None
Amino-acetic Ethyl Ester, Glycocollic Ester, NH2.CH2COOC2H5, b.p. 149°, b.p.10 52°, is an oil resembling cocoa in odour, which is easily soluble in ether, alcohol, and water. In aqueous solution, however, it changes into di-aci-pipera- zine (p. 391), and in ether into tri-glycyl-glycine ester (p. 392). The ester is particularly suitable for the preparation of various derivatives of glycocoll (B. 34, 436). Glycocollic Ester Hydrochloride, HCl.NHa.CH2COOC2HB, m.p. 144°, is formed by the passage of HC1 gas into a mixture of alcohol and glycocoll, and can be employed as a method of estimation of glycocoll on account of its slight solubility in alcoholic hydrochloric acid (B. 39, 548). It is also obtained from methylene-amino-acetonitrile (see below), aceturic acid (p. 388) (B. 29, 760), or from the reaction product of hexamethylamine and potassium chloroacetate (C. 1899, I. 183, 420), by the action of alcoholic hydrochloric acid, whereby the ester hydrochloride results. This is also formed by pouring excess of alcohol on Glycyl Chloride Hydrochloride, HC1.NH2CH2COC1, which is prepared from pre- cipitated glycocoll and phosphorus pentachloride in acetyl chloride, as a crystal- line powder (B. 38, 2914). Glycocollamide, Amino-acetamide, NHaCHaCONH2) is produced when glycocoll is heated with alcoholic ammonia to 160°. It is a white mass which dissolves readily in water, and reacts strongly alkaline. The HCl-salt results on heating chloracetic ester to 70° with alcoholic ammonia. Glycocoll Hydrazide, NH,CH,CO.NHNHa, m.p. 80-85°, is obtained from glycocoll ester and hydrazine hydrate, as a hygroscopic crystalline mass ; hydro- chloride, C2H7N,9.2HC1, m.p. 201° (J. pr. Ch. [2] 70, 102). Glycocoll Nitrile, Amino-acetonitrile, NHaCH2CN, b.p.15 58°, is prepared from glycoll nitrile and alcoholic ammonia at o° ; hydrochloride, m.p. 165°; sulphate, C,H4Nt.HaS04, m.p. 101° (J. pr. Ch. [2] 65, 189 ; B. 36, 1511). NITROGEN DERIVATIVES OF THE HYDROXY-ACIDS 387 Methylene A mino-acetonitrile, CH2=NCH2CN, m.p. 129°, with decomposition, is formed from formaldehyde, ammonium chloride, and potassium cyanide ; also from glycocoll nitrile and formaldehyde. It may consist of a double molecule. It is remarkable for its crystallization (J. pr. Ch. [2] 65, 192 ; B. 36, 1506). COOH COO Methyl Glycocoll, Sarcosine, \ or | \ , m.p. 210-220* CH2NHCH3 CH2NHaCH3 with decomposition, was first obtained by Liebig (1847) as a decomposition product of the creatine contained in beef extract. Its name is derived from ffdpt, flesh. Volhard (1862) prepared it synthetically by the action of methyl- amine on monochloracetic acid ; and it is also produced when creatine or CO,H NHa methyl glycocyamine, \ , or caffeine is heated with barium CH2N(CH8).C=NH hydroxide solution. It dissolves readily in water but with difficulty in alcohol. The nitrile of sarcosine is obtained together with methylamine from methylene cyanhydrin, the additive product of formaldehyde and hydrocyanic acid (A. 279, 39 ; J. pr. Ch. [2] 65, 188). When melted it decomposes into carbon dioxide and dimethylamine, yielding at the same time sarcosine anhydride (p. 392). It forms salts with acids, which show an acid reaction. Ignited with soda-lime it evolves methylamine. Sarcosine yields methyl hydantoin with cyanogen chloride and creatine (q.v.) with cyanamide. Sarcosine Ethyl Ester, CH3NHCH2- C02C2H6) b.p.10 43° (B. 34, 452). Dimethyl Glycocoll, (CH3)2NCH2COOH, is prepared by the hydrolysis of its nitrile, dimethylarmno-acetonitrile, (CH3)2NCH2CN, b.p. 138°. This is formed by the action of dimethylamine on methylene-amino-acetonitrile (above) or on glycollic nitrile. Dimethylamino-acetic Methyl Ester, (CH3)2NCH2COOCH3, b.p. 135°, is obtained