1610 J.C.S. Perkin I1The Mechanism of the Vilsmeier-Haack Reaction. Part 111.1*2 Structuraland Solvent EffectsBy Paolo Linda, Antonio Lucarelli, Gianlorenzo Marino," and Gianfranco Savelli, lstituto di ChimicaNew kinetic data on the Vilsmeier-Haack reaction of heterocyclic compounds are reported which permit theconclusions that (i) the reaction is very selective, as shown by a p value of -7.3 for the formylation of thiophenderivatives in chloroform, (ii) the rate of substitution is only affected to a small extent by the polarity of the solvent,and (iii) the rate of substitution is highly dependent on the nature of amide. The reaction with NN-dimethyl-acetamide-carbonyl chloride complex proceeds ca. 5 x 1 O3 times slower than the reaction with correspondingNN-dimethylformamide complex.Organica, Universita di Perugia, Via Eke di Sotto 10, 06100 Perugia, ItalyIN previous papers lf3 we have investigated the kinetic derivatives with dimethylformamide (DMF) and phos-features of the Vilsmeier-Haack formylation of thiophen phoryl chloride or carbonyl chloride in 1,2-dichloro-ethane (DCE).The use of carbonyl chloride displayed Part 11, S. Alunni, P. Linda, G. Marino, S. Santini, and G.Savelli, J.C.S. Pevkin II, 1972, 2070. great advantages over that of phosphoryl chloride.2 This paper is considered as Part XVII of the series Electro- In the former case the electrophilic complex, which has philic Substitutions in Five-membered Rings. Part XVI, S .Clementi, F. Fringuelli, P. Linda, G. Marino, G. Savelli, and A.an be as aTaticchi, J.C.S. Perkin II, 1973, 2097. crystalline salt and the reaction between this comple1974 1611and the aromatic substrates exhibited very simplekinetics.In continuation of our studies on the reaction betweenthe COC1,-amide complex and the heterocyclic com-pounds, we now report data on (a) the selectivity of thereaction, through the determination of the p constantfor the formylation of thiophen derivatives in chloro-form, (b) the influence of solvent on the reaction rate,and (c) the effect on the reactivity and the selectivity ofthe electrophilic reagent, due to the substitution of amethyl group for hydrogen in the amide.RESULTS AND DISCUSSIONp For the Formylation of Thiophen Derivatives.-The rates of formylation of a number of thiophenderivatives with the carbonyl chloride-dimethylform-amide complex have been determined in chloroform at30".The compounds examined include unsubstitutedand 2-phenyl-, 2-methoxy-, 2-methyl-, 2-t-butyl-, 3-methyl-, 2-chloro-, and 2-bromo-thiophen. The firstfive compounds listed yielded a single substitutionproduct, the 5-formyl isomer. The 3-methyl derivativegave a mixture of 86.5% 3- and 13.5% 4-methylthiophen-2-carbaldehyde. The reactions of the halogeno-deriv-atives were complicated by the occurrence of someside-reactions (halogen exchange and carbonyldehalogen-ation) and therefore the corresponding rate data couldnot be employed for the determination of the p constant.The reactions were followed by titrating the acidpresent in the hydrolysed mixture using the procedurepreviously described.l The rate constants and therelative rates (referred to thiophen) are listed in Table 1.TABLE 1Rate data for the formylation of thiophen derivatives inchloroform2-Methoxy 55,500 1.01 x 1062-t-B~tyl 21.8 3982- Ethyl 11.9 217%Methyl 10.8 1962-Phenyl 9.81 1783-Methyl 2.83 7 cVnsubstituted 0.1 1 1a At 30".Substituent 105k,/l mol-1 s-1 a k/kH a6 Relative rates of substitution at the 5-position.Calculated The values are corrected for the statistical factor.from overall rate and isomeric distribution.Following a procedure already used by andother authors in