[CONTRIBUTION FROM
THE
DEPARTMENT OF CHEMISTRY AND CHEMICAL ENGINEERING
OF THE UNIVERSITY OF PENNSYLVANIA]
THE MICHAEL CONDENSATION. V*. THE INFLUENCE OF THE EXPERIMENTAL CONDITIONS AND THE STRUCTURE O F THE ACCEPTOR UPON THE CONDENSATION RALPH CONNOR
AND
WM. R. McCLELLAN
Received October 20, 1938
A general representation of the Michael condensation is shown in the following equation, in which Ll, L,and L3 represent labilizing groups:
I 1
i
-C=C-L1
+
Ik
-C-C-L1 Piperidine or N~OR’
L2-CH-L.q
(1)
L-c-L3
I
1
Examplest have been reported in which Ll is -COOR1, -COR2, 4 N 3 , -CONH:, -NO: or -SOZR6and in which I&, L,or both are -COOR1, One of the -COR1, 4 N 7 , - C O N H & -NO:, -S02R10 or -CHOll. two labilizing groups in the addendum may be aryll0J2. If a very effective labilizing group is present in the addendum, a second labilizing group
* This report is part of a paper presented a t the Seventh Organic Symposium of the American Chemical Society held a t Richmond, Virginia, Dec. 29, 1937. The literature of this field is so extensive that no attempt has been made to include a complete bibliography. The citations given were selected either because of their priority or because of the general interest of their contents. MICHAEL, J. prakt. Chem., [2], 36, 349 (1887). 2 KOHLER, Am. Chem. J.,37,385 (1907). a VORLXNDER, Ann., 320, 66 (1902). 4 HERRMANN AND VORLANDER, Abhandlungen der Naturjorschenden Gesetlschaft zu Halle, 21, 251 (1899); Chem. Zentr., 1899, 1,730. MEISENHEIMER AND HEIM,Ber., 38, 466 (1905). 6 KOHLER AND POTTER, J. A m . Chem. SOC.,67, 1316 (1935). ‘I THORPE, J. Chem. Soc., 77,923 (1900). * KOHLERAND SOUTHER, J. Am. Chem. Soc., 44,2903 (1922). 9 KOHLER, ibid., 38, 889 (1916). lo CONNOR, FLEMING, AND CLAYTON, ibid., 58, 1386 (1936). 11 MEERWEIN, J. prakt. Chem., [2], 97,225 (1918). 12 BORSCHE, Ber., 42,4496 (1909); KOHLERAND ALLEN,J. Am. Chem. Soc., 46,1522 (1924); MEERWEIN LVD KLINZ,J. prakt. Chem., 121, 97, 237 (1918). 570
THE MICHAEL CONDENSATION
571
may be unnecessary1s. The acceptor may be acetylenic1*,rather than olefinic, or it may be a quinone16. Either the acceptor" or the addendum17 may be vinylogs18of the structures indicated above. By no means all of the possible combinations of these groups have been studied and many which have been tested have failed; nevertheless, this reaction has made available many types of compounds that would be difficult to obtain by 'any other methods now available. I n addition to the more obvious types of compounds prepared by direct condensation, the products have been used for the following varied types of substances: dihydroresorcin01s~~, cyclohexenones20,terpene derivativesz1, pyridines22,piperidones%, pyryllium salts", cyclopropanes%,c o u m a r i n ~and ~ ~ derivatives of hydrogenated polycyclic hydrocarbons26. Considering the numerous applications of this reaction it must often be used by investigators who are not familiar with some of its limitations which are probably generally understood by those who have worked in the field. This paper, therefore, is presented to summarize our experiences with the various conditions used for carrying out the reaction and to show, from new data and the work of others, the influence of the structure of the unsaturated compound (acceptor:) upon its reactivity in the condensation$. Experimental conditions.