UNIT PROCESSES
Friedel-Crafts Acylations T H E le\reling off noted t w o >-ears ago and the decline last year in the number and variety of Friedel-Crafts acylations seem to have stabilized. T h e fertile ingenuit? of organic chemists continues to provide unique and interesting examples of this important reaction. This reaction class still continues to provide one or more key links in the successful synthesis of complex molecules in such diverse fields as dyes, perfumes. steroids, terpenes, alkaloids, and antibiotics as well as many more directll- obvious applications. T h e Tabulation form established in previous revieirs is undergoing a n experimental test of major importance. T h e tables \vith complete lists of references ]vi11 be provided separatell- by the editor in photoprint form for those wrho need them.
Catalysts T h e importance of polyphosphoric acid as a mild reagent for effecting ringclosure acylations is a significant factor in the appearance of an extensive review of this reagenr's utility (60). Zinc oxide is claimed to be a very effective nonhalogen catalyst for aryl acylations (67). Better yields with less undesirable by-products are obtained when nitromethane is included in the reaction medium for a q l a t i n g phenols and phenol ethers. Tetrachloroethane seemed to be the most desirable solvent (64). Silicon tetraacetate gave only moderate or fair yields of 2-acetylthiophene with stannic chloride, zinc chlo-
K. LeROl NELSON i s associate professor of organic chemistry at Brigham Young University. He graduated from Utah State Agricultural College and obtained his Ph.D. from Purdue University in 1952. Previous experience includes postdoctoral research at UCLA and teaching at Purdue and Wayne Universities. Nelson i s a member of the ACS, British Chemical Society, American Institute of Chemists, Sigma Xi, Lambda Upsilon, AAAS, AAUP, and Utah Academy of Sciences, Arts, and Letters.
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The complete annotated bibliography of the FreidelCrafts Acylations Review together with tables of formulas. Address: Editor, I/EC, 1 155 Sixteenth St., N.W., Washington 6, D. C., sending cash, money order, or check payable to American Chemical Society. ride: beryllium chloride, or boron trifluoride, but with titanium tetrachloride the yield was 94y0. T h e same systems failed for acetylation of benzene. Only aluminum chloride and ferrichloride were effective ( 8 3 ) . Aluminum chloride cannot be used in the acylation of selenophene ivhile zinc chloride and stannic chloride give poor yields. T h e best system utilized 85% phosphoric acid with acid anhydrides ( 3 8 ) . Baliah and Mathecr have reported the effect of a variety of catalysts and solvents on the relative proportions of a- and p-sulfonl-1arion products from naphthalene ( 7 ) . Polyphosphoric acid was ineffective for the ring closure of N-p-toluenesulfonyl0-anilinopropionyl chloride ( 77). A mixture of aluminum chloride and zinc chloride gave a small yield of 2-acetyl4-methylaniline via a pseudo-Fries rearrangement, Lvhereas aluminum chloride alone gave tar andzincchloride alone gave a cyzlized product (2).
the rate of benzoylation of benzene is first-order in aromatic and in aluminum chloride. T h e enthalpy and entropy of activation are, respectively, 15.1 and -26.7. T h e polar effect of the medium is indicated by the decreasr in rate as cyclohexane is added ( 7 9 ) . T h e rates of benzoylation of substituted benzenes correlate \vel1 using u + constants. Toluene gives 9.3y0ortho, 1.4c/;: meta, and 89.37, of the para isomer (20).
ilroinat ic
Benzene Toluene tert-Butylbenzene Chlorobenzene +Xylene m-Xylene p-Xylene
Relative Rate of Benzoylation 1
110 73 0.0115
1120 3940 140
Crude competitive rates of acetylation of the paracyclophanes indicate significant differences between members of the series ([6.6]/'[4.4] = 1 . 6 ; [4.4]/ [3.4] = 7.0; [4.4]/[2.2] = 100; [3.4]/[2.2] = 2.6) (25). Ferrocene is much more reactive than benzene or even anisole. T h e first acyl substituent deactivates even the second ring (18). Attempted acylation of phenol in toluene solution with phthalic anhydride gave only a product from toluene. I t was presumed that phenol forms a species such as phenoxyalumin u m chloride which is less reactive than toluene (65). T h e relative concentrations of phenol and toluene were not taken into account, but must be a significant factor.