from the interaction of chloracetic acid and dimethylamine. It is isomeric with betaine, into which it changes when heated. Betaine, on the other hand, when heated above its melting point (293°) is isomerized to a large extent into dimethyl amino-acetic methyl ester (B. 35, 584) : (CH3)2NCHaCOOCH3 •<-> (CH3)3NCHaCOO. COO Trimethyl Glycocoll, Betaine, Oxyneurine, Lycine, \ \ , has already CH2N(CH3)3 been mentioned (p. 330) in connection with choline, from which it is prepared by oxidation. Its hydrochloride is prepared by the union of monochloracetic acid with trimethylamine (B. 2, 167 ; 3, 161 ; 35, 603) : aCHaCOOH+N(CH3)3=ClN(CH3)3CH2COOH. Similarly, chloroacetic ester and trimethylamine yield Betaine Ester Hydro- chloride, C1N(CH3)3CH2.CO2C2H5, m.p. 143° (B. 38, 167). Betaine is also obtained by the methylation of glycocoll by means of methyl iodide, potassium hydroxide, and methyl alcohol. It occurs in beet-root (Beta vulgaris) (Scheibler, B. 2, 292 ; 3, 155), and is to be extracted from the " melasse " of the beet-sugar factory, in which it is the substance which gives rise to the trimethylamine obtained there- from (p. 165). It also occurs in the leaves and stalks of Lycium barbarum, in cotton seeds, and in germ of malt and wheat (B. 26, 2151). It crystallizes in deliquescent crystals in which iheacid, HON(CH3)3CHaCOOH, may be present. At 100° this ammonium hydroxide derivative loses one molecule of water, forming a cyclic ammonium salt, ON(CH3)3CH2CO, m.p. 293°, with conversion into dimethyl amino-acetic methyl ester (see above). Iodine in potassium iodide precipitates a periodide from an aqueous solution of betaine (C. 1904, II. 950)- ' The action of ethylamine, diethylamine and triethylamine on chloracetic acid produces ethyl glycocoll, diethyl glycocoll, and triethyl glycocoll, triethyl betaine, (C,H,)3NCHaCOO. Similarly to betame 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 | (C2H5)2NCH2CN > (C2H5)aN(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+NH8=HCO.NH.CH2COOH+C02+H20. Glyoxylic Acid. Formyl Glycine. Acetyl Glycocoll, A cetamine A cetic Acid, Aceturic Acid, 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 Sulphoglycine, 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)S, 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+l] 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)CO9C2H6, 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, C,0H7SO2.NHCH(CH8)COOH, m.p. 152*. Benzoyl Alanine, C8H6CO.NHCH(CH3)COOH, m.p. 165°, is resolved by means of brucine into the components \d- and /]- 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, [a]^=+2'70 ; in hydrochloric acid solution it is much greater, [a]?=+io-4«> (B. 39, 462 ; 40, 3721)- Nitrous acid converts d-a.la.nine into the ordinary ^-lactic acid (p. 364) ; on the other hand, nitrosyl bromide (p. 384) changes d-alanine into /-bromopro- pionic acid, which with ammonia yields /-alanine. This, with nitrosyl bromide, gives d-bromopropionic acid, which ammonia converts into ^-alanine (Wolden's inversion, p. 364 ; B. 40, 3704). d-Alanine is also obtained by the reduction, with sodium amalgam, of /-fi-chloralanine, C1H2CH(NH2)COOH. The ester of this acid is obtained from /-serin e ester (j8-hydroxy-a-aminopropionic ester) and PCI 6 ; since /-serine can be converted into d-glyceric acid and this into /-tartaric COOH acid, the formula of rf-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 ^-alanine into l-Trimethyl PropionicBetaine, (CH3)3NCH(CH3)COO, which also results from the interaction of ^-a-bromopropionic acid and trimethylamine (B. 40, 5000). Triethyl Propionic Betaine is formed by hydrolysis of the iodo-ethylate of Diethylatninopropionitrile, (C2H5)2NCH(CH3)CN, b.p.27 81°, the reaction product of lactic acid nitrile and diethylamine (B. 36, 4188). Iminodipropionic Acid, Hoco>CH— 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-acids 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 6eMzoy/-derivative, rf-acid [a]*=+8°, /-acid [a]^=-7-90; ethyl ester, b.p.n 6!