[CONTRIBUTION FROM
THE
WILLIAM H. NICHOLS LABORATORY, NEW YORK UNIVERSITY]
CONDENSATION OF AMIDES WITH CARBONYL COMPOUNDS : BENZYL CARBAMATE WITH ALDEHYDES AND tclplia KETO ACIDS* ARTHUR E. MARTELL
AND
ROBERT M. HERBST
Beceived July 29, 19.41
The condensation of amides with carbonyl compounds was observed as early as 1870 by Roth (1) who prepared benzylidenediacetamide by heating benzaldehyde with acetamide. CcH&HO
+ 2CH&OXHz
-+
CeH&H(NHCOCHa)2
+ HzO
Soon thereafter Bischoff (2) observed the formation of analogous compounds by the condensation of urethan with a series of aldehydes. Bischoff also noted that chloral and bromal reacted with only one mole of urethan forming compounds which appeared to be the products of simple addition of the urethan to the carbonyl group of the aldehyde. Mochelles (3) has described similar derivatives of chloral with a number of amides and succeeded in converting these into unsaturated compounds by the elimination of water. OH
RCHO
+ R/CO?;H~--+
RCHXHCORI --+
RCH=-KCOR’
+H~O
More recently Noyes and Forman (4) studied the condensation of a series of aldehydes with acetamide, and obtained in yields of six to fifty-four per cent the products resulting from the condensation of two moles of amide with one mole of aldehyde. Condensations of simple amides with simple ketones have not been observed. Aside from products such as pyvuril, NH-CO-NH2
I CO whose formation INH-CO-NH I
CH3-C-
1 Abstracted from a thesis presented by Arthur E. Martell to the faculty of New York University in partial fulfillment of the requirements for the degree of Doctor of Philosophy. 878
CONDENSATION OF AMIDES
879
from urea and pyruvic acid was observed by Grimaux ( 5 ) , it remained for Bergmann and Grafe (6) to initiate the study and demonstrate the usefulness for synthetic purposes of the condensation products of simple amides with alpha keto acids. These authors prepared a , a-diacetaminopropionic acid, CH&(NHCOCH3),COOH, and a-acetaminoacrylic acid, CH2=.C(NHCOCH3)COOH, by the interaction of acetamide and pyruvic acid and developed a method for the synthesis of pyruvylamino acids RCHI:NHCOCOCH~)COOH,from the former. More recently Shemin and Herbst (7) have studied the interaction of acetamide and phenylpyruvic acid, benzoylformic acid and tx-ketoglutaric acid, and have reported the formation of a-acetaminocinnamic acid, a , a-diacetaminophenylacetic acid and a-acetamino-a-hydroxyglutaryl lactone, respectively. Methods of synthesizing peptides from such condensation products have been developed (8). However, the usefulness of these methods for the preparation of free peptides is impaired by the necessity of applying hydrolytic procedures for the removal of acyl groups. Such procedures usually cause a certain amount of splitting of the peptide linkages, even under. carefully controlled conditions. Since Bergmann and Zervas (9) had demonstrated the ease with which the carbobenzoxy1 group could be removed from derivatives of amino axids and peptides by catalytic hydrogenation, a study of the applicability of the carbobenzoxyamino derivatives of alpha keto acids in peptide syntheses was indicated. As the first step in this direction a study of the condensation of benzyl carbamate with aldehydes and alpha keto acids was undertaken. Benzyl carbamate was found to condense readily with both aliphatic and aromatic aldehydes. Condensations were carried out with isovaleraldehyde benzaldehyde, anisaldehyde, piperonal, and furfural. In all cases one mole of aldehyde reacted with two moles of benzyl carbamate. No attempt was made to isolate intermediates in the Condensation reaction. The condensation of benzyl carbrimate with alpha keto acids led to a greater variety of products. From the reaction with pyruvic acid only a , a-dicarbobenzoxyaminopropionic acid could be isolated. However, two products were obtained by the interaction of benzyl carbamate with phenylpyruvic acid, depending upon the temperature at which condensation took place. After reaction a t 95" only a , a-dicarbobenzoxyamino-,!3phenylpropionic acid could be isolated, while a t 135" the only product obtained was a-carbobenzoxyaminocinnamic acid. It was further observed that a , a-dicarbobenzoxyamino-P-phenylpropionic acid lost a molecule of benzyl carbamate on heating at 140" with the formation of a-carbobenzoxyaminocinnamic acid. The reverse of this reaction, addition of the amide to the aminocinnamic acid derivative, did not take place. When a-ketoglutaric acid was condensed with benzyl carbamate, the lac~
