1658
JOHN
n. ROBERTS AND D A V I D Y. CURTIN TABLE I
P' N
Synthesis E
\RD NCiHeO
A C
N(i-CsHdz N(n-GHeh N(CHdz N(CnHs) a
N(n- CsHd z N(cyclo-CsHii)a Nc&sO NCH(CHs)(CHz)r
C 30 C 36 A 37 A o r B 83 85 D 15 C 53 C 43 70 A 70 D 30 C C 31
N(CzHs) I N (CzHs)z NHCHa N H (i-CaH7)
C C A A
--(CHdrKH( It-CdHg) W (CzHs) P -(cHZ)4--CHzCHaCH(CHs)--N(CzHs)z -( CHz)sN(CPHI)~ -CH(CHs) (CHdaN(CzHa)a -(CHI) 6N(CnHs)3 -( CH2)BNCiHaO
A D D D A D D
.
Pet. ether Acetone Water A1c.-pet. ether Alc. abs. A1c.-ether
190(3) 115-116 87-88 >265 247-248 (dec.) 190-192
8.85 CiDHzaNzOa 7.94 CieHzsNzOz.HC1 C~iHsNz02.HC1~2HzO 6 . 7 3 6.92 CprHazNaOa.HC1 9.01 CisHiINzOs~HCld 8.68 CI,HZZOPNZ.HCI
178-179 184-185 204-207 58-60
CirHzeNsOz.HCI CI~HZDWZOZ.HCI CizHi4iYzOz.HCI CiiHi~NzOz
195-197 183-184 158-159 175-176 174-182 (5) 206-208 40-42
CisHmN~0z.HCI Ci6H2nNaOrHCI CisHzzXzOvHCI C~~HziNnOz.HC1 CiiHz4NzOzg CiaHzeNzOz~HCI CiaHz4NzOs
Solvent 84 Hz0 Ether-alc. 35 Alc. 80% Ether-alc. 2 . 5 Pet. ether 59 Pet. ether
N(C*3)2 N(CzHs)z
N(n-C4H9)2
N, Formula Calcd. 10.60 CisHuNzOa.Hz0 C1aHirNz0s.HCl 9.92 CitHisNzOz 9.98 CirHieNzOrHCl 12.84 CizHirNzO, C14HisNzOz CvHisNz0t.HCI 9.01 CieHzaNzOn.HC1 9.26 CiaHleNzOa 10.43 CiaH1sNz0z~HCl CisHzoN20rHCI~C~He0 8 . 1 7 9.44 CaHzaNzOn~HC1 8.62 CiiHza0zNz.HCI
% '
E
N (i-C3Hi)i
A1c.-ether Pet. ether Ale. abs. A1c.-ether Acetone A1c.-ether
M. p.. OC. orb. p. (mm.) 98-103' or 96-98 195-196 (dec.) 94-95' 186-187 104-105 45-47b 235-236 207-209 161-167 ( 2 . 5 ) 203-204 79-80 181-182' 214-216
Yield,
NC~HIQ
-CHzCH(CHy)---CH( CHI) CHa----(CHz)s-(CHI) 3-
Vol. 68
40 29 2.8 28
Acetone Acetone Alc.-ether Ether Pet. ether 9 . 5 Alc. abs. 35 Alc. abs. 4 Acetone 62 Ah.-ether 57 Pet. ether 65 Alc-ether 30 Pet. ether
%
Found 10.59 9.53
9.55 12.93
8.96 9.25 10.37 8.46 9.41 8.55 9.17 7.52 6.75 6.89 8.83 8.50
9.44 9.33 9.44 9.36 11.00 10.75 11.38 11.72 9.44 9.01 9.01 8.62 9.72 8.27 8.85
9.50 8.73 8.65 8.46 9.84 8.07 8.83
*
Prepared Sachs (ref. %(a))m.p. 117-118'. Walls (ref. 2(b)) m.p. 46-47". 6 Shriner and Hickey m. p. 144-145". by Dr. M. T. Lemer. e Kharasch and Fuchs (ref. 2(d)) obtained this compound as a mixture with its isomer. The preparation from the diamine eliminates the rearrangement which they describe. I Hot stage melting point. responding increase in efficiency, and branching of this chain is unfavorable. Increasing the size of R' and R" does not increa.se the efficiency in wheals t o any marked extent, but does increase corneal anesthetic effect. When either R' or R." is H, the efficiency is decreased, even for a compound of the same molecular weight. The: compounds in which R is methylene were not tested, because the hydrochlorides, soluble in water, rapidly decomposed and deposited a precipitate of phthalimide.