similar studies, the oPc and C T ~ +constants (derived for benzenes) were used for thedetermination of the p constant (-7.3) for the reactionof the thiophen ring (Figure) (correlation coefficientComparison with other reactions shows that formyl-ation by dirnethylformamide and phosgene is almost asselective as chlorination by molecular chlorine (p3 P.Linda, G. Marino, and S. Santini, Tetvahedrotz Letters,4 G. Marino, Rend. Accad. Naz. Lincei, 1965, 38, 700.5 S. Clementi and G. Marino, J.C.S. Pevkin 11, 1972, 71.6 G. Marino, Adv. Hetevocyclic Chem., 1971, 13, 298.Y = 0.982).1970, 4223.-8.7) and hydrogen exchange 7a (p -7.2) and definitelymore selective than tin tetrachloride catalysed acetyl-ation (p -5.7).Solvent Efects.-A study on the effect of solvent onthe rate of substitution has been carried out for theformylation of furan and 2-methylfuran.The range of solvents suitable for a kinetic study islimited by many factors.Solvents of very low polaritysuch as benzene or hexane cannot be used because of thevery low solubility of the DMF-COC1, complex in thesesolvents. Protic solvents, such as water, alcohols, andcarboxylic acids cannot be used since they induce2 - OMe \I I-1.0 - 0.5 0 a+Plot of log h/kH against of constants for the formylation ofsubstituted thiophens by DMF-COC1, in chloroform a t 30"hydrolytic decomposition of the complex. Dimethyl-formamide cannot be used since the kinetics are com-plicated by a reaction between the electrophilic complexand dimethylformamide itself .s The solvents examinedin this study were chloroform (E 4 7 ) , 1,2-dichloroethane(E 10.35), and acetonitrile (E 38-8).In all these solventsthe reactions follow pure second-order kinetics, firstorder in substrate and first order in complex. The rateconstants are reported in Table 2.TABLE 2Solvent effects on foriiiylation rates105R,/l mol-l s-1 a t 20", 1 l,%Dichloro-Chloroform ethane Acetonitrile SubstrateFuran 6.99 12.5 3.942-Methylf uran 2820 4270 964Polar solvents should stabilize the electrophilic cation(in which the positive charge is more localized) morethan the intermediate and consequently slow down the(a) A. R. Butler and C. Eaborn, J . Chew. SOC. (B), 1968, 370;(b) A. R. Butler and J. B. Hendry, ibid., 1970, 848.D. S. Noyce and G. V. Kaiser, J . Org. Chew., 1969,34, 1008.9 6. J , Martin, S.Poignant, M. L. Filleux, and M. T. Que-rneneur, Tefrahedvon Lettevs, 1970, 50611612 J.C.S. Perkin I1reaction rate; this would explain the smaller rate ofsubstitution observed in the most polar solvent, aceto-nitrile.However, the rate observed in chloroform is smallerthan that in the more polar 1,2-dichloroethane: it ispossible that specific hydrogen bond interactions areresponsible for this inversion. Anyhow, solvent effectsare, on the whole, small.A.iutide Structure Efect.-It is well known that theuse of dimethylacetamide (DMA) in place of dirnethyl-formamide leads to acetyl derivatives. However, noquantitative comparison between the rates of these tworeactions (acetylation and formylation) has beenreported so far.2-Methylfuran and 2-methoxythiophen proved to besubstrates of suitable reactivity for such a comparativestudy.Accordingly the rate constants for the acetyl-ation of these two compounds by the DMA-COC1,complex have been determined at 20" in 1,2-dichloro-ethane and compared with the rate constants obtainedusing DMF under the same experimental conditions(Table 3). The data of Table 3 show a dramatic rateTABLE 3Effects of ainide structurek,/l mol-l s-l a t 20" in DCESubstrate DMF-COC1, DMA-COCl, K D ~ ~ / R D M ~2-Methylfuran 4.27 x lom2 1.15 x 3.7 x lo32-Methoxythiophen 0.2 4-10 x 10-5 4.9 x 