-Secondary amines (for example piperidine) are the safest catalysts in that they seldom cause any reaction other than normal condensation. In reactions in which ring closure, rearrangement,27 or the formation of trimolecular compoundsz8must be avoided, amines ~ ~ K O H LAND E RENGELBRECHT, J . A m . Chem. SOC.,41, 764 (1919); ANDREWS AND CONNOR, i&id., 67, 895 (1935). 14 MICHAEL, J . prakt. Chem., [2], 49, 22 (1894). 16 SMITH AND JOHNSON, J . Am. Chem. SOC.,69,673 (1937). 16 KOHLER AND BUTLER, J . Am. Chem. SOC.,48,1040 (1926). 17 INQOLD, PERREN, AND THORPIC, J . Chem. SOC.,121,1771 (19%). 18 FUSON, Chem. Rev., 16, 1 (1935). 1 9 BREDT,Ber., 24, 603 (1891); VORLHNDER, ibid., 27, 2053 (1894); Ann., 294, 253 (1897); MICHAEL, Ber., 27, 2126 (1894); KNOEVENAGEL, Ber., 27, 2337 (1894). 20 KNOEVENAGEL AND SPEYER, Ber., 36,397 (1902). 21 BARDHAN, BANERJI,CHATTERJEE, AND CHATTERJEE, J . Chem. Soc., 1936, 476. 22 KNOEVENAGEL, Ann., 281, 33, 35 (1894); 908, 225 (1898). 23 BARAT, J . Ind. Chem. Soc., 8,699 (1931); ALLEN AND SCARROW, Can. J . Research, 11, 395 (1934). 24 ALLENAND BARKER, J . A m . Chem. Soc., 64, 743 (1932); DILTHEY, J . Prakt. Chem., [21, 94, 53 (1916). 25 KOHLER AND DARLING, J . A m . Chem. SOC.,62, 424, 1174 (1930). 26 HAWTHORNE AND ROBINSON, J . Chem. Soc., 19S6, 763. $ The influence of the structure of the addendum upon its reactivity has been discussed earlier.fg See also Andrews and Connor.l* 27 MICHAEL AND Ross, J . Am. Chem. SOC.,64, 4598 (1930). 28 MICHAEL AND ROSE,ibid., 66, 1632 (1933).
572
RALPH CONNOR AND W. R. McCLELLAN
give satisfactory results. Unfortunately, they often fail to bring about reactions that do occur in the presence of sodium alkoxides (examples will be found in the tables) and even in favorable cases the rate is rather slow with amines. The use of piperidine as a catalyst is described in part A of the experimental part of this paper. One-sixth to one-third of a n equivalent of sodium ethoxide (see part B of the experimental description) may cause condensation in cases where amines do not. This condition is less drastic and is less likely to cause side reactions than the use of one equivalent of sodium ethoside. The equivalent of catalyst (see parts C, D and E of the experimental) is the most likely to cause condensation and also side reactions. If a reactant or TABLE I COMPARISON OF LABILIZING GROUPSIN ACTIVATING THE ACCEPTOR ACCEPTOR
CsHsCH = CHCOCsHs . . . . . . . . . . . . . CsHsCH CHCOOCzHs.. . . . . . . . . . . CeHsCH= CHCOOCzHs. . . . . . . . . . . . Coumarin . . . . . . . . . . . . . . . . . . . . . . . . . Coumarin ......................... CeHsCH= CHCN. . . . . . . . . . . . . . . . . . p-OzNCeHdCH = CHCOCaHs p-O~NCsH~CH=CHCOOC~Hs.. ....
ADDENDUM
CsHsCHzCOOCzHs C~HSCHZCOOCZHS CsHsCHzCOOCzHs CsHrCHzCOOC2Hs CsHsCH&OOCzHs CaHsCHzCOOCzHs CHz(C0OCzHs)z CHz(C0OCzHs)z
YIELD, % $:$ : ~-
90 0
A, c A
85 55 0
C C
Ob 90 0
A C A A
0 In this and the following tables, the letters designating the conditions used for carrying out the reactions refer to the corresponding sections in the experimental part describing the general methods for carrying out the condensation. In making comparisons in the tables it should be borne in mind that C, D and E represent more severe conditions than B, and B represents more severe conditions than A. Therefore, an acceptor which reacts under condition A may be considered more reactive than one which does not react under other conditions; it is not permissible, however, to compare an acceptor which is reactive under condition C, D, or E, with one which is not reactive under condition B or A. b BORSCHE, Ber., 43,4496 (1909).