Steric Effects Kinetic Studies Schubert and l f y h r e combined kinetic and isotope studies to gain further elucidation of the mechanism of acidcatalyzed decarbonylation. T h e results are said to be in complete agreement with the general acid-base catalysis mechanism of successive bimolecular proton transfer steps. Proton transfer to the aromatic is rate-controlling in the higher sulfuric acid concentrations and largely controlling a t lower concentrations ( 7 4 ) . I n benzoyl chloride solution
Steric hindrance provided by merh)l groups in 2.5-dimethylfuran prevent aldehyde formation via the Vilsmever reaction. Phenyl groups in the same location give a very poor yield (77). Homologs of pivalyl chloride are capable of acylating anisole. With less reactive aromatics the major course of reaction involves elimination of carbon monoxide, followed by alkylation of the aromatic. T h e replacement of a methyl group by an ethyl group increases the rate of aluminumchloride-catalyzed elimination of
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carbon monoxide by a factor of 3 to 4 for each replacement ( 4 0 ) . Ring-size factors influence thr position of ring closure in w-arylalkanoic acids. With methylene chains of two to six units the ring closes from the 4- to the 3- position of toluene. A mixture was obtained for seven methylene units (with some evidence for methyl migration). The yield of ring-closed ketone was 70 to 807, for two to five methylene units, dropping to 7 to 10% for six and seven units and increasing to 20 to 35Y0 for 8 to 15 units. Ring-closure for 7 to 15 units was at position 2 ( 4 6 ) . I n a similar study with naphthalene, ring closure occurred from the 1- to the 2position for two to nine methylene units with closure to position 7 for six to nine units. High-dilution techniques were used for four to nine units ( 4 5 ) . Ultraviolet spectra indicate that the carbonyl group is turned out of the plane of the aromatic ring for rings of six to nine members (46). Steric interactions are shown also by the electronic spectra of 2. 2’-diaroylbiphenyls (33).
Mechanism and Product Studies
A small amount of 5-formyl product has been found along with the 3-formyl derivative of S-guaiazulene ( 7 8 ) . T h e formylation product of thianaphthene has definitely been shown to be the 3isomer (37). Radioactive halogen and carbon-14 have been used to study the mechanism of Friedel-Crafts processes (42, 69). Acetylation of AT-methylpyrrole using magnesium bromide in ether is taken as evidence in contradiction of previously held ideas regarding the supposed reaction between the so-called N-methylpyrrole Grignard and an acid choride (43). Gerecs and Windholz have described the effect of excess sodium aluminum chloride and excess hydrochloric acid on the Fries reaction. They conclude that the ortho rearrangement is favored by a complex involving aluminum chloride and a proton (36). Several substituted fi-hydroxyacetophenones do not undergo a reverse Fries reaction (27). Cullinane and Edwards have outlined a procedure for analyzing and recovering hydroxyketones from noncrystalline reaction products (26). a- andp-Hydroxyketones are distinguished quantitatively by means of a mixture of diisopropoxyaluminum chloride and triisopropoxyaluminum. Only the fi-hydroxyketone is reduced. T h e acetone is determined in the distillate with hydroxylamine. T h e a-isomer gives a fluorescence with diisopropoxyaluminum chloride which provides a convenient photometric determination (75).