° (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.ia 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 V aline, 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 tf-formyl valine, yielding /- Valine and d-V 'aline. The latter, m.p. 315°, [a]^)=+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 ^-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-Aminocaproic Acids. a-Amino-n-caproic Acid, CH3[CH2]3CH(NH2)CO9H, is prepared from a-bromo-n-caproic acid and ammonia. It is resolved into its optical component by means of its 6«w^oy/-derivative (B. 33, 2381 ; 34, 3764). a-Amino-isocaproicAcids. Leucine.— (CH3)2CHCH2CH(NH2)COOH, optically acti^fe leucine. Leucine (from Aev/cos, 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 390 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 by conver- 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 leucine, 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 isovaler aldehyde, ammonium cyanide, and hydrochloric acid ; or by decomposing the condensation product of isobutyraldehyde and hippuric acid (A. 316, 145) : NH4NC /NH, NH3 C,H6C:N v (CH,),CHCH2CHO - -^(CH3)aCHCHaCH< •< >C XX)OH O.CCK || (CH3)2CHCH The resolution of the rac.-&e«^o^^Mctw^,(CH3)4CHCH2CH(NHCOC,H6)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, C4H9CH(NH3C1)COC1 (B. 38, 615). a-Amino-sec.-butyl Acetic Acid, Isoleucine, C^6>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]^=+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. d-Isoleucine is prepared from ^-valeric aldehyde by the cyanhydrin synthesis (B. 40, 2538 ; 41, 1453)' a-Amino-cananthic Acid, CH8[CH2]4CH(NH2)CO2H (B. 8, 1168). a-Amino caprylic Acid, CH3[CH2]6CH(NH2)CO2H (A. 176, 344). a-Aminopalmitic Acid, CH3[CH2]13CH(NH2)CO2H (B. 24, 941). a-Aminostearic Acid, CH3[CH2]16CH- (NH2).CO2H, 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 uber 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 amino -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 : NH^CO— CH2NNH _:>. HOCO— CH2 <CH2— C0> :I:<:::2:H2NCH2— CO a-y-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 C1CH2CO.NHCH2COOH - > NH2CH2CO.NHCHaCOOH - > Chloracetyl Glycine. Glycyl Glycine. NHS C1CH2CO.NHCH2CO.NHCH2COOH - > Chloracetyl Glycyl Glycine. NH 8CH 2CO.NHCH 2CO.NHCH 2COOH. Diglycyl Glycine. The esters of the halogen acylamino-acids are easily converted by ammonia into dipeptide anhydrides, dioxopiperazines (see above). (b) Again, the halogen-acyl-amino acids can be converted into their chlorides, united with other amino-acids and then be acted on by ammonia : C4H,CHBrCO.NHCH2COCl - > » Bromisocaproyl Glycine Chloride. NH3 C4HfCHBrCO.NHCH2CO.NHCH2COOH - > Bromisocaproyl Glycyl Glycine. C4H,CH(NH2)CO.NHCHtCOOH, 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, C6H5.CONHCH2CON3, unite with amino-acids, splitting off N3H, and easily forming acyl derivatives of the di- and polypeptides. 3. Higher polypeptide~s result from heating the methyl esters of lower peptides : 2NH2CH2CO.NHCH2CO.NHCH2CO2CH3 > Diglycyl Glycine Ester. NH 2CH 2CO. [NHCH 2CO] <NHCH 2CO2CH s. F jntaglycyl 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. [a? +/] -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- zine, NHCH 2CO. NHCH 2CO, 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(CHS)CH2CO, m.p. 150°, b.p. 350°, is obtained by heating sarcosine (B. 17, 286). Glycyl \d+l\- 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). &- Alanyl Glycine, CH3CH(NH2)CO.NHCH2COOH, m.p. 235° with decomposition, is produced from d-a.la.nyl 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 CHI(CH°)'>NH' m'p' 275°* The anhydride is best obtained from alanine ester at 180°. It is reduced by sodium and alcohol to jSS-dimethyl piperazine (B. 38, 2376; C. 1902, I. 631). l-Alanyl ^-Alanine is produced from /-bromopropionyl d-alanine and ammonia, [0]?