product undergoes alcoholysis readily in the presence of alkoxides or if the sodio derivative of the active methylene compound is not readily formed, the sodio derivative may be prepared by the use of metallic sodium (see part E of the experimental description) or sodamide26. The solubility of the reactants is the chief consideration in selecting a solvent. Methanol, ethanol, benzene, ether, and dioxane have all given satisfactory results. With sodium alkoxides as catalysts the best results are obtained by allowing the reaction to stand a t room temperature for twenty to one hundred-fifty hours. Higher temperatures may give lower yields, presumably because they favor retrogressi~n~~ and increase 29
INGOLD A N D POWELL, J . Chem. SOC., 119, 1976 (1921).
573
THE MICHAEL CONDENSATION
the side reactions. However, if ring closures or the formation of trimolecular compounds are desired, the reaction may be carried out under reflux. With secondary amines the reaction is usually so slow that a long reflux period is necessary. INFLUENCE OF CY
NO.
1 2
3 4
5 6 7 8 9 10 11 12
13 14 15 16 17 18 19
-
AND
TABLE I1 p SUBSTITUTION UPONTHE REACTIVITY OF
ACCEPTOR
THE
ADDENDUM
CeHsCH= CHCOCaHs. . . . . . . . . . . . . . CeHsCHzCOOCzHa CeHsCH=C(COOCzHs)COCeHs., . . CeHsCH2COOC2Hs Ce,HsCH= CHCOOCsHh . . . . . . . . . . . . CsHsCHzCOOC,Hs CsHsCH=C(CsHs)COOCzHs.. . . . . . . CeHsCHzCOOCzHs CH&H = CHCOOCzHs. . . . . . . . . . . . . CsHsCHzCOOCzHs CH,CH=C(CHa)COOC2Hs. . . . . . . . . CeHsCHzCOOCzHs (CH,)2C=CHCOOCzHs. . . . . . . . . . . . CeH&HzCOOCzHs CsH6CH = CHCOCeHs. . . . . . . . . . . . . . CHaCH (COOCzHs), CeHsCH=C(CH3)COCsHs. . . . . . . . . . CH&H(COOCzHs)2 CHaCH= CHCOOC2Hs. . . . . . . . . . . . . CH&H(COOCzHa)z CH3CH=C(CHa)COOCzHs. . . . . . . . . CH3CH(COOCzHs)2 CH,CH= CHCOOCzHs. . . . . . . . . . . . . CH3CH (CN) COOCzHs (CH3)ZC=CHCOOCaHs. . . . . . . . . . . . . CH&H(CN)COOCaHs CeHsCH= CHCOOC2H6. . . . . . . . . . . . Anthrone CeHsCH = C (C0OczHs)z. . . . . . . . . . . . Anthrone ~-OZNC~H~C CHCOOCHa H= . . . . . . CHz(COOCH3)z VL-O~NC~H~CH=C(CH~)COOCH~. . . CHz(C0OCHa)z Coumarin ......................... CH2(COOC&)z 3-Methylcoumarin . . . . . . . . . . . . . . . . . CH2 (COOCzH6)z
ACCEPTOR^
-
[IELD,
%
90 0 85 0 90 40 20 42
0 84 15 50 17 0 91 95 0 54 0
>ONDIl’lONSb
B, c C C C C C C Ee E B* C Ce C’ A A0 B B, D Db
Dh
-
For examples of the replacement of the OL hydrogen of CH2=CHLt by methyl, compztre 5 and 6 , 8 and 9, 10 and 11,16 and 17,18 and 19;for the influence of p substitution compare 5 and 7, 12 and 13. For the influence of phenyl compare 3 and 4;of carbethoxyl, 1 and 2;of benzoyl, 2 and 3. * The explanation of this column is given in footnote a of Table I. This yield represents rearrangement-retrogression products81 as reported by Holden and L a p ~ o r t h a ~ . Michael and RossZ7report this result. 8 This represents the rearrangement product31 reported by Michael and Rossa3. 1 This was reported by Thorpe’ and is a rearrangement product. 0 This was reported by Gravela. h The authors are indebted t o Messrs. R. A. Cardinali and R. E. Houghton for these experiments. 5
