5922
J . Org. Chem. 1989,54,5922-5926
cm-'; 'H NMR (CDC13)6 5.87 (s, 1 H, H-2), 4.16 (quartet, J = 7.2 Hz, 2 H, H-9), 2.90 (dd, J = 5.2 Hz, 1H, H-7), 2.80-2.70 (m, 1 H, H-6), 2.50-2.16 (m, 5 H, H-4, H-7, H-11), 2.15-2.08 (m, 1H, H-5), 1.83-1.70 (m, 1H, H-5), 1.48(quintet, J = 8.0 Hz,2 H, H-12), 1.33 (sextet, J = 7.2 Hz, 2 H, H-13), 1.27 (t, J = 7.2 Hz, 3 H, H-lo), 0.92 (t, J = 7.2 Hz, 3 H, H-14); 13CNMR (CDClJ 6 199.43 (C-1), 172.69 (C-8), 166.04 (C-3), 124.95 (C-2), 60.46 (C-9),42.97 (C-6), 37.53 (C-11), 34.66 (C-7), 29.75 (C-4), 29.09 (C-12), 28.68 (C-5), 22.34 (C-13), 14.22 (C-lo), 13.85 (C-14). Anal. Calcd for Cl,H,OS: C, 70.56; H, 9.30. Found: C, 70.55; H, 9.27. 6-(Carbethoxymethyl)-3-phenyl-2-cyclohexen-l-one (9). The reaction of 3-phenyl-2-cy~lohexen-l-one~~~ (3.0 g, 17.4 mmol) with LDA (19.2 mmol) and ethyl bromoacetate (3.5 g, 20.9 "01) was conducted in a fashion similar to that of method A. The crude material was purified by Kugelrohr distillation to yield 3.90 g (87%) of 9: bp 100-130 OC/O.Ol mmHg; IR (film) 1720, 1650, 1600 cm-'; 'H NMR (CDC13) 6 7.58-7.50 (m, 2 H, Ar protons), 7.47-7.38 (m, 3 H, Ar protons), 6.43 (s, 1 H, H-2), 4.18 (quartet, J = 7.2 Hz, 2 H, H-9), 3.00-2.75 (m,4 H, H-4, H-6, H-7), 2.4+2.25 (m, 2 H, H-5, H-7), 2.03-1.80 (m, 1 H, H-5), 1.29 (t, J = 7.2 Hz, 3 H, H-lo); 13C NMR (CDCl3) 6 199.39 (C-l), 172.50 (C-8), 159.06 (C-3), 138.39 (Ph), 130.01 (Ph), 129.97 (Ph), 128.84 (Ph), 128.74 (Ph), 126.03 (Ph), 124.56 (C-2), 60.49 (C-9), 42.89 (C-6), 34.61 (C-7), 28.64 (C-5),28.06 (C-4), 14.22 (C-lo). Anal. Calcd for C16H18O3: C, 74.40; H, 7.02. Found: C, 74.55; H, 7.12. 6-( Carbethoxymet hyl)-3-ethoxy-2-cyclohexen-1-one (10). The reaction of 3-ethoxy-2-cyclohexen-1-one (3.0 g, 21.4 mmol) with LDA (23.5 mmol) and ethyl bromoacetate (4.3 g, 25.7 "01) was conducted in a fashion s i m i i to that of method A. The crude material was purified by flash chromatography on silica gel eluted with 10% to 40% ethyl acetate in hexane to yield 2.70 g (56%) of 1O1OCIR (film) 1720,1655,1600 cm-'; 'H NMR (CDCl,) 6 5.35
(s, 1H, H-2), 4.16 (quartet, J = 7.5 Hz, 2 H, H-9), 3.95-3.85 (m, 2 H, H-11), 2.93 (dd, J = 4.5 Hz, 1 H, H-7), 2.79-2.65 (m, 1 H, H-6), 2.63-2.50 (m, 1 H, H-4), 2.45-2.35 (m, 1H, H-4), 2.27 (dd, J = 7.8 Hz, 1H, H-7), 2.15-2.07 (m, 1 H, H-5), 1.87-1.70 (m, 1 H, H-5), 1.36 (t, J = 7.5 Hz, 3 H, H-12), 1.27 (t, J = 7.5 Hz, 3 H, H-10); '3C NMR (CDC13) 6 198.96 (C-l), 177.53 (C-3), 172.72 (C-8), 101.99 (C-2), 64.38 (C-ll), 60.44 (C-g), 42.33 (C-6), 34.79 (C-7), 29.03 (C-4), 27.15 (C-5), 14.23 (C-lo), 14.15 (C-12). Simplified Procedure Utilized in the Excess Cyclohexenone Low-Temperature Study, Method B. The reaction of 2-cyclohexen-1-one(3.0 g, 31.2 mmol) with LDA (25 mmol) and ethyl bromoacetate (5.21 g, 31.2 "01) was conducted in a fashion similar to that of method A. The normal isolation and purification procedure yielded 3.70 g (65%) of 6. In a similar fashion the other 3-substituted-2-cyclohexen-1-ones were examined under these conditions, and the yield of the alkylated product is shown in Table I. Simplified Procedure Utilized in the Excess LBTSA Low-Temperature Study, Method C. The reaction of 2cyclohexen-1-one (2.0 g, 20.8 mmol) with LBTSA (22.9 mmol) and ethyl bromoacetate (4.60 g, 27.5 mmol) was conducted in a fashion similar to that of method A, with the exception that the dienolate was stirred for 30 min a t -78 "C before ethyl bromoacetate was added. The normal isolation and purification procedure yielded 2.65 g (70%) of 6. In a similar fashion the other 3-substituted2-cyclohexen-1-oneswere examined under these conditions, and the yield of the alkylated product is shown in Table I. Registry No. 1, 930-68-7; 2, 1193-18-6; 3, 6301-49-1; 4, 10345-87-6; 5, 5323-87-5; 6, 111248-50-1; 7, 83108-31-0; 8, 123540-67-0; 9, 123540-68-1; 10, 587756743; ethyl iodoacetate, 623-48-3; ethyl bromoacetate, 105-36-2.
