2070 J.C.S. Perkin I1The Mechanism of the Vilsmeier-Haack Reaction. Part 11.l~~ A KineticStudy of the Formylation of Thiophen Derivatives with Dimethylform-amide and Phosphorus Oxychloride or Carbonyl Chloride in 1,2-Dichloro-ethaneBy S. Alunni, P. Linda, G. Marino,' S. Santini, and G. Savelli, lstituto di Chimica Organica, UniversitB diPerugia, Via Eke di Sotto 10, 061 00 Perugia, ItalyThe kinetic order of the reaction of thiophen derivatives with dimethylformamide and phosphorus oxychloride in 1.2-dichloroethane depends on the reactivity of the substrate. Reactions of relatively inert substrates (such as thio-phen and the methylthiophens) follows third-order kinetics, first-order in each reagent. On the other hand reactionsof very labile substrates (such as 2-methoxythiophen) follow second-order kinetics, the rates being independentof the concentration and the nature of the substrate.The observed kinetics are consistent with a mechanism in-volving an equilibrium leading to an electrophilic complex, which then attacks the heterocyclic substrate. Accord-ing to the reactivity of the substrate, the rate-determining step is either the attack of the complex on the aromaticcompound or the formation of the complex. The reactions with the complex formed from dimethylformamide andcarbonyl chloride follow pure second-order kinetics, first-order in substrate and first-order in complex.ALTHOUGH many studies have been devoted to thenature of the complex formed from dimethylformarnideand phosphorus oxychloride 3-8 and several hypotheseshave been formulated on the mechanism of the Vilsmeier-Haack f0rmylation,~9 lo no kinetic study of this reactionhas yet been accomplished. Five-membered hetero-aromatic rings, because of their high reactivity towardelectrophilic substitution, are especially suitable sub-strates for the study of reactions with mild electro-philes.ll Accordingly, we have undertaken a completekinetic study of the Vilsmeier-Haack formylation ofthese compounds.We now report the main kineticfeatures of the formylation of thiophen derivativeswith dimethylformamide as the amide, phosphorusoxychloride or carbonyl chloride as the halide, and1 ,%dichloroethane as the solvent.RESULTS AND DISCUSSIONKinetics of the Reaction with Dimethyljormamide andPhosphorus 0xychloride.-The reactions were carriedout by mixing equimolecular amounts of heterocyclicsubstrate, phosphorus oxychloride, and dimethylform-amide in dichloroethane and were followed by titratingthe acid present in the hydrolysed mixture.Duringthe reaction the number of equivalents of acid dropsfrom 4 (3 HC1 and the first hydrogen of H,PO,) to 3,since one equivalent of acid is consumed by the di-methylamine formed.The reactions of substrates of relatively low reactivity(thiophen, 2-methylthiophen, and 3-methylthiophen) obeythird-order kinetics (i), first-order in each component.Rate = kOb,[Het] [Me,N-CHO] [POCI,] (i)Reactions of very reactive substrates (2-methoxythio-Part I (preliminary account), P. Linda, G.Marino, andS. Santini, Tetrahedron Letters, 1970, 4223.This paper is considered as Part XV of the series ' Electro-philic Substitutions in Five-membered Rings,' Part XIV,S. Clementi and G. Marino, J.C.S. Perkin 11, 1972, 71.H. Bosshard and H. Zollinger, HeZv. Chim. Acta, 1959, 42,1659.H. Bredereck, R. Gompper, and K. Klemm, Chem. Bey.,1959, 92, 1456.phen) follow second-order kinetics, the rates beingindependent of the substrate concentration ; the ob-served k values are, in this case, equal to the rateconstants k, relating to the formation of the electro-philic adduct.Substrates of intermediate reactivity (%methylfuran)exhibit kinetics of order between 2 and 3. Second-order plots exhibit downward and third-order plotsupward curvature, respectively.This kinetic behaviour is consistent with a mechanisminvolving an equilibrium leading to an electrophilicadduct C (l), followed by an attack of the latter on theheterocyclic substrate (2), with formation of an inter-mediate which is finally converted into the formylderivative by the action of water (3).klk-1k 1Me,N*CHO + POCl, C (1)Heterocycle + C --w intermediate (2)3H20Intermediate --w formyl derivative + H,PO, + 2 HCI + Me,NH,Cl (3)Depending on the reactivity of the substrate, therate-determining step is either the attack of the electro-phile on the aromatic compound (third-order kinetics)or the formation of the adduct C (second-order kinetics).The Equilibrium of Complex Formation.-The equili-brium constant for the formation of the electrophiliccomplex from dimethylformarnide and phosphorusoxychloride in dichloroethane has been determinedby measuring spectrophotometrically the equilibriumconcentration of the ' free ' dimethylformarnide.The2. Arnold and A. Holy, Coll. Czech. Chem. Comm., 1962, 27,6 G. J. Martin and M. Martin, Bull. SOC. chim. France, 1963,7 G. J. Martin, S. Poignant, M. L. Filleux, and M. T. Quemen-8 H. Fritz and R. Oehl, Annalen, 1971, 749, 169.!a M. de Maheas, Bull. SOC. chim. France, 1962, 1989.10 G. Hazebroucq, Ann. Pharm. France. 