103decrease (ca. 4-5 x lo3 fold) in passing from formyl-ation to acetylation of a given substrate.With regard to the sensitivity to substituent effectsof these reactions, we have obtained data which permita comparison of the effects of a 2-methyl group on thereactivity of position 5 in the pyrrole nucleus.Owing tothe very high reactivity of pyrrole derivatives informylation, we were unable to use the direct kineticmethod; accordingly we determined the relative ratesby a competitive procedure, which had been usedsuccessfully in previous studies.1° The relative rates of2-methylpyrrole with respect to pyrrole were 12.0 and53-2 for formylation and acetylation, respectively (thevalues are not corrected for the statistical factor).The lower reactivity and the higher selectivity ofacetylation relative to formylation should be the resultof a greater stability of cation (I), compared with (11),due to the electron-donating effects of the methyllo (a) P. Linda and G.Marino, Tetrahedron, 1967, 23, 1739;(b) S . Clementi and G. Marino, ibid., 1969, 25, 4599.l1 W. J. King and F. F. Nord, J . Org. Chern., 1948, 13, 635.l2 W. J. King and F. F. Nord, J . 0 ~ g . Chem., 1949, 14, 405.l3 Y. L. Gol'dfarb and P. A. Kostantinov, Bull. Acad. Sci.,U.S.S.R., Div. Chem. Sci., 1950, 992.group bonded to the positively charged carbon. Alsosteric effects, due to the larger size of the methyl group,Me Me Me, +/HMe' C I Meoperate in the same direction and can contribute to theobserved difference in reactivity between the tworeagents.EXPERIMENTALMateviaZs.-All the substrates and some products wereavailable from previous studies. 5-Chloro-,11 5-bromo-,lZ5-ethyl-,11 5-t-butyl-,l3 5-phenyl-,l* and 5-methoxy-thio-phen-2-carbaldehyde,15 5-methylfuran-2-carbaldehyde,16 5-methylpyrrole-2-carbaldehyde,17 and 2-methoxy-5-acetyl-thiophen l8 were prepared according to the literature.1,2-Dichloroethane, chloroform, dimethylformamide, di-methylacetaniide, and acetonitrile were purified by standardprocedures.Commercial carbonyl chloride (20% solutionin toluene) was used without further purification.Product A naZysis.-All the substrates examined, exceptZ-chloro- and 2-bromo-thiophen, gave, under kineticconditions, the expected aldehydes or ketones in very highyield, as checked by g.1.c. analysis of the products. Both2-chloro- and 2-bromo-thiophen gave comparable amountsof 5-chlorothiophen-2-carbaldehyde and thiophen-2-carb-aldehyde as main products.Kinetics.-The preparation of the DMF-COCl, complexand the kinetic method were described previously.1 Anidentical procedure was applied to the dimethylacetamide-carbonyl chloride complex.Cowzfietitive Experiments.-Stock solutions of 2-methyl-pyrrole, pyrrole, and the appropriate amide-carbonylcomplex in 1,2-dichloroethane (molar ratio 1 : 5 : 0.1) wereleft a t ZOO for 1 h and then poured into a 10% aqueousNaOH solution.The mixture was extracted with chloro-form, the organic layer was washed twice with water, dried(Na,SO,), and finally distilled off. The residue wasanalysed by g.1.c. on a C. Erba fractometer model GI,equipped with a flame ionization detector, using a 2 m x2 mm column packed with Carbowax 20M 10% andoperated at 150".We thank the C.N.R. for financial support.[4/846 Received, 26th April, 19741l4 P. Demerseman, N. P. Buu-Ho'i, and R. Royer, J . Cham.l5 E. Profft. Annalen. 1959. 622. 196.SOC., 1954, 4193., - . - .- ,l6 vST. J. Traynelis, J.'J. Miskel, and J. K . Sowa, J . Org. Chem.,1957, 22, 1269.l 7 S. Gronowitz, ,4. B. Hornfeldt, G. Gestbon, and R. A.l8 Y. L. Gol'dfarb, U. P. Litvinov, and V. I. Shvedov, ZhurHoffmann, Arkiv Kerni, 1961, 18, 133.obshchei Khi,m., 1960, 30. 535