880
A. E. MARTELL AND R. M. HERBST
tone of a-carbobenzoxyamino-a-hydroxyglutaricacid was formed. The interaction of benzoylformic acid and benzyl carbamate gave only a small amount of carbobenzoxybenzalimine rather than the diaminophenylacetic acid derivative expected by analogy to the condensation with acetamide (7). The course of the various condensation reactions is summarized in the accompanying scheme. 0 (A)
/I
RCX
+ (B) CsHsCHzOCONHz
NHCOOCH~CBH~
I -+ RCX I
NHCOOCHzCeHs
I XBLRCX
I
NHCOOCHzCsHs
(C)
OH
(D)
I NHCOOCH2CsHb
I
NCOOCHzCeHs f-----f
R'=CX
II
RCX
(E)
(F)
When X = H, R = (CH&CHCHz-, CsH5-j (p)C&OC&-, 3,4-CHz02C&-, or C4HsO-, When X = COOH, R = C H r , C J I & H r , -CH2CHzCOOH, or C6H5-. R' = R minus H except for CeHb, where formula (E) is structurally impossible,
The primary reaction is the addition of benzyl carbamate to the carbonyl group of the ketonic compound with the formation of an intermediate of type (C). This intermediate may be stabilized by the formation of a lactone as in the case of a-ketoglutaric acid. The second step in the reaction may be either the direct replacement of the hydroxyl group of ((2) by another benzyl carbamate residue, or the elimination of a molecule of water with the formation of unsaturated intermediates of types (E) or (F). In the latter case the reaction is completed by the addition of a second molecule of benzyl carbamate at the site of unsaturation. The second addition reaction probably involves saturation of a carbon-nitrogen double bond as in (F). The failure of a-carbobenzoxyaminocinnamic acid to react with benzyl carbamate may be cited in support of this interpretation. Other aminocinnamic acid derivatives have shown similar unreactivity towards the further addition of amides (7). On the other hand the addition of acetamide (7) as well as benzamide and propionamide (10) to a-acetaminoacrylic acid with the formation of a ,a-diacylaminopropionic acid derivatives has been observed.
881
CONDEXSATION O F AMIDES
This apparent discrepancy may be ascribed to the tendency of the phenyl group in the aminocinnamic acid derivatives to hold the side chain double bond in a position conjugated with the aromatic ring and thus prevent the tautomeric shift of the double bond to the carbon-nitrogen position. In certain cases the facts permit a choice between the several possible routes. The formation of a ,a-dicarbobenzoxyamino-P-phenylpropionic acid from phenylpyruvic acid probably involves the direct replacement of the hydroxyl group of intermediate (C) by a benzyl carbamate group. The intervention of an unsaturated intermediate may be ruled out in this case. A similar mechanism is probably involved in the formation of the diacylamino derivatives of aldehydes. The fact that carbobenzoxybenzalimine, C6H6CH=NCOOCH2C8H5, could exist in a reaction mixture in the presence of an excess of benzyl carbamate supports this view. However, this postulate still lacks rigorous experimental verification. In the case of a-ketoglutaric acid the stabilization of the intermediate of type (C) by lactone formation determines the route followed, while in the case of pyruvic acid the data do not permit designation of a choice. The condensation products of both aldehydes and keto acids were hydrolytically decomposed into their components by merely boiling for a few minutes with dilute aqueous hydrochloric acid. Simply boiling its aqueous solution sufficed to decompose a-carbobenzoxyamino-a-hydroxyglutaryl lactone into a-ketoglutaric acid and benzyl carbamate. 0
NHCOOCH~CBH~
NHCOOCH2CsH6
X = H or COOH
Catalytic hydrogenation of the products on the other hand led to the formahion of primary amines from the aldehyde derivatives and alpha amino acids from the keto acid derivatives. YHCOOCH~CBHS I (H)
-+
IRCX
I
NHCOOCHzCeH5
K Hz
I RCHX
ilHCOOCH2CeHa
(€0 C-
I
R'=CX
+ CsH6CHz
+ XHa 3- COz
X = H or COOH
Benzylamine, anisylamine, and piperonylamine were obtained in excellent yield by hydrogenation of the respective dicarbobenzoxyamino derivatives over palladium oxide catalyst. On similar treatment the