=— 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.NHCHaCOOH, m.p. 246° with decomposition, is prepared from chloracetyl glycyl glycine and ammonia ; methyl ester, m.p. m°, when heated passes into pentaglycyl glycine ester, slightly soluble in water (B. 39 472). NITROGEN DERIVATIVES OF THE CARBOXYLIC ACIDS 393 Triglycyl Glycine is prepared from chloracetyl diglycyl glycine ; ester. NH2CH2CO.NHCH2CO.NHCH2C9.NHCH2COOC2H6, 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, C4H9CH(~NH2)CO[NHCH2COJ5NHCH2COOH, is prepared from bromisocaproyl pentaglycyl glycine and ammonia (B. 39, 461). jS-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 betaine. p-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 /?-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, | /NH, by the Hofmann inversion (p. 159) by means of bromine and alkali (B. 26, R. 96 ; C. 1905, I. 155 ; 1906, I. 818) ; methyl ester, b.p.1B 58° ; amide, m.p. 40° ; fi-Dimethylamine Propionic Methyl Ester, (CH3)2NCHa- CH2COOCH3, b.p. 154°, is prepared from £-iodopropionic ester and dimethyl- amine. Heat partially transforms it into its isomer fi-Trimethyl Propiobetaine, (CHS}3NCH8CH2COO, which in its turn undergoes transformation on melting into trimethylamine acrylate, CH2:CHCOONH(CH3)3 (B. 35, 584). p-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)CHaCOOH, 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 8-amino -car boxy lie acids as well as of some of the higher acids is that when heated they part with water arid 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 oj-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 8-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) : ^JCO^H'01^ C.H4{M£g>NCHaCH2CHaBr w-Bromethyl Phthalimide. I «-Brompropyl Phthalimide. I «- C6H4 y-Aminobutyric Acid. fi-Aminovaleric Acid. Similarly, €-bromo-amyl phthalimide can be made to yield €-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 potassiuni 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 CH,.CH2.NH | )>C:NOH > | | ; CH2.CH/ CH2.CH2.CO CH2.CH2.C:NOH CH2.CH2.CH2, I I > I >NH CHa.CH2.CH2 CH2.CH2.CO / CH2.CH2.CH2V CH2.CH,.CH2.NH | >C:NOH > | | CH2.CH2.CH/ CH2.CH2.CH2.CO For considerations on the course of these transformations and on the BecRmann inversion generally, see A. 346, 27. y-Aminobutyric Acid, Piperidic Acid, m.p. 183-184°. It is formed (i) when piperidyl urethane, CH2<£^2£^2>N.CO2C2H5, is oxidized with nitric acid (6.16,644); (2) by means of potassium phthalimide ; either — (a) by the double decomposition of bromethyl phthalimide with sodium malonic ester (see above), or (b) from w-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-DimethylAminobutyric Methyl Ester, (CH3)2N[CH2]3COOCH3, b.p. 172°, is prepared from y-chlorobutyric ester and dimethylamine. On heating rt is decomposed into butyrolactone and trimethylamine. The isomeric y-7> i- methyl Butyrobetatne , (CH3)3N[CH2]3COO, which is obtained by exhaustive methylation of butyrolactam in alkaline solution (B. 35, 617) undergoes the same decomposition. y-Aminovalerie Acid, CH3CH(NH2)CH2CH2CO2H, 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-8-aminovaleric Acid, SO2[NH(CH2)4CO2H]2, m.p. 163°, are formed by the oxidation of benzoyl piperi- dine, CH2<£^3£ga>NCOC6H5, 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 8-Amino-n- valeric Acid, NH2.CH2CH2CH2CH(CH3)CO2H, m.p. 168° ; a-Ethyl 8-Amino-n- valeric Acid, NH2CH8CHaCH2CH(C2H6)CO2H, m.p. 200-200-5°; a-Propyl 8- Amino-n-valeric Acid, NHaCH2CH2CH2CH(C3H7)CO2H, m.p. 186° (B. 24, 2444). A /?