) by the double decomposition of bromethyl phthalimide with sodium malonic ester (see above), or (b) from «o-bromopropyl phthalimide and potassium cyanide, and decomposing the phthalyl y-aminobutyric nitrile (B. 23, 1772). The acid is most conveniently obtained from its lactam (p. 395) by means of barium hydroxide solution (B. 33, 2230). y-Dimethyl Aminobutyric Methyl Ester, (CH3)2N[CH2]3COOCH3, b.p. 172°, -is prepared from y-chlorobutyric ester and dimethylamine. On heating it is decomposed into butyrolactone and trimethylamine. The isomeric y-Tri- methyl Butyrobetafne, (CH3)3N[CH2]3COO, which is obtained by exhaustive methylation of butyrolactam in alkaline solution (B. 35, 617) undergoes the same decomposition. y-Amino valeric Acid, CH3CH(NH2)CH2CHaCO2H, m.p. 193°, results from the decomposition of phenylhydrazone laevulinic acid by sodium amalgam (B. 27, 2313). Both y-amino-acids, when heated, pass into lactams. 8 -Amino-n- Valerie Acid, Homopiperidic Acid, NH2(CH2)4CO2H, m.p. 158°, is produced by the putrescence of fibrin, flesh, and gelatin (B. 31, 776). The benzoyl derivative of this acid and also Sulpho-S-aminovaleric Acid, SO2[NH(CH2)4CO2H]2, m.p. 163°, are formed by the oxidation of benzoyl piperi- dine, CH2<£^2£^2>NCOC6H6, and of sulphopiperidine by KMnO4 (B. 21, 2240) ; the acid is prepared from phthalimido-propyl malonic diethyl ester (B. 23, 1769). By method 2 (p. 393) the following are also prepared : a-Methyl S-Amino-n- valeric Acid, NH2.CHaCHaCHaCH(CH,)CO2H, m.p. 168° ; a-Ethyl S-Amino-n- valeric Acid, NH2CHaCHaCHaCH(CaH6)CO2H, m.p. 200-200-5°; a-Propyl 8- Amino-n-valeric Acid, NHaCHaCHaCH2CH(C8H7)CO2H, m.p. 186° (B. 24, 2444). A j8- or y-M ethyl S-Amino-n-valeric Acid, m.p. 134°, with decomposition, is pre- pared from its lactam (p. 396) (A. 812, 185). 8-Trimethyl Valerobetaine, (CH3)3N[CH2]4COO, of which the hydrobromide is obtained from y-bromopropyl malonic esters and trimethylamine, by hydrolysis, and the action of hydrobromic acid. The substance itself is converted by heat into the isomeric ^Dimethylamine Valeric Methyl Ester, (CHs)2N[CH2]4CObCH8, b.p. 186-189°, together with 8-valerolactone (B. 37, 1853). 8-Amino-n-octanic Acid, Homoconiinic acid, C?H7CH(NH2)[CH2]3CO2H, m.p. 158°. The benzoyl compound is obtained by oxidation of benzoyl conine with KMn04 (B. 19, 504). e-Aminocaoroie Acid, c-Leucine, NH2[CHa]6CO2H, m.p. 204°, is obtained NITROGEN DERIVATIVES OF THE CARBOXYLIC ACIDS 395 from phthalimidobutyl malonic ester, from c-benzoyl aminocapronitrile, C,H6- CONH[CH2]5CN (B. 40, 1839), or from its lactam, the hexamethylene ketone- isoxime, by boiling with hydrochloric acid. Similarly, various acids can be prepared from their lactams, such as methyl e-aminocaproic acid and methyl isopropyl e-aminocaproic acid. €-Aminocaproic acid is oxidized by permanganate to adipic acid ; nitrous acid produces two isomeric hexenic acids instead of the expected e-hydroxycaproic acid (p. 375) (A. 343, 44). £-Amino-n-heptylic Acid, NH2[CH2]6COOH, m.p. 187° with decomposition, is also prepared from its lactam, the isosuberone oxime (q.v.) ; also from the phthalimido-amyl malonic ester, or benzoyl amyl aminomalonic ester (B. 40, 1840). On heating, it no longer yields a simple lactam (B. 35, 1369). Per- manganate oxidizes it to pimelic acid (A. 343, 44). lo-Aminocapric Acid, NH2[CH2]9COOH, m.p. 188°, is prepared from azelaic monoamido-acid, NH2CO[CH2]9COOH, and alkali hypobromite ; benzoyl deriva- tive, m.p. 97°. These products are not identical with those obtained from benzoyl dekamethylene imine (p. 365) by oxidation (C. 1906, II. 1126). y, §-, £-, and £- Lactams: Cyclic Amides of the y-, S-, «-, and £-Amino-carboxylic Acids. These bodies are formed when the y-, 8-, and c-amino-acids are heated to their point of fusion, when they then lose water, and undergo an intramolecular condensation. Some