882
A. E. MARTELL AND R . M. HERBST
analogous derivatives of isovaleraldehyde and furfural failed to yield simple amines. The nature of the products formed has not been established. Application of the same technique to a,a-dicarbobenzoxyaminopropionic acid led to the formation of alanine, while a,a-dicarbobenzoxyamino-0-phenylpropionic acid and a-carbobenzoxyaminocinnamic acid were both converted in good yield into 0-phenylalanine. a-Carbobenzoxyamino-a-hydroxyglutaryl lactone failed to behave in the same way. On reduction, most of the nitrogen was recovered as ammonia, both with the hydrogenation technique successfully employed in the above cases and with the method previously applied with success to the acetamide analog (7). EXPERIMENTAL
Benzyl carbamate. Benzyl chlorocarbonate was prepared by a method essentially that of Bergmann and Zervas (9). The amide was prepared by slowly pouring the acid chloride obtained from 100 g. of benzyl alcohol into a liter of ice-cold aqueous ammonia (d = 0.90) with rapid stirring [comp. Thiele (11)l. The amide formed rapidly with heat evolution, and precipitated. Aiter the reaction mixture had stood at room temperature for half an hour, the product was filtered off by suction, washed thoroughly with cold water, and air dried. The yield of practically pure benzyl carbamate was 139 g. (95%), m.p. 86". By recrystallization from toluene (200 ml.) the product was obtained in the form of glistening rectangular plates (130 g.), m.p. 87". Recrystallization from water also gave a satisfactory product. a-Keto acids. Benzoylfonnic acid was prepared by the oxidation of mandelic acid as suggested by Acree (12). The purity of the product was greatly enhanced by recrystallization from dry toluene. Phenylpyruvic acid was prepared by the hydrolysis of a-acetaminocinnamic acid, following the directions of Herbst and Shemin (13). a-Ketoglutaric acid was prepared from ethyl succinate and ethyl oxalate by the method of Neuberg and Ringer (14). Condensation of Benzyl Carbamate with Aldehydes and a-Keto Acids General procedure. Ten grams of benzyl carbamate was heated without solvent for varying lengths of time under reflux with the aldehyde or keto acid. The amount of carbonyl compound used, the conditions employed, and the results obtained in each case are summarized in Table I. All condensations except those with isovaleraldehyde were carried out under reduced pressure (10-15 mm.). The condensation products of benzyl carbamate with aldehydes were purified by crystallization from benzene or toluene, while the alpha keto acid derivatives were crystallized from ethyl acetate with the addition of petroleum ether when necessary. The purification of a,a-dicarbobenzoxyaminopropionicacid was greatly simplified by carefully washing the crude product with cold water prior to recrystallizing from ethyl acetate. It was also found advantageous with a,a-dicarbobenzoxyamino-8phenylpropionic acid and o-carbobenzoxyaminocinnamic acid t o separate the products from unreacted benzyl carbamate by extracting the reaction mixture with cold dilute aqueous alkali. Acidification of the alkaline aqueous extracts liberated the free acids, which were then recrystallized as just indicated.
883
CONDENSATION OF AMIDES
TABLE I CONDENSATION OF BENZYLCARBAMATE WITH CARBONYL COMPOUNDS
-
-
COMPD NO.
RAMEIa CARIONYL OMPD.
CARBONYL COMPOUND
:ME0 1 PEMP., OC
.
REACTION HB.)
Isovaleraldehyde I1 Benzaldehyde
4
100
4
80
1
I11 Anisaldehyde
5
100
4
I
4
IV
Piperonal
5
110
5
V
Furfural
4
100
3
Pyruvic acid
4
70
2
VI1 Phenylpyruvic acid
6
95
4
VI11 Phenylpyruvic acid I X a-Ketoglutaric acid
6
135
3
10
80
4
5
125
12
VI
Benzoylformic acid
X
0
nELD,
%
Dicarbobenzoxy-3-methyl butylidenediamine 1 Dicarbobenzoxybenzylidenediamine Dicarbobenzoxy-p-methoxybenzylidenediamine Dicarbobenzoxy-3,4methylenedioxybenzylidenediamine Dicarbobenzoxyfurfurylidenediamine a ,a-Dicarbobenzoxyaminopropionic acid a,a-Dicarbobenzoxyamino-p-phenylpropionic acid a-carbobenzoxyaminocinnamic acid a-Carbobenzoxyamino-ahydroxyglutaryl lac. tone Carbobenzoxybenzaliminc
__
124
55
175
68
193
65
204
63
163
49
139
85
141
48
160
71
176
90
240
25
- -
Ten grams of benzyl carbamate was used in each case. TABLE I1 ANALYSESOF CONDENSATION PRODUCTS
I
CAICULATED
CoYPD'
NO.