1 100
INDUSTRIAL
AND
N e w Methods Sensitive hydroxy compounds can be successfully subjected to Friedel-Crafts reactions through protection by reaction with trimethylchlorosilane ( 7 7 ) . An improved process for ester production of phenols with hexadecamethylene-l,6dicarboxylic acid is an aid to Fries production of diketones (47). Carbonyllabeled ketones are prepared from sodium salts of the aliphatic acids with the aromatic and oxalyl chloride in carbon disulfide ( 7 4 ) . Pyridine can be benzoylated in poor yield via a complex reaction involving pyridine, ethyl benzoate, aluminum, mercury, and mercuric chloride. The reaction is thought to involve an anionic intermediate produced by a 2-electron transfer from metal to ester
(5). Applications Zinner and Brossmann have obtained a variety of amino ketones using acylamino acid chlorides or amino acid chloride hydrochlorides (86). Several aryl esters were produced by acylations with aryl chloroformates (22). A number of interesting 1,2-diketones hake been obtained with oxalyl chloride ( 4 ) . The same reagent in petroleum ether gives a glyoxylic acid-substituted S-guaiazuletie. In methylene chloride carbon monoxide is eliminated, giving a bis-Si-guaiazulyl ketone (66). 7 - M e thoxy 1 - methyl - 4 - oxo - 1.2.3,4tetrahydro-1 -arsenanaphthalene and 1H7-methoxy -l $6-dioxo - 2.3.3a,4.5,6 - hexahydro-3a-arsenabenzonaphthene have been synthesized by ring-closure acylations from 3-methoxyphenylarsine bearing one or two propionic acid groups ( 5 0 ) . 3-Acetyl-2,6-dimethyl-4-pvrone is produced under typical acetylating conditions (82). An interesting variety of ”benzo” cyclopentenones result from reactions of benzene, substituted benzenes, and phenanthrene with oc,O-unsaturated acid derivatives. These products could be considered as resulting from stepwise or simultaneous acylation and alkylation utilizing both the acyl and olefinic portions of the acid in Friedel-Crafts reactions with a single aromatic moiety (6, 30: 5 7 ) . Analogous products involving combined acylation-alkylation of cyclopentene and cyclohexane have also been reported (29). Because it is not possible to pick for inclusion those applications of FriedelCrafts reactions which suit the particular interests of any one reader, attempt has been made to select those which, taken together, will give a fair representation of the variety available for selection. Among those selected is the interesting case of conversion of y-lactones to cyclopentenones possibly via the y,b-un-
ENGINEERING CHEMISTRY
-
saturated acid Lvhich undergoes ring closure to the olefinic bond with polyphosphoric acid (62). Cram and Reeves have utilized ring-closure acylation to make additional polymeth>-lene bridges between the t\co benzene rings of [4.4] paracyclophane ( 2 4 ) . A substituted aminonitrile !ed. via a Hoesch-type re[2action, to 1-(3,4-dimethoxyphenVl)-2(4-methoxyphenyl)ethylamino]-ethan -1 one (56). Rinehart and Motz have separated the t\yo possible tetrasubstituted ferrocenes resulting frotn diacetylation of 1.1 ‘-dimethylferrocene. The two substances are geometric isomers (68). Two w-(2-thienyl)-alkanoic acid chloride molecules with five. eight, or nine methylene uniu react together via simultaneous or successive “intermolecular” acylations to give large-ring diketones in yields up to 15yc(38). Sargent claims the first examples of successful acylation of 9,lO-dihydro.tr-acetylacridine ( 7 2 ) . Apparent olefin acylation occurs in small yield on the 1 .I-dimethylmonoenolic form of 1,1,3-trirnethyl-~ and 131.3,3-tetramethyl-2,4,6-trioxocyclohexane(67). A number of long-chain unsaturated ketonic acids have been prrpared using half-esters of long-chain dicarboxylic acids with several olefins ( 5 4 ) . 4 0 x 0 6,7 -methylenedioxy 1,2,3.4 - tetrahydronapth [c]isocoumarin was obtained by ring closure (47). Hydroxynitroketones formed by Fries rearrangement give chalcones a t an unusually rapid rate (76). Friedel-Crafts acylations have provided key units in the studies of the structural details of constituents of Calophyllum inophyllum nuts (.59), Oxalis cernua flowers ( 8 ) , neuroplegic compounds derived from phenothiazine (52, 73) and related systems (34). podocarpic acid derivatives and analogs ( I 2 . 32, 87), khellin (28): diphenhydramine analogs (23), tetracycline analogs (55)! Tabernanthe iboga alkaloids ( 4 9 ) . dehydroabietane derivatives (44). and new musk odorants ( 7 9 ) .