of them have been obtained by the reduction of the anil chlorides of dibasic acids — e.g. succinimide and dichloromalem anil chloride. The names y-lactams and S-lactams have been given them to recall the lactones. They are cyclic acid- amides. Just as the lactones, under the influence of the alkali hydroxides, yield hydroxy-acid salts, So ihe lactams, when digested with alkalis or acids, pass into salts of the amido-acids, from which they can be formed on the application of heat. Further, the y- and o-lactams bear the same relation to the imides of the y- and S-alkylene diamines as the lactones to the oxides of the y- and 8-glycols (p. 371). These relations are apparent in the following arrangement : CH2CH2OH CH2CH2OH CH2CH2NH2 CH2CH2NH2 /CHaCH2OH CH2< XCH2CH2OH xCH2CH2NH, !N:H2CH2NHa Tetramethylene Glycol. Tetramethylene Diamine. Pentamethylene Glycol. Pentamethylene Diamine. CH,CHtv CH2CH/ Tetramethylene CH2CH2X 1 >NH CH2CH/ Tetramethylene XH.CH.v ^CHaCH/ Pentamethylene XCH2CH2V CH2< >NH XCH2CH/ Pentamethylene Imine, Oxide, Imine, Oxide. Piperidine. Tetrahydrofur- Tetrahydro- furane. pyrrol. CHaCO v 1 >o CH2CH/ CH2CO v 1 >NH CH2CH/ /CH2CO v CH2<( >0 \CH2CH/ ,CH2CO v CH2< >NH XCH2CH/ •v-Butyrolactone. •y-Butyrolactam, fi-Valerolactone. fi-Valerolactam, a-Pyrrolidone. a-Piperidone. CH2CO y-Lactams : y-Butyrolactam, a-Pyrrolidone, I CH2CH unites with water to form a crystalline hydrate, C^HyON+HaO, m.p. 35°. It is best prepared from succinimide by electrolytic reduction (B. 33, 2224). Isopropyl pyrrolidone, C4H6ON.C3H7, b.p. 222°, is similarly prepared from isopropyl- succinimide, and n-Phenyl Butyrolactam, C4H6ON.C,H6, from succinanil. It can also be produced by reduction of dichloromalem anil dichloride (A. 295, 396 ORGANIC CHEMISTRY 27). Pyrrolidone possesses feebly basic and acid properties. Its sodium salt reacts with iodomethane, producing n-methyl pyrrolidone, C4H8O.NCH3, an oil. When boiled with P2S6 in xylol, pyrrolidone is converted into Thiopyrrolidone, C4H7SN, the potassium salt of which, with iodomethane, gives Thiopyrrolidone ^-Methyl Ether, b.p. 170° (B. 40, 2831, 2848) : CH,— NH . CH2— NH x CH2 - N. | )>CO - > | >CS - > I >CSCH,. CH2— CH/ CH2— CH/ CH2— CH/ Pyrrolidone. Thiopyrrolidone. ^-Methyl Ether. The ^t-methyl ether, on reduction, breaks up into methyl mercaptan and pyrrolidine (p. 335). CHa— CH(CH,k •y-Valerolactam, ^-Methyl Pyrrolidone, \ /NH, m.p. 37°, can be CHa - - - CO/ distilled without decomposition. By reduction with sodium and amyl alcohol it is changed into a-methyl pyrrolidine (p. 335) (B. 23, 1860, 2364, 3338 ; 23, CH,— CH2X 708). pf}-Dimethyl Pyrrolidone, aa-Dimethyl Butyrolactam, \ >NH, m.p. C(CH8)2C(X 66°, b.p. 237° (C. 1899, I. 874). S-Lactams : B-Valerolactam, a-Ketopiperidine, a-Oxopiperidine, a-Piperi- done, CHa<cH2 CH ^NH' m'P- 39~4°°' b-P- 256°» is obtained, amongst other methods, by the isomerization of cyclopentanone oxime (A. 312, 179). a- Methyl 8-Valerolactam, 0-Methyl Piperidone, CH2<>NH, m.p. 55°, is isomeric with the ft- or y-Methyl Piperidone, m.p. 87°, obtained from j6-methyl cyclopentanone oxime (A. 312, 186). a-Ethyl 8- Valerolactam, f$- Ethyl Piperidone, Valerolactam, p-Propyl Piperidone, CH2<'>NH, m.p. 59°, b.p. 274°. §-n-Octanolactam, Homoconiinic Acid Lactam, CH2<CHaCO >NH , m.p. 84°. CH2.CH— C3H7 The amino-acids are not poisonous, but their y- and 8-lactams are violent, strychnine-like poisons, affecting the spinal cord and producing convulsions. These bodies will be met with again among the pyrrole and pyridine derivatives, as tetrahydropyrrole and piperidine compounds (Vol. II.). CH2.CH2.COX c-Caprolactam, \ /NH, m.p. 69°, is obtained by the trans- CH2.CH2CH/ formation of cyclohexanone oxime (A. 312, 187) ; and from €-aminocaproic acid (p. 394). It acts, physiologically, as a nerve poison. /J-Methyl cyclo- hexanone oxime and also oximes of the terpene ketones menthone and tetrahydro- carvone can be converted into two methyl e-caprolactams , m.ps. 44° and 105° (structure, A. 346, 253) and two isomeric methyl isopropyl e-caprolactams, menthone isooxime, m.p. 120°, and tetrahydrocarvone isooxime, m.p. 104° (A. 312, 197. 