- or y-M ethyl S-Amino-n-valeric Acid, m.p. 134°, with decomposition, is pre- pared from its lactam (p. 396) (A. 312, 185). S-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 8-Dimethylamine Valeric Methyl Ester, (CHa^NfCH^COOCHa, b.p. 186-189°, together with 8-valerolactone (B. 37, 1853). S-Amino-n-octanic Acid, Homoconiinic acid, C3H7CH(NH2)[CH2]3CO?H, m.p. 158°. The benzoyl compound is obtained by oxidation of benzoyl conine with KMnO4 (B. 19, 504). c-AminocaDroic Acid, c-Leucine, NH2[CH2]6CO2H, m.p. 204°, is obtained NITROGEN DERIVATIVES OF THE CARBOXYLIC ACIDS 395 from phthalimidobutyl malonic ester, from t-benzoyl aminocapronitrile, CtH6- CONH[CH8]BCN (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 c-aminocaproic acid. e-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],COOH, m.p. 188°, is prepared from azelaic monoamido-acid, NH2CO[CH2],COOH, and alkali hypobromite ; benzoyl deriva- tive, m.p. 97°. These products are not identical with those obtained from benzoyl dekamethylene inline (p. 365) by oxidation (C. 1906, II. 1126). y-, 8-, e-, 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 dichloromalein anil chloride. The names y-lactams and 8-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 the 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 8-lactams bear the same relation to the imides of the y- and 8-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 CH2CH2NH2 /CH2CH2OH /CH2CH2NH. I I CH2< CH/ CHjCHjOH CH2CH2NH2 XCH2CH2OH N:H2CHaNHt Tetramethylene Tetramethylene Pentamethylene Pentamethylene Glycol. Diamine. Glycol. Diamine. CH2CH2\. CH2CH2v xCH2CH2v xCH2CH2' >0 | >NH CH2< >0 CH2< CH2CH/ CH2CH/ <XCH2CH/ \:H2CH2 Tetramethylene Tetramethylene Pentamethylene Pentamethylene Imine, Oxide, Imine, Oxide. Piperidine. Tetrahydrofur- Tetrahydro- furane. pyrrol. CH2CO x CH2CO v /CH2CO v /CH2CO v >0 | >NH CH2< >0 CH2< >NH CH2CH/ CH2CH/ XCH2CH/ N:H2CH/ v-Butyrolactone. y-Butyrolactam, J-Valerolactone. J-Valerplactam, a-Pyrrolidone. a-Piperidone. CH2CO y-Lactams v_/in2^v^ v : y-Butyrolactam, a-Pyrrolidone, \ "/NH, m.p. 25°, b.p. 245°, CH2CH2 unites with water to form a crystalline hydrate, C4H7ON+H2O, 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.C6H6, from succinanil. It can also be produced by reduction of dichloromalein 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, C4H6O.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) : CHX— NH . CH2— NH x CH2 xX \co > I \CS > I >CSCH8. CH2— CH/ CH2— CH/ CH2— CH/ Pyrrolidone. Thiopyrrolidone. >/, -Methyl Ether? The ^r-methyl ether, on reduction, breaks up into methyl mercaptan and pyrrolidine (p. 335). CH2— CH(CH3k y-Valerolactam, 8-Methyl Pyrrolidone, \ /NH, m.p. 37°, can be v^-Jrl 2~ — ... .- . . — C_/(j 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 2 — CH 2 v 708). fifi-Dimethyl Pyrrolidone, aa-Dimethyl Butyrolactam, \ /NH, m.p. C(CH3)2CCX 66°, b.p. 237° (C. 1899, I. 874)- 8-Laetams: 8-Valerolactam, a-Ketopiperidine, a-Oxopiperidine, a-Piperi- CH CO done, CH2<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, B-Methyl Piperidone, CH2<^(CHs,^P>NH, m.p. 55°, Url 2 L/rl 2 is isomeric with the j8- or y-Methyl Piperidone, m.p. 87°, obtained from /S-methyl cyclopentanone oxime (A. 312, 186). a-Ethyl 8-Valerolactam, p-Ethyl Piperidone, m.p. 68°, b.p.42 141° (B. 23, 3694). a-Propyl 8- Valerolactam, B-Propy I Piperidone, CH2<S^CijH7^?