-I I1 I11 IV V VI VI1 VI11 IX
X
EMPIBICAL FOBMULA
C,%
E,%
N>%
68.1 70.7 68.7 66.4 66.3 61.3 66.9 68.9 55.9 75.3
7.1 5.7 5.8 5.l 5.3 5.4 5.4 5.0 4.7 5.4
7.6 7.2 6.7 6.4 7.4 7.5 6.2 4.7 5.0 5.9
-- -
FOUND
z:, ---- 372 448 297 140
C,%
H,%
N, %
68.2 70.6 68.6 66.4 66.3 61.4 67.1 68.9 55.7 75.6
6.8 5.7 5.7 5.0 5.4 5.6 5.4 5.2 4.5 5.4
7.4 7.1 6.5 6.4 7.5 7.3 6.2 4.6 5.0 5.8
-
Neut.
equ1v.
386 453 291 140
884
A. E. MARTELL AND R. M. HERBST
Both types of products usually crystallized in the form of needles. Exceptions were the products derived from benzaldehyde and furfural, which separated from hot benzene as gelatinous masses that disintegrated t o colorless powders on drying. Both products were precipitated from ethyl acetate as colorless powders on addition of petroleum ether. The lactone of a-carbobenzoxyamino-a-hydroxyglutaric acid crystallized from ethyl acetate as hard, dense prisms, but separated from the same solvent on the addition of petroleum ether as fine needles. All of the products were insoluble in petroleum ether, ligroin, and cold water, but showed appreciable solubility in hot benzene, toluene, ethyl acetate, and ethyl alcohol. I n Table I1 are summarized the results of elementary analyses of the compounds described in Table I. a-Carbobenzoxyaminocinnamic acid from a,a-dicarbobenzoxyamino-P-phenylpropionic acid. a , a-Dicarbobenzoxyamino-P-phenylpropionicacid (1.0 g.) was heated on an oil-bath at 140" for one hour. The reaction mixture was extracted with cold dilute aqueous alkali. Upon acidification of the aqueous extract and recrystallization of the precipitate from ethyl acetate and petroleum ether, 0.45 g. (68% yield) of a-carbobenzoxyaminocinnamic acid, m.p. 159", was obtained. A small amount of benzyl carbamate, m.p. 85", was isolated by recrystallization of the alkali-insoluble residue from hot water and from toluene. Benzyl carbamate with a-carbobenzoxyaminocinnamicacid. A mixture of 0.15 g. of benzyl carbamate and 0.25 g. of a-carbobenzoxyaminocinnamic acid was heated on an oil-bath a t 95" for 16 hours. A small amount (47'%) of benzyl carbamate, m.p. 86", and 0.23 g. (92%) of unchanged a-carbobenzoxyaminocinnamic acid, m.p. 160°, were recovered from the reaction mixture by the procedure described above.