203). CH2.CH2.CH2.NH t-Heptolactam, \ , m.p. 25°, b.p.. 156°, is prepared from CH2.CH2.CH2CO heptamethylene ketoxime or suberone oxime. It can be broken down into J-aminoheptylic acid (p. 395), which on warming with nitrous acid is converted into e£-heptylenic acid (A. 312, 205). u. Fatty A<5id Nitramines, Nitramine Acetic Acid, CO2HCH2.NHNO2, m.p. 103°, is prepared by hydrolyzing its ethyl ester (m.p. 24°), which results on treating nitrourethane acetic ester, C2H6O2C.N(NO2).CH2CO2C2H5, with ammonia (B. 29, 1682). 12. Isonitramine Fatty Acids are obtained in the form of their sodium salts when sodium isonitramine acetoacetic esters and sodium isonitramine mono-alkyl acetoacetic esters, or the explosive dinitroso-compounds of the hydrazo-fatty acids, such as hydrazoisobutyric acid (p. 416), are acted on by UNSATURATED HYDROXY-ACIDS 397 the alkalis (B. 29, 667 ; A. 300, 64). They are converted into hydroxylamino- fatty acids by dilute mineral acids (p. 381). Acid reducing agents change them to amino-f atty acids, whilst alkaline reducing agents produce diazo-acids (p. 402) and hydrazino-acids (see below). Isonitramine Acetic Acid, CO2HCH2N<^QTT, is a syrupy liquid. Isonitra- mine Isobutyric Acid, CO2HC(CH3)2.N(NO)OH, m.p. 94°. Their lead salts dissolve with difficulty. 13 (a). Hydrazino-fatty Acids are obtained, together with the diazo-acids, when the isonitramine-fatty acids are acted on with alkaline reducing agents. Their carbamide derivatives are obtained in the form of nitriles when hydrocyanic acid becomes added to the ketone semicarbazides. Hydrazino- acetic Acid, NH2NH.CH2COOH, m.p. 152°, with decomposition (B. 31, 164). (See also Amidohydantome Acid Ester and Carbamidohydrazo-acetic Ester.) a-Hydrazinopropionic Acid, Amino-alanine, NH2NH.CH(CH3)CO8H, m.p. 1 80°, is formed from a-isonitramine propionic acid (B. 29, 670), and from the addition product of hydrocyanic acid and acetaldehyde semicarbazone (A. 303, 79). a-Hydrazinobutyric Acid, NH2NH.C(CH3)2CO2H, m.p. 237° with decomposition. It is formed when steam acts on its benzal derivative. The latter is made by acting on acetone semicarbazide, NH2CONHN=C(CH3)2, with hydrocyanic acid, when carbamido-hydrazino-isobutyronitrile is produced. This is then decomposed with hydrochloric acid, and benzaldehyde is added (A. 290, 15). 13 (b). Hydrazo-fatty Acids. — When a hydrazino-fatty acid is treated with acetone and potassium cyanide, a hydrazo-nitrile acid results : thus, from a-hydrazino-isobutyric acid we get Hydrazo-isobutyronitrilic Acid, ^^3^>C.NHNH.C<^3^2, m.p. 100°. When hydrazine sulphate (i mol.), acetone (2 mols.-), and potassium cyanide (2 mols.) react, the product is Hydrazo- isobutyronitrile, ^^C.NH.NH.C^2, m.p. 92°. Hydrochloric acid con- verts both nitriles into Hydrazo-isobutyric Acid, m.p. 223°. Its dinitroso-compound is decomposed by alkalis into isonitramine isobutyric acid (see above), a-hydroxy-isobutyric acid and nitrogen (A. 300, 59). 1 4 . Azo-f atty Acids. — Bromine water oxidizes hy drazo-esters and hy drazonitriles to the corresponding azo-bodies. Azo-isobutyronitrile, ^^^C.NrN.C^^J1^2. m.p. 105°, when heated alone, or, better, with hot water, passes into tetramethyl succinic nitrile (A. 290, i). B. UNSATURATED HYDROXY-ACIDS, HYDROXY-OLEFINE CARBOXYLIC ACIDS a-Hydroxy-oleflne Carboxylic Acids are obtained by the action of cold hydro- chloric acid on the nitriles, the addition products of hydrocyanic acid and olefine- aldehydes. Vinyl Glycollic Acid, CH2:CHCH(OH)COOH, m.p. 33°, b.p. 129°, is prepared from its nitrile, acrole'in