Acknowledgment.-Thanks
are due Messrs.
[CONTRIBUTION FROM THE CONVERSE
E. F. She1bel-g and L. F. Reed for the microanalyses herein reported.
Summary A series of N-alkamine substituted phthalimides is most Of whose members are effective local anesthetics, especially for parenteral rather than topical use. NORTH CHICAGO,
ILLIXOIS RECEIVED -4PRIL 29, 1940
MEMORIAL LABORATORY OF HARVARD UNIVERSITY]
Metalation of Benzotrifluoride BY JOHN D. ROHERTS' AND DAVIDY. CURTIN
Aromatic substituents groups which direct occurs more rapidly than nuclear metalation. In ortho-para in electrophilic substitution reactions the present work the metalation of benzotrisuch as nitration and sulfonation appear to exert fluoride has been investigated since the trifluoroa similar influence in the nuclear metalation of methyl group is known to be resistant to chemical substituted benzenes.2 No studies have been re- attack3t4and strongly meta-directing in nitration4 ported of the influence in metalation reactions and in chlorination6 reactions. Benzotrifluoride is readily metalated in refluxing of groups which lead to metu substitution with electrophilic reagents. In general, reaction of such ether solution by n-butyllithium. Carbonation groups with the customary metalating agents of the metalation products gave a 48% yield of a (1) National Research Fellow, 1945-1946 (2) See Morton Chem Rev 36, 1 (1944), for a summary of u ork on orientation in nuclear metalation reactions notably by C Llmdn Morton and Wittig dnd their collaborators
(3) Gilman and Woods, THISJOURNAL, 66, 1981 (1944). (4) Swarts, Bull. sci. acad. roy. Belg.. 6, 389 (1920); C h e m . Zentr.. 92, 11, 32 (1921). (5) Wertyporoch, Ann., 493, 153 (1932).
Aug., 1946
METALATION O F
BENZOTRIFLUORIDE
1659
mixture of solid acids which was found to consist of 0- and m-trifluoromethylbenzoic acids in a ratio of about five to one. Little, if any, of the p isomer appeared to be present. A competitive metalation experiment was carried out with anisole and benzotrifluoride. The reaction of 0.1 mole of n-butyllithium with a mixture of 0.1 mole of anisole and 0.1 mole of benzotrifluoride resulted after carbonation in a 40% yield of almost pure o-anisic acid. Since benzene is metalated only slightly under the conditions used in the metalation of benzotrifluoridej6it is clear that the trifluoromethyl group activates the benzene ring toward metalation. However, the result of the competitive experiment indicates that the activating influence of a trifluoromethyl group is less than that of a methoxyl group. From a number of previous experiments on the relative rates of substituted benzenes' and from the present work the following approximate relationships between the degrees of activation of the aromatic nucleus by various substituent groups may be inferred
The operation of the coordination step of this mechanism would be expected to aid the reaction by increasing the polarization of the carbon-metal bond of the metalating agent and by enhancing the inductive effect of the electron-attracting substituents. In addition, the initial coordination might aid the reaction by tending t o counteract the expected decrease in acidity of the 0- and phydrogens associated with the resonance of unshared electron pairs on the substituent groups with the aromatic ring. It should be noted that the formulation of the reaction mechanism as a nucleophilic attack on hydrogen obviates any necessity for the operation of the time-variable tautomeric effect (electromeric effect) which plays an important part in determining the rate and orientation of the electrophilic nuclear substitution reaction. This explanation is not completely satisfactory, however, since a number of apparently contradictory observations have been reported. For example, although 5-carbazolylbenzene is monometalated in an o-position and dimetalated in the two o-positions of the benzene ring,g triphenylamine,l0 triphenylarsinell and triphenylphosF > C1 phine12 are metalated in the m-position. FurtherF > -0CHs > -CFa > H more, while dibenzothiophene is