The nature of h.-An arrangement of labilizing groups in the order of their ability to activate the double bond of the acceptor would be very CONNOR AND ANDRBWS, J . A m . Chem. SOC.,68,2713 (1934). HOLDEN AND LAPWORTH, J . Chem. SOC.,1931,2368. 33 MICHAEL AND Ross, J . A m . Chem. Soc., 6S, 1150 (1931). a4 GRAVEL, Naturaliste canadien, 67,181 (1931);Chem. Abstr., 28, 169 (1934). 31 32
574
RALPH CONNOR AND W. R. MCCLELLAN
useful. Unfortunately, no such table of reactivities or “negativities” can be made from the data at hand. In some cases, ring c l o s ~ r e s ~ ~ J 9 ~ ~ ~ ~ (as in some cases where L1 is -COCK or -CONH2) or rearrangement^^^ render the yields of doubtful significance in comparing reactivities; in other cases not enough examples have been studied to justify a comparison. However, it can be said that an unsaturated ketone is more reactive than the corresponding ester and the latter more reactive than the nitrile. Specific examples of these facts are given in Table I and many others are to be found in the literature. Substitution on the a and B atoms.-This subject has already received some attention in studies on the Michael reaction. In general, the conclusions are similar to those reached by Ingold, Perren, and ThorpeI7 TABLE I11 OF REMOTESVBSTITUTION UPON THE REACTIVITY OF INFLUENCE ACCEPTOR
ADDENDUM
o-OZNCeHICH=CHCOOCHs.. . . . . . . . . . . . . . m-OzNCsH4CH= CHCOOCHa. . . . . . . . . . . . . . p-OzNCsH,CH= CHCOOCHa . . . . . . . . . . . . . . Coumarin.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6-Bromocoumarin . . . . . . . . . . . . . . . . . . . . . . . . . CsH.d2H=CHCOCsHz(CHs)s(2,4,6). . . . . . . . m-O2NCsHnCH= CHCOCsHs. . . . . . . . . . . . . . . p-OzNCsH4CH=CHCOCsHs. . . . . . . . . . . . . . .
CHt(C0OCHs)z CHz(COOCHa)2 CHz(C0OCHa)z CHz(COOC?H& CHZ(C0OCsHs)z CHZ(COOCHI)I CHz(COOC2Hr)r CHz(COOC2Hs)i
TEE
ACCEPTOR
YIELD. $ % :::: --
70 95
0
B B B
54
D
0
B, D
70 95 90
B A, B A
on the self-condensation of substituted glutaconic esters. The conclusions may be summarized as follows (for examples, see Table 11): (1) In a system, CH2 = CHL1, the reactivity of the acceptor decreases as the hydrogens are replaced by larger groups. This is true whether substitution is made on the a or /3 carbon atom. (2) The reactivity of the acceptor is decreased if the substituent is alkyPr30, aryl, carbethoxyl or acyl. The magnitude of this effect probably is largely dependent upon the size of the s u b s t i t ~ e n talthough, ~~!~ according to Ingold, Perren, and Thorpel’, in the case of negative groups such as -COOR and -CN the spatial effect may be modified by a polar effect which will render the system less unreactive than might be expected from the size of such groups. The above generalities are probably adequate for almost all cases; however, at least one exception is known. This is the case of ethylcin*o
See also Thorpe’ and Kohler and EngelbrechP.