cyanhydrin, b.p.17 94°, or the amide, m.p. 86°, b.p.j, 155-158°. When heated with acids it is partly converted into an a-ketone-acid — propionyl formic acid, CH3CH2CO.COOH. This also results, together with various condensation products, when vinyl glycollic acid is acted on by alkalis (Rec. trav. Chim. 21, 209). Propenyl Glycollic Acid, a-Hydroxypentenic Acid, CH3CH:CHCH(OH)COOH, is obtained from crotonaldehyde cyanhydrin. Boiling dilute acids convert it directly into an ay-keto-acid — laevulinic acid (B. 29, 2582) : CH3CH:CH.CH(OH)COOH - > CH3CO.CH2CH2COOH. a-Ethoxy-acrylic Acid, CH2:C(OC2H6).CO2H, m.p. 62°, is obtained by hydrolysis of its ethyl ester, b.p. 180° (comp. Acetal of Pyroracemic Ester, p. 408) (B. 31, 1020). /?-Hydroxy-olefine Carboxylic Acids are obtained by condensation of olefine aldehydes with a-halogen-fatty esters by means of zinc (comp. mode of formation 398 ORGANIC CHEMISTRY I2a, p. 358). When an available hydrogen atom is present in the a-position, these acids readily lose water, as when, for instance, they are boiled with sodium hydroxide, forming di-olefme carboxylic acids (B. 35, 3633, C. 1903, 555 ; 1906, II. Br.CH2COaR CH8CH:CH.CHO - — - > CH3CH:CH.CH(OH)CH2COaR 0-Hydroxy-hydrosorbic Acid. - > CH3CH:CH.CH:CHCOaH. Sorbic Acid. ft-Hydroxy-hydrosorbic Acid is an oil, slightly soluble in water ; ethyl ester, b.p.? 100°. a-Methyl Hydroxy-hydrosorbic Ester, b.p.16 111°. a-Ethyl fi-Hydroxy sorbic Ester, b.p.16 111°. a-Ethyl fi-Hydroxy-hydrosorbic Ester, CH3CH:CHCH- (OH)C(CH3)2CO2R, b.p.17 119°, is stable. a-Dimethyl fi-Vinyl Hydracrylic Acid, Vinyl Hydroxypivalic Acid, CH2:CH.CH(OH)C(CH3)2CO2H, b.p.a, 159°; ethyl ester, b.p.lg 106°, is prepared from acrolein bromisobutyric ester and zinc. In benzene solution, P2O6 causes the splitting off of water, and simultaneously the addition of benzene, forming the compound C,H6.CH2CH:CHC(CH3)2CO2R. 0-Hydroxy-acrylic Acid, CH(OH):CHCO2H, and £-Hydroxycrotonie Acid, CH3C(OH):CH.CO2H. Both these acids and their homologues are the starting points for the aci-forms (p. 40) of the fi-aldo- and f}-keto-carboxylic acids, such as formyl acetic ester and acetoacetic ester : aci-iorm CH(OH):CHCO2C2H$ a.jj keto-iorm CHO.CH2CO2C2H6 CH3CO.CH2CO2C2H6. Formyl Acetic Ester. Acetoacetic Ester. In the free state formyl acetic ester exists as /J-hydroxy-acrylic ester (act- modification), whilst acetoacetic ester is more stable in the keto-form. Since the aci- or enol-iorm is usually looked on as being a subsidiary form, and the aldo- or keto-iorm, the fundamental modification, those derivatives, such as (1-alkoxy- and j3-acyloxy-olefi.iie carboxylic acids, which are undoubtedly of the enol-form, will be described with the latter. y- and 8-Hydroxy-olefine Carboxylic Acid are known in the form of their lactones, of which some are obtained by distillation of the y-keto acids, and others from /Jy-dibromo- or dichloro-fatty acids with the loss of 2 molecules of halogen acid. These A1- and A1 -lactones are changed back into y-keto- or aldehyde acids by hydrolysis. A*-Butene Lactone, Crotolacfone,CH:CH.CH2COO, m.p. 4°, b.p.15 96°, is formed from /Jy-dichlorobutyric acid when heated alone or with potassium carbonate (C. 1905, II. 45 ; B. 35, 9422). y-Ethoxycrotonic Acid, C2H5OCH2CH:CHCOOH, m.p. 45°, b.p.26 148°, is obtained from y-ethoxy-jS-hydroxybutyronitrile, the addition product of hydro- cyanic acid to epiethylin, C2H5OCH2CH.CH2Q (C. 1905, I. 1138). A*- Angelic Lactone, CH3C==CHCH2COO, m.p. 18°, b.p. 167°, and ^-Angelic Lactone, CH3CH.CH.CHCOO, b.p.25 83°, are prepared from Isevulinic acid and acetyl laevulinic acid. The AMactone can be formed from the AMactone by various methods ; the change is, however, reversible. The AMactone, in contra- distinction to the AMactone, can be condensed with aldehydes at the a-CH2 group (A. 319, 180). Mesitonic acid (aa-dimethyl