metalated by F > -N(CH& butyllithium t o give 4-lithodiben~othiophene,'~ O > S > N phenylcalcium iodide effects metalation metu to These relationships are the ones that would be the sulfur linkage.14 I n a t least one case the rate predicted if the inductive effect were most im- of stirring of the reaction mixture was found to portant in determining the ease of reaction. The influence the course of the metalation r e a ~ t i 0 n . l ~ inductive effects of the groups mentioned are such In addition, i t should be noted that cumene is as to be expected to increase the acidity of the metalated by amylsodium in the 0- and p-posiring hydrogens. Hence, if the inductive effect tions16and if the inductive effect alone determines determines the reaction rate, the primary process the orientation in this metalation reaction the mof the reaction seems best formulated as the re- isomer would be the expected product of a nucleomoval of a ring hydrogen (as a proton) by a nucleo- philic attack by the anion of the metalating agent. philic attack by the anion of the metalating agent.8 Experimental The predominantly o-orientation observed with the substituents mentioned above is best acMetalation of Benzotrifluoride.-To a solution of ncounted for by assuming that the reaction involves butyllithium prepared from n-butyl chloride (23 g., 0.25 lithium metal (3.0 g., 0.43 gram atom) and 100 ml. an initial coordination of the metallic atom of the mole), of ether was added benzotrifluoride (25 g., 0.17 mole). The metalating agent with an unshared electron pair mixture was refluxed for six hours and then poured onto 500 on the substituent group followed by the removal g. of powdered Dry Ice. After the excess carbon dioxide of an o-hydrogen by the anion of the metalating had evaporated, water was added and the non-acidic material removed with ether. The aqueous residue was acidiagent. fied and extracted with ether. Evaporation of the ether extract gave 15.5 g. (48%) of a mixture of trifluoromethylbenzoic acids. The crude product was crystallized from petroleum ether (b. p. 70-90") giving 10.5 g. of o-trifluoromethylbenzoic acid., m. p. 102-107O. One recrystallization from the same solvent raised the melting point to 108-109°. The amide was prepared in the usual way an! crystallized from benzene-petroleum ether, m. p. 162-163 , Reported melting points are 108.5"for the acid and 161O for the amide."
(6) Gilman, Pacewitz and Baine, THIS JOURNAL, 62, 1514 (1940). 17) (a) Wittig and Merkle, Bcr., 76B, 1491 (1942); (b) Wittig, Pieper and Fuhrmann, ibid., 73B, 1193 (1940); (c) Wittig and Fuhrmann. zbid., 738, 1197 (1940); (d) Gilman and Stuckwisch. T H I S JOURNAL, 67. 877 (1945). (8) See Refs. 2 and 7 c for somewhat different viewpoints.
(9) Gilman and Stuckwisch, THISJOURNAL, 66, 1729 (1943) (10) Gilman and Brown, tbid., 62, 3208 (1940). (11) Gilman and Stuckwisch, ibid., 63,3532 (1941). (12) Gilman and Brown, ibid., 61, 824 (1945). (13) Gilman and Jacoby, J . Org. Chem., 3, 108 (1938). (14) Gilman, Jacoby and Pacewitz, ibid., 3, 120 (1938). (15) Morton and Fallwell, THISJOURNAL, 60, 1924 (1938). (16) Morton, Massengale and Brown, ibzd., 67, 1620 (1945). (17) De Brouwer, Bull. SOL. chim. Belg., 39, 298 (1930).
THOMAS S. LOGAN
1660
The mother liquors from the crystallization of the o-acid were evaporated to dryness and attempts were made to separate the components by fractional crystallization. Only a small quantity (0.22 g.) of the pure m-isomer was obtained, m. €1. 103-104.5" (lit.l* m. p. 103'), which was identified by conversion to isophthalic acid (methyl ester, m. p. 62-63'). The balance of the solid crystallization residues (4.1 g.) was analyzed by hydrolysis with hot 80% sulfuric acid and separation of the resulting phthalic acids by the method of Srnith.'s From 1.08 g. of the crystallization residue tliere was obtained 0.36 g. (38%) of phthalic acid, 0 56 g. (48%) of isophthalic acid and 0.02 g. (2y0)of terephthalic acid. On this basis the composition of the original mixture of trifluoromethylbenzoic acids was ortho, 83%; meta, 16%; and para,