Does the Reaction of Cu+ with H202Give OH Radicals? A Study of Aromatic Hydroxylation Manfred K. Eberhardt,* Glenda Ramirez, and Erick Ayala Department of Pathology, Uniuersity of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico 00936 Received May 30, 1989
The reaction of Cu+ with HzOz was studied by using the isomer distribution obtained with fluorobenzene, anisole, and nitrobenzene as a probe for OH radicals. The reaction with benzene in presence of 5 X M Cu2+ gave a maximum yield of 69% phenol. The isomer distributions obtained with fluorobenzene, anisole, and nitrobenzene are almost identical with those obtained in the radiation-induced hydroxylation under similar conditions, In experiments with benzene and nitrobenzene we have shown that Cu3+produced via Cu2++ OH does not hydroxylate these aromatic compounds in neutral or weakly acidic solutions (pH 5.0-6.0). We therefore conclude that in the reaction of Cu+ with H20zthe OH radical is the major reactive species that reacts with aromatic compounds.
The Cu' autoxidation has been studied extensively1i2 ever since the hydroxylating properties of the Cu+-02 for4and against5 the system were d i s ~ o v e r e d . Evidence ~~~ intermediate formation of OH radicals has been presented.6 Recently a group of Japanese workers7 have exam(1) Zuberbiihler, A. Helu. Chim. Acta 1970,53,473-485. (2) Rainoni, G.; Zuberbtihler, A. Chimia 1974,28, 67-70. (3) Udenfriend, S.; Clark, C. T.; Axelrod, J.; Brodie, B. B. J. Biol. Chem. 1954,208, 731. (4) Nofre, C.; Cier, A.; Lefier, A. Bull. SOC.Chim. Fr. 1962,530. ( 5 ) Dearden, M. B.; Jefcoate, C. R.; Lindsay-Smith, J. R. Aduances in Chemrstry Series; Gould, R. F., Ed.; American Chemical Society: Washington, DC, 1968; Vol. 77, Part 111, p 260, and references cited therein. (6) For a discussion on the nature of the primary oxidants mediated by metal ions, see also: Walling, C. In Oxidases and Related Redox System; King, T. E., Mason, H. S., Morrison, M., Eds.; Pergamon Press, Oxford, 1982; pp 85-97. (7) Ito, S.; Yamasaki, T.; Okada, H.; Okino, S.;Sasaki, K. J. Chem. SOC.,Perkin Trans. 2 1988, 285.
0022-3263/89/1954-5922$01.50/0
ined the Cu+-02-induced hydroxylation of benzene and concluded that the reaction proceeds via OH radicals. At the same time we published a paper8 on the reaction of Cu+-02 using DMSO as a OH radical probe, reaching the same conclusion as the Japanese workers. It was suggested by both groups that the H202produced in the autoxidation reacts with Cu+ to give OH radical in a Fenton-type reaction. There is considerable evidence for this reaction in the literature.*12 It is frequently quoted without any references. However, contrary evidence was presented by (8) Eberhardt, M. K.; Colina, R.; Soto, K. J. Org. Chem. 1988,53,1074. (9) Que, B. G.; Downey, K. M.; So, A. G. Biochemistry 1980,19,5987. (IO) Buxton, G. V.; Green, J. C.; Sellers, R. M. J. Chem. SOC.,Dalton Trans. 1976, 2160. (11) Czapski, G.; Aronovitch, J.; Smuni, A:, Chevion, M. Oxyradicak and their Scauenger System; Cohen, G., Greenwald, R. A., Eds. Elsevier: Amsterdam 1983; Vol. I: Molecular Aspects, p 111. (12) Goldstein, S.; Czapski, G. J. Am. Chem. SOC.1983, 105, 7276.
0 1989 American Chemical Society
J. Org. Chem., Vol. 54, No. 25, 1989 5923
Aromatic Hydroxylation Scheme I
Table I. Phenol Yields in the Reaction of Benzene with Cu+-H2O2. Effect of Cuz+and pH reactants,' M phenol, exDt cu+ Cu2+ D H ~ time, h mol X IO6 1 2 x 10-3 5 x 10-2 0.5 469 2 2 x 10-3 5 x 10-2 0.5 586 3 2 x 10-3 5 x 10-2 0.5 513 4 2 x 10-3 5 x 10-2 0.5 498 5 2 x 10-3 5 x 10-2 0.5 454
R
R
r!
t
@-
6
1
6
OH
7
+ Cut + Ht
5 9
+ Cu2' + OH-
?
io
@-OH
Johnson et al.13 These authors postulate the formation of a Cu3+species. To decide between these two possible pathways, we have examined the hydroxylation of a number of aromatic compounds by Cu+-H202, comparing the isomer distributions obtained with those obtained in the radiolysis of dilute aqueous solutions.
Results and Discussion In the present study we wish to distinguish between the possible reaction steps in eq 1-4. CU++ H202
ArH ArH
-+
CU'+ + OH-
-
+ 'OH
Cu+ + H202
Cu3+(aq)
+
H
- -
'OH
+ Cu3*(aq)
ArH
e t
HzO
(1) (2)
ArOH
Ar