laevulinic acid, p. 423) gives rise to a-Dimethyl ^•-Angelic Lactone, m.p. 24°, b.p. 167°. The isomeric aa^-trimethyl-^-butero- lactone is prepared from the corresponding dibromo-acid. Iso-octenolactone, (CH8)2CHCH2CH.CH:CH.COO, is obtained from iso-octenic acid dibromide (C. 1905, II. 457 ; A. 347, 132). y - Methyl - and y - Ethyl - oj3 - dichloro - and - aj8 - dibromo - butene Lactone .CH.CX:CXCOO, b.p.22 120°, b.p.4 110°; m.p. 69°; m.p. 51°, are prepared om mucochloric acid and mucobromic acid (p. 402) by means of magnesium R from alkylhalides (6.88,3981). NITRO- AND AMINO-OLEFINE CARBOXYLIC ACIDS 399 Parasorbie Acid, or Sorbin Oil, CH3CH2CHCH:CHCOO, or CH3- CHCH2CH:CHCOO, b.p. 221°, occurs, together with malic acid, in the juice of ripe and unripe mountain ash berries (Sorbus aucuparia). It is optically active : [a]j = +40-8, and is a strong emetic. It passes into sorbic acid (p. 305) when heated with sodium hydroxide or hydrochloric acid (B. 27, 344). Pi-olefme 8-lactones have been obtained from coumalic acid and isodehy- dracetic acid by the splitting-off of carbon dioxide : Conmalin, CH=CH — CH=CH.COO, m.p. 5°, b.p.30 120°, has an odour like that of coumarin (A. 264, 293). Mesitene Lactone, fib-Dimethyl Coumalin, CH3C=CH— C(CH3)=CH.COO. m.p. 5* '5°. b.p. 245°. When heated with ammonia it changes to the corre- sponding lactam, so-called pseudo-lutidostyril, mesitene lactam (below). Diallyl Butyrolactone, (CH2:CHCH2)CCH2CH2COO, b.p. 267°, is prepared from succinic ester, allyl iodide, and zinc (comp. the general method of formation of tert.-a-hydroxy-acid esters from oxalic ester, alkyl halides, and zinc, p. 358) (J. pr. Ch. [2] 71, 249). Ricinoleic Acid, C18H34O3, is an unsaturated hydroxy-carboxylic acid (p. 302). NITRO- AND AMINO-OLEFINE CARBOXYLIC ACIDS a-Nitro-dimethyl Acrylic Acid, (CH3)2C:C(NO2)COOH. Its ester, b.p.?4 121°, is prepared by nitrating dimethyl acrylic ester (p. 299) with fuming nitric acid. Alcoholic potassium hydroxide converts it into the potassium salt of an isomeric r*TT nitro-acid ester, £H3^C.CH(NO2)COOC2H5 ; ammonia decomposes it into acetone and nitro-acetic ester (p. 380) ; reduction with aluminium amalgam produces nitrodimethyl acrylic ester. a-Aminodimethyl Acrylic Acid Ester, (CH3)2C:C(NH2)COOC2H5, b.p.lg 94°, is converted by hydrochloric acid into dimethyl pyroracemic acid (p. 408). j8-Amino-acids and /3-Hydrazino Olefine Carboxylic Acids. This group contains the reaction-products of ammonia and the hydrazines on j8-ketone-acid esters such as acetoacetic esters and alkyl acetoacetic esters. Thus, B-Aminocrotonic Ester, CH3C(NH2):CH.CO2C2H6, is produced ; also, Methyl NH— NH Pyrazolone, • \ . This behaves desmotropically, and because of its CH3C:CH.CO close connection to the j8-ketone-acid esters will be considered with them (p. 418). S-Diolefme Lactams. H— C a-Pyridone, 8-Aminopentadiene Acid Lactam, CHf^ /NH, m.p. 106°, ^ Ck / / is obtained from the reaction-product of ammonia and coumalic acid after the elimination of carbon dioxide (B. 18, 317). It can be converted into the XH-CCK odourless Ethylimide, CH<f >N.C2H6, b.p. 258°, and a-Ethoxypyridine, XCH=CHX XH— C(O.C2H6k CHC /N, b.p. 156°, which possesses an odour like that of pyridine NCH - CH/ (B. 24, 3144) (see Vol. II.). Pseudolutidostyril, [3, 5]- Dimethyl a-Pyridone, Mesitene Lactam, XH - CO, CH3— C< >NH, XCH=C(CH3K m.p. 1 80°, b.p. 305°, is formed when ammonia acts on mesitene lactone, and from the two monocarboxylic acids of this lactam by the elimination of CO. (A. 259, 168). 