Hydrolysis of Condensation Products General procedure. The condensation products of benzyl carbamate with aldehydes were hydrolyzed by boiling one gram of the derivative with 50 ml. of normal aqueous hydrochloric acid in an atmosphere of nitrogen for the time indicated in Table 111. When hydrolysis was complete, a solution of an equimolar amount of 2,4-dinitrophenylhydrazinein a mixture of 10 ml. of concentrated hydrochloric acid and 15 ml. of 95% alcohol was added, and the mixture boiled under reflux for five minutes. After cooling the fiolution, the 2,4-dinitrophenylhydrazonewhich separated was filtered off and purified by recrystallization from alcohol. The identity of the hydrazones was established on the basis of their melting points and mixed melting points with authentic samples. The condensation products with a-keto acids were hydrolyzed by boiling one gram of the derivative with 100 ml. of normal aqueous hydrochloric acid for the time interval indicated in Table 111. The lactone of a-carbobenzoxyamino-a-hydroxyglutaric acid was hydrolyzed by merely boiling with water. The hydrolysates were treated with an equimolar amount of 2,4-dinitrophenylhydrazine dissolved in 100-150 ml. of normal aqueous hydrochloric acid. The dinitrophenylhydrazones so obtained were recrystallized from aqueous alcohol and identified by their melting points and mixed melting points with authentic samples. The data relating to the individual cases are summarized in Table 111. Reduction of the Condensation Products General procedure. The reduction of the condensation products was accomplished by dissolving or suspending the substances (2-3 9.) in absolute alcohol (50-100 ml.) and shaking with palladium oxide (0.1 g.) in an atmosphere of hydrogen in a Burgess-
885
CONDENSATION OF AMIDES
TABLE I11 HYDROLYSIS OF CONDENSATION PRODUCTS 2,4-DINITROPHENYLHYDRAZONE COYPD. N O .
TIME OF HYDROLYSIS
OF CARBONYL COMPOUND
CARBONYL COMPOCND FORMED
Yield, %
M.p.
'C.
Ref.
~~
I I1 :I11 IV
V VI VI I VI11
IX X
15 min. 15 min. 15 min. 15 min. 15 min. 30 min. 3 hr. 4 hr. 5 min. 10 min.
Isovaleraldehyde Benzaldehyde Anisaldehyde Piperonal Furfural Pyruvic acid Phenylpyruvic acid Phenylpyruvic acid a-Ketoglutaric acid Benzaldehyde
89 99 99 97 93 98 96 94 100 80
124 240 252 266 227 217 192 192 217 239
15 16 17 17 18 19 a
20 16
a This derivative has not been described previously. It was obtained in the form of fine orange-yellow needles on crystallization from &% alcohol. Anal. Calc'd for ClaHlpNaOB:N, 16.3. .Found: N, 16.4.
TABLE IV REDUCTIONOF CONDENSATION PRODUCTS
-
~
COMPD. NO.
BUBBTANCE IBOLATED
M.P.,'C.
IELD
%
M.P., "c.
-
___
I1 Benzylamine hydrochloridt
260 de- 93 camp.
253 de- 89 I11 Anisylamine hydrochloride camp. IV Piperonylamine 260 de- 90 hydrochloride camp. VI Alanine 280 de- 60 VI1 &Phenylalanine
VI11
YITROQEN DERIVATIVE
&Phenylalanine
camp. 250 decamp.
62
250 de- 85 camp.
-
REF.
-
N-Benzylbenzamide Benz ylurea Anisylamine picrate Piperonylamine picrate Alanine a-PhenylureidoB-phenylalanine 3-Phenyl-5-benzylhydantoin a-Phenylureido$-phenylalanine 3-Phenyl-5-benzylhydantoin
105 21, 148 22,23 190 decamp 200 decamp
%
Found
15.2 14.6 15.6
177 decamp
24
171
180 decamp
24
172
-
Parr low-pressure hydrogenation apparatus. The reduction of the aldehyde derivatives was complete in two hours, that of the keto acid derivatives in four hours. The amines formed by hydrogenation of the aldehyde derivatives were isolated
886
A . E. MARTELL AND R. M. HERBST
after filtering off the catalyst, by acidifying the alcoholic solution with hydrochloric acid and evaporating to dryness. Recrystallization of the hydrochloride residue from absolute alcohol served to remove the contamination of ammonium chloride. The identity of the hydrochlorides was established by their melting points, and by conversion into suitable derivatives and comparison with samples of known identity as indicated in Table IV. The amino acids formed by the reduction of the keto acid derivatives usually separated from the alcoholic solution during the hydrogenation. After filtration they were separated from the catalyst by extraction with water. Purification was accomplished by recrystallization from hot water, alone or with the addition of alcohol when necessary. Their