-
Unexpected Results In several cases the reactions are accompanied by unexpected products. Ethylene reacts with benzoyl chloride in the presence of excess aluminum chloride to give 3-methyl-1-phenyl-2-buten-1-one 3-chloro-3-methyl-1-phenylbutanand 1-one (53). An exocyclic double bond rearranged into an endocyclic position out of conjugation before olefinic ringclosure acylation ( 73). 4-Arylcyclohexylacetic acids rearrange to give ringclosure products to be expected from 2arylcyclohexylacetic acids (58). 2,4,6Trimethylacetophenone rearranges to 3:4:5trimethylacetophenoneon heating
1-uromonapnmaiene ( / I ) . iicyianon 01 thymol ethers is accompanied by loss of the isopropyl group. T h e group was not removed from the parent ether under reaction conditions omitting the acylating agent ( 7 0 ) . A tertiary butyl group is eliminated from the 7-position in ring closure leading to 3a,4,5,6-tetrahydroperinaphthan-I-one but not in closure leading to the analogous acenaphthen-1-one (80). Some fluorine is replaced by chlorine in the phenacyl product from chlorobenzene a n d fluoroacetyl chloride (70). A methyl shift accompanies the ring-closure Fries reaction of bis-(2,6dimethylpheny1)malonate to give 4hydroxy-6,8-dimethylcoumarin (tautomer of ketone) (85). I n benzene solution 2,4,S-trimethoxybenzoyl chloride gives a symmetrical biphenyl with 1,2,4trimethoxybenzene while the expected symmetrical benzophenone is obtained in carbon disulfide (39). A number of significant failures were also reported. 2,4-Dichloro-l,3,5-trimethoxybenzene is not acetylated under a variety of conditions (37). 4-Bromonitrobenzene is similarly not acetylated, while the 2-bromo isomer suffers loss of bromine (7). Attempts to synthesize
O - C O ? H failed for n greater than 2 (84). Highly substituted coumarins fail to undergo Vilsmeyer formylation (57). Ring closures to the peri-position of naphthalene and indoline were not successful in all cases (3, 27. 63). All attempted cyclizations of 3-(4- [1-(2-~arboxamidophenyl)ethyl] - 2,s - dimethoxybenzoy1)propanoic acid ethylenedithio ketal failed (35). U n d e r various conditions ,V-arylsulfonyl derivatives of 4-(3-methoxyanilino) butanoic acid formed lactams rather t h a n the desired heterocyclic ketones (76). 2-Phenylpropanesulfonyl chloride failed to give ring-closure sulfonylation ( 75).
literature Cited (1) .4min: G. C., Fha, B. C., Vidya J . Gujarat Unin. 1, No. 2; 77-8 (1957). 12) Ardashev, B. I., Minkin, V. I., Zhur. Obshchei Khim. 27, 1261-3 (1957). (3) Astill, B. D., Boekelheide, V., J . Or,!. Chem. 23, 316-18 (19581. 14’1 Badische Anilin & Soda-Fabrik A.-G., Ger. Patent 891,081 (Sept. 24, 1953). ( 5 ) Bachman, G. B., Schisla, R . M., J. Org. Chem. 22, 1296-302 (1957). 16) Baker, W.; McOmie, J. F. W., others, J . Chem. Soc. 1957, pp. 4026-37.
Garz. chim. ital. 85, 1319-28 (1955). (9) Benington, F., Morin, R. D., Clark, L. C., Jr., J . Org. Chem. 22, 332-3 (1957). (10) Bergmann, F., Kalmus, A . , Breuer, J . Am. Chem. Soc. 79, 4178-81 (1957). (11) Berliner. E., Chu, Y. W., Shieh, N., J . Org. Chem. 23, 633-5 (1958). (12) Bible, R . H., Jr., J . Am. Chem. Sod.