400 ORGANIC CHEMISTRY 8. ALDEHYDE-ACIDS These are bodies which show both the properties of a carboxylic acid and of an aldehyde. Formic acid is the simplest representative of the class, and it is also the first member of the homologous series of saturated aliphatic monocarboxylic acids. But it and its derivatives have been, with repeated reference to its aldehydic nature, discussed before acetic acid and their higher homologues. The best known alde- hyde carboxylic acid, a compound of the aldehyde group CHO with the carboxyl group COOH, is glyoxylic acid, which is an oxidation product of ethylene glycol. I. Glyoxylic Acid, Glyoxalic Acid [Ethanal Acid] (HO)2.CH.CO2H or OCH.CO2H-f-H2O, was found by Debus (1856) among the products resulting from the oxidation of alcohol with nitric acid. It occurs in unripe gooseberries and other fruit, from which it disappears on the fruit ripening. Its formation and reactions are of significance in plant physiology (B. 25, 800 ; 35, 2446 ; 40, 4943). Just as chloral hydrate is to be considered as trichlorethidene glycol, CC13CH(OH)2, so crystallized glyoxylic acid can be regarded as the glycol corresponding with the aldehydo-acid, CHO.CO2H. All the salts are derived from the dihydroxyl formula of glyoxylic acid ; hence it may be designated dihydroxy-acetic acid. Like chloral hydrate, glyoxylic acid in many reactions behaves like a true aldehyde (B. 25, 3425). Methods of Formation. — Glyoxalic acid results (i) from the oxida- tion of alcohol (B. 27, R. 312), aldehyde and glycol, and is accompanied by glyoxal (p. 346) and glycollic acid (p. 362) ; (2a) by heating dichlor- and dibromacetic acid to 230° with water (B. 25, 714) ; (26) by boiling silver dichloracetate with water (B. 14, 578) ; (zc) the best method is by the action of potassium acetate on dichloracetic acid, producing diacetyl dihydroxyacetic acid (CH3COO)2CHCOOH, which on boiling with water yields glyoxylic acid (A. 311, 129). (3) From hydrazi-acetic acid (p. 405). (4) It is formed direct by reduction of oxalic acid and its ester (comp. also Glycollic acid, p. 362). (a) Electrolytic reduction of oxalic acid in sulphuric acid and with mercury cathode gives an 87 per cent, yield of glyoxylic acid (B. 37, 3187): COOH.COOH+Ha=COOH.CH(OH)2. (b) A similar reduction of oxalic ester produces glyoxylic ester (B. 37, 3591). (c) Reduction of oxalic ether with sodium amalgam in alcohol produces the alcoholate of glyoxylic ester, together with ketomalonic ester, desoxalic ester, and racemic ester (B. 40, 4942). Properties. — It is a thick liquid, readily soluble in water, and crystallizes in rhombic prisms by long standing over sulphuric acid. The crystals have the formula C2H4O4 (see above). It distils undecom- posed with steam. Salts. — The salts contain water of crystallization which, on being dried, give it up with partial decomposition. The calcium salt, (CjHjOa^Ca+zHjO, is sparingly soluble in water (A. 317, 147 ; C. 1904, II. 1705). Esters: Glyoxylic Ethyl Ester, CHO.COOC2H6, b.p. 130°, an easily poly- merized substance, is produced by the electrolytic reduction of oxalic ether, and ALDEHYDE-ACIDS 401 also from its alcoholate, C2H5OCH(OH)CO2C2H8, b.p. 137°, by the action of P2O6. This substance is prepared by the reduction of the oxalic ether with sodium amalgam (see above). Alcohol and hydrochloric acid produce Di-ethoxy acetic Ester, (CZH6O)2CHCO2C2H5, b.p. 199°, which, on hydrolysis, yields di-ethoxy- acetic acid. Glyoxylic ethyl ester develops a bright coloration with ammonia and methylamine in presence of air (C. 1906, I. 1654 ; B. 40, 49 53). ^Glyoxylic Methyl Ester, m.p. 53° (B. 37, 3591). Hydrazines, hydroxylamine, etc., give typical aldehyde derivatives with the esters (C. 1907, I. 401 )./ Reactions. — Glyoxylic acid exhibits all the properties of an aldehyde. It re- duces ammoniacal silver solutions with formation of a mirror, and combines with primary alkali sulphites (p. 195), with phenylhydrazine (B. 17, 577), with hydro- xylamine, thiophenol and hydrochloric acid (B. 25, 3426). When oxidized (silver oxide), it yields oxalic acid ; by reduction it forms glycollic acid and racemic acid, CO2HCH(OH).CH(OH)COOH. On