identity was established by analysis or by conversion into suitable derivatives and comparison with substances of known identity as indicated in Table IV. The reduction of the carbobenzoxyamino derivatives of isovaleraldehyde and furfural failed to give the expected primary amines. The nature of the products formed still remains undetermined. No glutamic acid could be isolated after the reduction of a-carbobenzoxyamino-cuhydroxyglutaryl lactone by the technique just described. After hydrogenation most of the nitrogen was present as ammonia, and excepting a small amount of a-ketoglutaric acid which could be isolated as the 2,4-dinitrophenylhydrazone,no effort was made to determine the fate of the carbon skeleton. Application of the technique successfully used in the conversion of the analogous acetamino derivative t o glutamic acid (7) likewise failed t o lead to the desired result. The pertinent data concerning the results of the hydrogenation experiments are summarized in Table IV. SUMMARY
1. The condensation of benzyl carbamate with a series of aldehydes including isovaleraldehyde, benzaldehyde, anisaldehyde, piperonal, and furfural has been studied. In each case two moles of amide reacted with one mole of the aldehyde. 2. The condensation of benzyl carbamate with alpha keto acids leads to a variety of products formed by the interaction of one mole of the keto acid with one or two moles of the amide. With pyruvic acid a ,a-dicarbobenzoxyaminopropionic acid is formed. From phenylpyruvic acid, depending on the conditions employed, either a ,a-dicarbobenzoxyaminop-phenylpropionic acid or a-carbobenzoxyaminocinnamic acid is formed. With a-ketoglutaric acid the lactone of a-carbobenzoxyamino-a-hydroxyglutaric acid is formed, while the reaction with benzoylformic acid appears to be abnormal and leads to the formation of carbobenzoxybenzalimine. 3. a,a-Dicarbobenzoxyamino-p-phenylpropionicacid is converted into a-carbobenzoxyaminocinnamic acid by heating. The reverse of this reaction does not take place. 4. A mechanism for the condensation of aldehydes and alpha keto acids with benzyl carbamate has been suggested. The reaction involves a primary addition of the amide to the carbonyl group, followed either by
CONDENSATION OF AMIDES
887
direct replacement of a hydroxyl group by another amide residue, or by elimination of water with the formation of unsaturated intermediates, to which a second mole of amide may add. 5. The hydrolysis of the condensation products with aqueous acid was studied and found to result in the regeneration of the original aldehyde or keto acid and benzyl carbamate. 6. The catalytic hydrogenation of the condensation products of the aldehydes was found to lead to the formation of primary amines, while reduletion of the keto acid derivatives leads to alpha amino acids. This consititutes a new method for the synthesis of primary amines from aldehydes, and for the conversion of alpha keto acids into alpha amino acids. SE,W YORK,N. Y. REFERENCES
ROTH, Ann., 164, 72 (1870). BISCHOFF, Ber., 7, 628 (1874). IMOCHELLES, Ber., 24, 1803 (1891). YOYES A N D FORMAN, J. Am. Chem. SOC.,66, 3493 (1933). GRIMAUX, Ann. chim. phys., (5) 11,356 (1877). BERGMANNAND GRAFE,Z. physaol. Chem., 176, 196 (1930). SHEMINAND HERBST,J. Am. Chem. SOC.,60, 1954 (1938). HEMI IN AND HERBST,J. Am. Chem. SOC.,60, 1951 (1938). HERBSTAND SHEWIN, Proc. Am. SOC.,Biol. Chem., XXXV, 59 (1941). (9) BERGMANNAND ZERVAS,Ber., 66, 1192 (1932).
(1) (2) (3) (4) (5) (6) (7) (8)
(10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24)
Unpublished data. DENT,Ann., 302, 245 (1898). \CREE, Am. Chem. J.,60, 389 (1913). ‘Organic Syntheses” Vol. XIX, p. 77, John Wiley and Sons, New York, (1939). NEUBERGANDRINGER,Baochem. Z., 71,226 (1915). ~ L L E N J. , Am. Chem. Soc., 62,2955 (1930). ISHRINER A N D FUSON, “The Systematic Identification of Organic Compounds,’’ p. 110, John Wiley and Sons, New York, (1935). BRADY,J. Chem. SOC.,1931, 756. BREDERECK,Ber., 66, 1833 (1932). ISTRAIN,J. Am. Chem. SOC., 67,758 (1935). KREBS, Z. physiol. Chem., 218, 157 (1933). BECKMANN, Ber., 23, 3331 (1890). PATERNO AND SPICA,Gam. chzm. ital., 6, 388 (1875). ~CANNIZZARO, Gazz. cham. alal., 1, 41 (1871). MOUNEYRAT,Ber., 33, 2393 (1900).
‘THIELE AND