79, 3924-5 (1957). (13) Biemann, K., Biichi, G., Walker, B. H., Ibid., 79, 5558-64 11957). 114) Billek. G., Herrmann, E. G., hfonatsh. 88,735-8 (1957). (15) Bordwell. F. G., Hewett, LV. A., J. Ore. Chem. 22, 980-1 (1957). (16) Braunholtz, J . T., hfann, F. G., J . Chem. SOC.1957, pp. 4174-82. (17) Ibid.,pp. 4166-73. 118) Broadhead, G. D., Osgerby, J. h l . , Pauson, P. L., Ibid., 1958, pp. 650-6. (19) Brown, H. C., Jensen, F. R . , J . Am. Chem. Soc. 80, 2291-6 (1958). (20) Ibid., pp. 2296-300. (21) Buu-Hoi’, N. P., Yen, V. Q., Xuong, N. D., J . Org. Chem. 23, 189-90 (1958). (22) Coppock, W. H . , Ibid., 22, 325-6 (1957). (23’1 Craig, P. S . , Olmstead, 11. P., Ibid. 22, 559-61 11957). 124) Cram, D. J., Reeves, R. A., J . Am. Chem. Soc. 80, 3094-103 (1958). (25) Cram. D . J., Wechter, Tir. J., Ibid., 80,3126-32 (1958). (26) Cullinane, N. M., Edwards, B. F. R., J . Chem. Sor. 1958, PP. 1311-12. (27) Ibid., pp. 43418.’ (28) Dann, O., Illing, G., Ann. 605, 146J7 (1957). (29) Dev, S., J . Indian Chem. SOC.34, 169-77 (1957). 130) De Walt, C. W., Jr., Hawthorne, J. O., others, J . Org. Chem. 22, 582-3 (1957). (31) Duncanson, L. A., Grove, J. F., others, J . Chem. Soc. 1957, 3555-64. (32) Fttizon, M., Delobelle, J., Comfit. rend. 246,2774-6 (1958). (33) Forbes, W. F., Wallenberger, F. T., others, J . Org. Chem. 23, 224-7 (1958). (34) Fujii, K.: Yakugaku Zosshi 77, 1065-8 (1957). (35) Gates, hi.,Dickinson, C. L.. Jr., J . Org. Chem. ?2, 1398-1403 (1957). (36) Gerecs, A , , Windholz, hl., Acta Chim. Acad. Sei. Hung. 8, 295-302 (1955). (37) Ghaisas, J. V. V., J . Org. Chem. 22, 703 (1957). (38) Gol’dfarb, Y . L., Taits, S. Z., Belen’kiY, L. I., Izuest. Aknd. Nauk S.S.S.R., Otdel. Khim. Nauk 1957, pp. 1262-5. (39) Govindachari, T. R., Nagarajan, K., Parthasarathy, P. C., J . Chem. SOC.1958, 912-13. (40) Grundy, hl. E., Hsu, W.H., Rothstein, E., Ibid., 1958, pp. 581-6. (41) Gupta, .4.S., Aggarwal, J . S., J . Sei. Ind. Research (India) 16B, 181-2 (1957). (42) Havinga, E., Chem. Mreekblad 53, 665-71 (1957). (43) Herz, W., J . Org. Chem. 22, 1260-1 (1957). (44) Hoehn, W. H . , U. S. Patent 2,805,255 (SeDt. 3.19571. (45) Huisgen, R., Rietz, U., Tetrahedron 2. 271-88 11958). (46: Huisgen, R., Vossius, V., Monatsh. Chem. 88, 517-40 (1957). (47) Jones, 3. B., Pinder, ’4. R., J. Chem. SOC. 1958, pp. 2612-18. (48) Kataev, E. G., Palkina, M. V.,
1491 Xlac Phillamy. H . B., Dzieman. R. L.. others, J . Am. Chem. Soc. 80, 2172-8 I 1958 1. (50) hlann, F. G.. Wilkinson, .\, J., J. Chem. Sac. 1957, pp. 3336-46. 151) hlarchant, A , . Ibid., 1957, pp. 3325-8. (52) hlassie, S. P., Cooke, I., Hills, LIT..A,, J . Or,e. Chem. 21, 1006-8 (1956’1.