boiling the acid with alkalis, glycollic and oxalic acids are produced (B. 13, 1931). This reaction is extramolecular, and completes itself by the intramolecular rearrangement of the glyoxal, under like conditions, into glycollic acid : COOH COOH COOH 2 1 • +HaO =| +| CHO CH2OH COOH. Glyoxylic Glycollic Oxalic Acid. Acid. Acid. The formation of glycollic and tartaric acids also occurs when glyoxylic acid is carefully heated (C. 1904, II. 1705) ; they are also formed by the interaction of glyoxylic, hydrocyanic, and hydrochloric acids. Ammonia causes the elimination of COa and the formation of formyl glycocoll (p. 388), and ultimately glycocoll (B. 35, 2438). For the change of glyoxylic acid by urea into allantoin (see p. 573). II. jS-Aldo-carboxylic Acids, HOC.CHR.CO2H, and their esters exhibit reactions of aci-iorm compounds and behave as p-hydroxy-£±- olefine carboxylic acids, HOCH : CRCO2H (pp. 397, 398), in which form they are most favourably constituted to yield esters. Formyl Acetic Acid, p-Aldopropionic Acid (half aldehyde of malonic acid). CHO.CH2COOH or CH(OH) : CHCO2H, appears to be formed by the hydrolysis of its acetal, Di-ethoxypropionic acid, (C2H5O)2CHCH2COOH. This is obtained by oxidation of jS -hydro xypropionacetal (p. 338) (B. 33, 2760) ; ethyl ester, b.p. I93° '• and also from orthoformic ester (p. 246), bromacetic ester and zinc (J. pr. Ch. [2] 73, 326) : HC(OCaH5)3+BrZnCH3COOC2H6=HC(OC2H5)2.CH2CO2C2H5+C2H6OZnBr. It readily loses alcohol, forming the ester of fi-Ethoxyacrylic Acid, C2H5OCH :- CHCOOH, m.p. 110°. This readily decomposes into CO2 and acetaldehyde. probably with the intermediate formation of formyl acetic acid. Formyl Acetic Ester, Hydroxymethylene Acetic Ester, fi-Hydroxyacrylic Ester, (C2H3O)CO2R, is obtained in the form of its sodium compound, NaOCH : CHCOjR, by the condensation of formic and acetic esters by means of sodium in benzene or ethereal solution : HCOOC2H5+CH3COOC2H5+Na=NaOCH:CHCOOC2H6+HOC2H5. The free ester is easily condensed to formyl glutaconic ester, HC(OH) : C(COaR)- CH : CH.CO2R, and trimesic ester, C6H3(CO2R)3. Concentrated sulphuric acid produces coumalic acid (q.v.). Acetyl chloride and sodium formyl acetic ester form an acetate, CH3CO.OCH : CHCO2C2H5, b.p.46 126°. This takes up 2 atoms of bromine producing a dibromide, b.p.34 154°, which indicates the structure of the acetate (B. 25, 1046). Nitrobenzoyl chloride produces two stereoisomeric nitrobenzoates (A. 316, 18). Cyanacetaldehyde, Hydroxymethylene Acetonitrile, (C2H3O)CN, is produced as a sodium salt from isoxazole and sodium ethoxide (P- 354)- a-Formyl Propionic Acid, OCHCH(CH3)CO2H or CH(OH) : C(CH3)CO2H ; acetal, (C,H6O)2CH.CH(CH3)CO2H, of which the ester is prepared from ortho- formic ester and a-bromozinc propionic acid, easily breaks down into alcohol and fi-Ethoxymethyl Acrylic Acid, C2H6OCH : C(CH3)CO2H, m.p. 109°. This is formed from bromo-methyl-acrylic acid and sodium alcoholate. It readily decomposes VOL. 1. ' . 2 D 402 ORGANIC CHEMISTRY into CO2, propionaldehyde and alcohol (B. 39, 3549). a-Formyl Propionic Ester, a-Hydroxymethylene Propionic Ester, HOCH : C(CH3)COaC,H,, b.p. 161°; acetate, b.p.4t 132° (A. 316, 333). III. y- and S-Aldo-carboxylic Acids. fi-Formyl Propionic Acid, y-Aldobutyric Acid (half aldehyde of succinic acid), CHO.CH2.CH2CO2H, is produced from acetal malonic acid (C2H5O)2CH.CH2CH- (COaH)2, when the latter is heated with water to igo° ; or, better, by boiling aconic acid (q.v.) in water, when CO2 is given off (B. 37, 1801). It forms crystals, soluble in water. When evaporated with sodium hydroxide solution, it yields a small quantity of terephthalic acid (Vol. II.) ; reduction converts it into butyro- lactone. Its nitrile serves for the derivation of fi-cyanopropionacetal, CNCH2- CHaCH(OC2H5)2, b.p. 45 106°, the reaction product of y-chloropropionacetal and KNC (B. 34, 1924). fi-Formyl Isobutyric Acid, a-M ethyl B-Aldobutyric Acid, CHO.CH2CH(CH8)C02H (C. 1899, I. 557). 