>NH, m.p. 59°, b.p. 274°. • CH2 CH2 8-n-Octanolactam, Homoconiinic Acid Lactam, CH2<CH2CO >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.COv c-Caprolactam, \ /NH, m.p. 69°, is obtained by the trans- CH2.CH2CH/ formation of cyclohexanone oxime (A. 312, 187) ; and from e-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 c-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 £-Heptolactam, , m.p. 25°, b.p.8 156°, is prepared from CH2.CH2.CH2CO heptamethylene ketoxime or suberone oxime. It can be broken down into £-aminoheptylic acid (p. 395), which on warming with nitrous acid is converted into e£-heptylenic acid (A. 312, 205). 11. Fatty Acid Nitramines, Nitramine Acetic Acid, COaHCHa.NHNO,, m.p. 103°, is prepared by hydrolyzing its ethyl ester (m.p. 24°), which results on treating nitrourethane acetic ester, C2H6O2C.N(NO2).CH2CO2C2H6, 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-fatty acids, whilst alkaline reducing agents produce diazo-acids (p. 402) and hydrazino-acids (see below). NO Isonitramine Acetic Acid, CO2HCH2N<[QTT, is a syrupy liquid. Isonitra- mine Isobutyric Acid, COaHC(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.CHaCOOH, m.p. 152°, with decomposition (B. 31, 164). (See also Amidohydantoine Acid Ester and Carbamidohydrazo-acetic Ester.) a-Hydrazinopropionic Acid, Amino-alanine, NH2NH.CH(CH3)CO2H, 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, , m.p. 100°. When hydrazine sulphate (i mol.), acetone (2 mols.), and potassium cyanide (z mols.) react, the product is Hydrazo- isobutyronitrile, ^.NH.NH.C2, 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 hydrazonitriles to the corresponding azo-bodies. Azo-isobutyronitrile, ^^^C.NrN.C^^1'^. 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, acrolein cyanhydrin, b.p.17 94°, or the amide, m.p. 86°, b.p.21 155-158°. When heated with acids it is partly converted into an a-ketone-acid • — propionyl formic acid, CH,CH2CO.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.CH2CH,COOH. 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). /3-Hydroxy-oleflne Carboxylic Acids are obtained by condensation of olefine aldehydes with a-halogen-fatty esters by means of zinc (comp. mode of formation 39$ ORGANIC CHEMISTRY I2«, 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.CH,COaR CH8CH:CH.CHO - — - > CH3CH:CH.CH(OH)CH2COaR £-Hydroxy-hydrosorbic Acid. — > CH3CH:CH.CH:CHCOaH. Sorbic Acid. fi-Hydroxy-hydrosorbic Acid is an oil, slightly soluble in water ; ethyl ester, b.p.a 100°. a-Methyl Hydroxy-hydrosorbic Ester, b.p.15 m°. a-Ethyl fi-Hydroxy sorbic Ester, b.p.15 m°. 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.28 159°; ethyl ester, b.p.lt 106°, is prepared from acrolein bromisobutyric ester and zinc. In benzene solution, P2O5 causes the splitting off of water, and simultaneously the addition of benzene, forming the compound C,H6.CH2CH:CHC(CH3)2CO2R. 0-Hydroxy-acrylie Acid, CH(OH):CHCO2H, and £-Hydroxycrotonic Acid, CH,C(OH):CH.CO2H. Both these acids and their homologues are the starting points for the aci-forms (p. 40) of the fi-aldo- and fi-keto-carboxylic acids, such as formyl acetic ester and acetoacetic ester : aci-iorm CH(OH):CHCO2C2HS CH3C(OH):CH.CO2C2H§ keto-iorm CHO.CH,CO2C2H5 CH3CO.CH2CO2C2H6. Formyl Acetic Ester. Acetoacetic Ester. In the free state formyl acetic ester exists as j8-hydroxy-acrylic ester (aci- 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 fi-alkoxy- and fi-acyloxy-olefine 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 /?y-dibromo- or dichloro-fatty acids with the loss of 2 molecules of halogen acid. These A1- and A'-lactones are changed back into y-keto- or aldehyde acids by hydrolysis. tf-Butene Lactone, CrotoJactone,CH:CH.CHzCOO, m.p. 4°, b.p.15 96°, is formed from