(531 hlatsumoto. T.. Hata, K . , Nishida, T., Ibid., 23, 106~-7(1958). (54) hleshcheryakov, A. P., Petrova, L. V., Izrest. Akad. h’auk S.S.S.R., Otdel. Khim. n h u k 1958, pp, 106-7. (55) Moshfegh, A , , Fallab.? S., Erlenmeyer, H., Helz’. Chim. Acta 40, 1157-66 (1957 I . ( 5 6 ) N. V. Philips Gloeilampenfabricken, Brit. Patent 789,033 (Jan. 15, 19583. (57) Naik, R. M., Thakor, V. M,, J . Org. Chem. 22, 1630-3 (1957). (58) Phillips, D. D., Chatteriee. D. N., J . Am. C h m . Soc. 80, 1360-6 71958i. (59) Polonsky, J., Bull. soc. chim. France 1957, pp. 1079-87. (60) Popp, F. D., McEwen. W. E.. Chem. Rew. 58, 321-401. f61) Prill. E. J.. U. S. Patent 2.802.032 (Aug. 6, 1957). (62) Kai, C., Dev, S , J. Indran Chern. Sac. 34, 178-82 (1957). (63’1 Rapoport. H., Tretter, J . R., J . Org. Chem. 23, 248-51 (1958). (64) Reichel, I.. VB1i:eanu. R.. ‘4cad. rep. populore Romtne. Baza cercetdri $&t. T i m i p z r a , Studii cercetdri jtiint. Ser. I 4, 15-26 (1957). (65) Ibid., pp. 27-34. (66) Reid, D. H.. Stafford, M’. H., Stafford, W. L., J . Chem. SOG.1958, pp. 1118-27. (67) Riedl, W.. Cer. Patent 941,372 (Aprjl12,19561. (68) Rinehart, K. L., Jr., M o t z , E(. L., Chcm. and Ind. (London) 1957, p. 1150. (69) Roberts, R . M., Brandenberger, S. G., Panayides, S. G., J . Am. Chem. Soc. 80,2507-9 (1958). (70) Royer, R., Demerseman, P., others, Bull. SOC. chin;. France 1957, pp. 1379-88. (71) Runge, F., Herbst, H.: Angezc. Chem. 68. 618 11956). (72j’Sargent, L. 3.. J . &,e. Chem. 22, 1494-6 (1957). (73) Schmitt, J., Bortard, J.. others, Bull. soc. chim. France 1957, pp. 938-47. (74’1 Schubert, W. M., Myhre, P. C., J . Am. Chem. SOC.80, 1755-61 (1958). (75) Simonvi, I., Toklr, G., Magyar Rlm., FOlYbi7flt 63. 11-14 11957). (7611 SzC11, T:, Bajusz. S.. Bid., 60, 5-7 (1954). ( 7 7 ) Traynelis, V. J., Miskel. 3. J.. Jr., Sowa, J. R., J . Org. Chem. 22, 1269-70 ’
11957).
(78) Ukita, C., hliyasaki, M., Hashi, hi., Pharm. Bull (Tokyo) 6, 223-4 (1958). (79) Weber, S. H . , Kleipool. R. J. C., Spoelstra, D. B., Rec. t r ~ chim. ~ . 76, 193-9
,.
(1,357) ,~,-
(80) Wenham, .4.J . M., Whitehurst, J. S., J . Chem. Soc. 1957, pp. 4037-41. (81) Wenkert, E., Jackson, B. G., J . Am. Chem. Soc. 80, 217-19 (1958). (82) Woods, L. L., J . Org. Chem. 22, 341-2 (1957). (83) Yur’ev, Y . K., Belyakova. Z . V , Zrfirov, N. S.,Zhur. Obshchei Khzm. 27, 3264-71 (1957). (84) Zelinski, R., O’Brien. G., J. Org. Chem. 23,641 (1958). (85) Ziegler, E., Maier, H., Monatsh. 89, 143-53 (1958). (86) Zinner. H . , Brossman. G . J . prakt. Chcm. [4],5 , 91-6 119571.
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