8-Aldovaleric Acid, y-Formyl Butyric Acid (half aldehyde of glutaric acid), CHO.CH2CH2CH2COOH, b.p. 240°, is prepared from j8-propionacetal malonic ester by hydrolysis and the loss of CO2 (B. 38, 2884) ; by boiling the ozonide of cyclopentene (Vol. II.) with water, associated with Glutaric Dialdehyde, b.p.10 71° (p. 347) and glutaric acid (B. 41, 1706). 8-Formyl y-Methyl Valeric Acid, HOC.- CH(CH3)CH2CH2COOH, b.p.12 154°, is obtained by the oxidation of citronellal acetal (p. 215) with permanganate (B. 34, 1498). IV. Aldo-olefine Carboxylie Acids. p-Formyl Acrylic Acid (half aldehyde of maleic acid), CHOCH : CHCOOH, m.p. 55°, b.p.10 145°, is produced by the oxidation of pyromucic acid (Vol. II.) by bromine and alkali. It is converted into succinic acid when heated with a solution of potassium cyanide (B. 38, 1272) : icH:CH.CH:CC02H -^->- CHO.CH:CHCOaH -^> HO2C.CHa.CHaCOOH. Pyromucic Acid. 0-Formyl Acrylic Acid. Succinic Acid. By the energetic action of chlorine and bromine on pyromucic acid, halogen derivatives of formyl acrylic acid are produced — mucochloric acid, m.p. 125°, and mucobromic acid, m.p. 122°. Similarly to the y-Keto-acids (p. 421), these acids can be looked on as being hydroxylactones, with which they are desmotropic (M. 25, 492) : <H.CH(OH) XH.CHO XBr.CH(OH) XBr.CHO andCH^ CBr<f / and CBrf oo XCOOH xcoo N:OOH __ Formyl Acrylic Acid. Mucolaroinic Acid. The esters of mucochloric and mucobromic acids, which, contrary to the acid, do not yield oximes, appear to be derived from the lactone formula ; there are, however, also esters which have been obtained from the normal aldehyde-acid. NITROGEN DERIVATIVES OF THE ALDEHYDE-ACIDS Dinitro-acetic Ester, (NOa)2CHCO2C2HB, is prepared from malonic ester and fuming nitric acid. It is a colourless liquid, which cannot be distilled without decomposition. It reacts strongly acid. Diaminoacetic Acid, (NH2)2CHCOOH, is as yet unknown. A derivative Tetramethyl Diaminoacetic Methyl Ester, [(CH3)2N]2CHCOOCH3, b.p.lt 57°, is obtained from diiodoacetic ester and dimethylamine. Dibromacetic ester, by the same reaction, yields Hydroxy-dimethyl Aminoacetic Dimethyl Amide, (CH3)1NCH(OH)CON(CH8)a, b.p.18 80° (B. 35, 1378) Diazoacetic Acid, N2CH.CO2H, is also a derivative of glyoxylic acid. As it contains two doubly-linked nitrogen atoms, it may be compared with the aromatic diazo-bodies (see Diazobenzene). How- ever, in the latter the extra -affinities of the diazo-group — N=N— or =N=N are combined to two atoms, whilst in diazoacetic acid they are joined to a single carbon atom, H/CH.COaH. Separated by acids NITROGEN DERIVATIVES OF THE ALDEHYDE-ACIDS 403 from its salts, it undergoes an immediate decomposition, but it is fairly stable in its esters and its amides. (i) The esters of the diazo-acids result when potassium nitrite acts on the hydrochlorides of the amino-fatty acid esters (p. 384) (Curtius, 1883, B. 29, 759) : HCl.(H2N)CH2C02CaH5 + KN08=N2:CHC02C2H6 Glycocoll Ester Diazoacetic Ester. Hydrochloride. The di- and poly-peptide ester hydrochlorides, which contain the NH2CH2CO- group, behave with alkali nitrites in the same way as glycocoll ester hydrochloride : highly crystalline diazo-esters are formed, such as Diazoacetyl Glycine Ester, N2CH.CONHCO2C2H6, m.p. 187°, as yellow crystals : Diazoacetyl Glycyl Glycine Ester, NH2CHCO.NHCH2CONHCH2CO2C2H6, etc. The homologous ' a-amino- acids, such as alanine leucine, also yield diazo-esters, if somewhat less readily ; but /f- and y-amino-esters give hydroxy-esters instead of diazo-compounds (B. 37, 1263). (2) The sodium salts of the diazo-acids are prepared by reduction of the iso- nitramine fatty acids (p. 396) by means of sodium amalgam (B. 29, 667) : H02NaCH2CO2Na+2H=2H20+Na:CH.C02Na. 