jSy-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, C2H6QCH2CH.CHaO (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 laevulinic acid and acetyl laevulinic acid. The A'-lactone can be formed from the A1-lactone by various methods ; the change is, however, reversible. The AMactone, in contra- distinction to the AMactone, can be condensed with aldehydes at the a-CH3 group (A. 319, 1 80). Mesitonic acid (aa-dimethyl laevulinic acid, p. 423) gives rise to a-Ditnethyl t^-Angelic Lactone, m.p. 24°, b.p. 167°. The isomeric aap-trimethyl-A*-butero- lactone is prepared from the corresponding dibromo-acid. Iso-octenolactone, (CH,)aCHCH2CH.CH:CH.COO, is obtained from iso-octenic acid dibromide (C. 1905, II. 457 ; A. 347, 132). y - Methyl - and y - Ethyl - a/3 - dichloro - and - aj8 - dibromo - butene Lactone R.CH.CX:CXCOO, b.p.22 120°, b.p,4 110°; m.p. 69°; m.p. 51°, are prepared from mucochloric acid and mucobromic acid (p. 402) by means of magnesium 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 = 4-40-8, and is a strong emetic. It passes into sorbic acid (p. 305) when heated with sodium hydroxide or hydrochloric acid (B. 27, 344). Di-olefine 8-lactones have been obtained from coumalic acid and isodehy- dr acetic acid by the splitting-off of carbon dioxide : Coumalin, 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. 51-5°, 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 nitro-acid ester, ~TT3^>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)COOC2H6, b.p.18 94°, is converted by hydrochloric acid into dimethyl pyroracemic acid (p. 408). £-Amino-acids and /3-Hydrazino define Carboxylic Acids. This group contains the reaction-products of ammonia and the hydrazines on /3-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 CH8C:CH.CO close connection to the jS-ketone-acid esters will be considered with them (p. 418). 8-Dioleflne Lactams. XH— CCk a-Pyridone, B-Aminopentadiene Acid Lactam, CH^ ">NH, m.p. 106°, 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— COV odourless Ethylimide, CH<f >N.C2H8, b.p. 258°, and a-Ethoxypyridine, XCH=CHX XH— C(O.C2H6U CHr^ ^N, b.p. 156°, which possesses an odour like that of pyridine XCH— CHX (B. 24, 3144) (see Vol. II.). Pseudolutidostyril, [^,5]-Dimethyl a-Pyridone, Mesitene Lactam, XH CO, CH3— Of >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 COt (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 monocar boxy lie 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-[-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) ; (20) by heating dichlor- and dibromacetic acid to 230° with water (B. 25, 714) ; (26) by boiling silver dichloracetate with water (B. 14, 578) ; (2c) the best method is by the action of potassium acetate on dichloracetic acid, producing diacetyl dihydroxy acetic 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+H2=COOH.CH(OH)2. (6) 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 un decom- posed with steam. Salts. — The salts contain water of crystallization which, on being dried, give it up with partial decomposition. The calcium salt, (C2HtO3)8Ca-f 2H2O, is sparingly soluble in water (A. 317, 147 ; C. 1904, II. 1705). Esters: Glyoxylic Ethyl Ester, CHO.COOC,H6, b.p. 130°, an easily poly- meriied substance, is produced by the electrolytic reduction of oxalic ether, and ALDEHYDE-ACIDS 401 also from its alcoholate, C2H5OCH(OH)CO2C2H5, b.p. 137°, by the action of P2O5. This substance is prepared by the reduction of the oxalic ether with sodium amalgam (see above). Alcohol and hydrochloric acid produce Di-ethoxyacetic Ester, (C2H5O)2CHCO2C2H6, 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, 4953). 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). 