THE MICHAEL CONDENSATION
575
576
RALPH CONNOR AND W. R. McCLELLAN
namate, which does not react with anthrone, although ethyl benzalmalonate (the a-carbethoxy derivative of ethyl cinnamate) gives a good yielda4of condensation product. Remote substitution.-Groups which are not attached directly to the double bond of the acceptor probably have a greater influence upon reactivity than is generally appreciated. The magnitude of their influence cannot be estimated but in predicting reactivity the possibility that remote groups may vastly alter the behavior of the acceptor must be borne in mind. Examples are given in Table 111. From the possibility of steric hindrance one might expect the ortho isomer to be the least reactive of the nitrocinnamic esters; actually the pura isomer is the least reactive. Apparently steric influences by ortho substituents are not extremely important-a fact confirmed by the reaction of benzalacetomesitylene. On the other hand, a p-nitro group does not always prevent reaction (c$ the case of Pnitrochalcone). In one case studied (6bromocoumarin) substitution by bromine gave a decrease in reactivity. EXPERIMENTAL
The general directions for carrying out the Michael condensation under the various conditions used are given below. In the cases in which 0% yield has been reported the recovery of unreacted materials was seldom less than 85% and never below 70%. A . Piperidine as a catalyst.-To equimolar quantities of the addendum and acceptor dissolved in absolute ethanol or methanol (50 ml. per 0.1 mole of addendum) was added piperidine (2.0 cc. per 0.1 mole of addendum), and the solution was heated seventy-two hours on a steam bath. The reaction mixture was cooled in ice and if a solid appeared it was removed by filtration and recrystallized from the appropriate solvent. When no solid formed the mixture was diluted with water, extracted with ether, and the ethereal washings were dried over sodium sulfate. Removal of the solvent gave a product which was crystallized or distilled. B . A small amount of sodium a1kozide.-A sodium ethoxide solution was prepared by dissolving sodium in the minimum amount of absolute methanol or ethanol. An amount of addendum corresponding to three to six times the number of moles of catalyst was then added, followed by a solution containing the amount of the acceptor equivalent t o the addendum. The solution of the acceptor was prepared by using a minimum of 2 1. of dry ether or thiophene-free benzene per mole of acceptor, plus whatever additional amount was necessary to make a homogeneous solution. The reaction mixture stood a t room temperature for a t least 20 hours, was acidified with acetic acid, and the organic layer was washed with water. The ethereal or benzene extracts were dried over anhydrous sodium sulfate, the solvent was removed on the steam bath, and the product was recrystallized or distilled. C . A n equivalent of sodium alkozide (hot).-To a solution prepared by dissolving 2.3 g. (0.1 gram atom) of sodium in 35 ml. of absolute methanol or ethanol was added 0.1 mole of the addendum and 0.1 mole of the acceptor. The mixture was heated on the steam bath for four hours, allowed to stand overnight, and diluted with 200 ml. of water containing 7 g. of acetic acid. The diluted reaction mixture was extracted
THE MICHAEL CONDENSATION
577
twice with ether, the extracts dried over anhydrous sodium sulfate and the ether was removed on the steam bath. The product was recrystallized or distilled. D. An equivalent of sodium alkoxide (room temperature).-These experiments were carried out exactly like those described under B except that the amount of sodium used was equivalent t o the active methylene compound. E . Use of the sodio-derivative in the absence of alcohol.-Sodium was powdered under xylene, and the xylene was replaced by dry, thiophene-free benzene by repeated decantation. The theoretical amount of the active methylene compound dissolved in dry thiophene-free benzene (300 ml. of benzene per mole of addendum) was added slowly t o the sodium suspended in benzene (300 ml. of benzene per mole of sodium). The mixture was heated on the steam bath until reaction had ceased, and a solution of the theoretical amount of the acceptor in dry benzene (175 ml. of benzene per mole of unsaturated compound) was added. The mixture was heated on the steam bath for ten hours, cooled and washed with an equal volume of water containing a slight excess of acetic acid. The benzene layer was dried over magnesium sulfate, the solvent was removed, and the residue was crystallized or distilled under reduced pressure. Acknowledgment.-The authors are grateful to the Faculty Research Committee of the University of Pennsylvania for a grant t o aid this investigation. SUMMARY
A brief summary has been given of the results to be expected when the Michael condensation is carried out under various experimental conditions. The influence of the structure of the acceptor upon the reactivity of the unsaturated compound has been discussed.