1966, 24, 793.11 G. Marino, Adu. Heterocyclic Chem., 1971, 13, 235.2886.1637.eur, Tetrahedron Letters, 1970, 50611972 2071K values, determined at five different temperatures,are in Table 1.The van't Hoff plot is linear; theTABLE 1Formation of the Me,NCHO-POCl, complex in1,Z-dichloroethaneEquilibrium constant Rate constant29.6 28.4 25.0 4.9534.4 21.0 29.6 7.9039.0 15-0 35.0 11.744.2 9.8 40.0 15.049.0 7.2t / "C K/1 mol-l t/"C 104k1/l mol-l s-lthermodynamic parameters (AH = -13.7 kcal mol-l,A S = -38.6 cal mol-l K-l) have been calculated by aleast-squares procedure. The rate constants (k,) forthe formation of the complex were evaluated fromexperiments carried out under pseudo-first-order con-ditions by use of a large excess of POCl,. The k,values were calculated from the equilibrium constantK = kl/k-, and the slopes of the plots of Ceq/Ceq - xagainst time, which yield k, + k-l. The ' true ' second-order rate constants were calculated by dividing thefirst-order constants by the initial concentration ofphosphorus oxychloride (Table 1).The activationparameters were AH$ = 15.8 kcal mol-l; A S =-20-7 cal mol-l K-l. The values reported are inserious disagreement with those determined by Martinand his co-workersJ7 who studied the formation of thecomplex between dimethylformamide and POCl, inchloroform or methylene dichloride at temperaturesranging from -60 to -20 "C by n.m.r. spectroscopy.The discrepancy of the values is large and cannot beascribed entirely to the different experimental con-ditions ; we cannot explain these differences.Among the structures previously suggested for thecomplex between dimethylformamide and phosphorusoxychloride are the covalent structure (I) and the ionicMe Me H Me H\ +/ N-C < \ / " N-C-CL(I 1 (It) (In)structures (11) and (111).Structure (I) has been dis-carded by arguments based on i.r. spectra, and anionic structure is generally accepted. Earlier re-searchers inclined towards the structure (11) butrecently structure (111) gained in favour on the basisof c h e m i ~ a l , ~ ~ ~ spectroscopic,8 and thermodynamic l2evidence.The kinetics observed are consistent with the hypo-thesis of a complex in equilibrium with the reagentsbut this, by itself, does not permit us to choose amongstructures (1)-(111). Information useful for this pur-pose can be obtained by a comparison of the k, valuesfor equation (2) with the k values obtainable in thereaction with the complex formed by dimethylform-amide and carbonyl chloride.When these substancesare mixed in an inert solvent, carbon dioxide is given offand the equilibrium is completely shifted towards theright with formation of a crystalline complex, thestructure of which is unequivocally l2 (IV) [the cationis the same as in structure (III)].Me H\ +/MeDetermination of k,.-The constants k , for step (2)of the formylation of 2- and 3-methylthiophen havebeen determined from equation (4) where So is thedx/d = k,(&),- x)(Ct) (4)initial concentration of the heteroaromatic substrate ,x the concentration of the product (determined experi-mentally by an acid-base titration), and C, is theinst ant aneous concentration of the elect rophilic com-plex, derivable from the expression (5), where A , isKes = C,/(Ao - x - cpthe initial concentration of both dimet h ylf or mamideand phosphorus oxychloride.The rates dx/dt were determined at several points fromthe plots of x against t by the tangent method; the k,values were hence calculated from equation (4) (Table 2).TABLE 2Rate constants for the formylation of thiophen derivatives104k,/Substrate Reagent T/"C 1 mol-1 s-1Thiophen Me,N.CHO-POCI, 58 0.0242-Methylthiophen Me,N.CHO-POCl, 40 0-632-Methylthiophen Me,NCHO-POCI, 50 1-812-Methylthiophen Rle,N-CHO-POCl, 68 3.453-Methylthiophen Me,N.CHO-POCI, 40 0-27 63-Methylthiophen Me,N*CHO-COC1, 40 0.89 0u Overall rate constants.The isomeric ratio 2-formyl : 5-formyl was 6.1 for the reaction with POC1, and 5.9 for thereaction with COC1,.Alternatively, k , values were calculated by the follow-ing empirical procedure.It was observed that, untilabout 50% reaction, the plots of C, against x are linear[equation ( S ) ] . Hence, from equations (4) and (6), weC, = C, - mx (6)(7) dxldt = K,(C, - T.VX) (So - X)obtain (7), which gives by integration equation (8).so - x(Calm) - - xk,m[S, - (C,/m)]t = InThe k, values obtained graphically from the plots oflog (So - x)/[(Co/m) - x ] against time are in excellentagreement with the values determined by the tangentprocedure (Table 3).l2 M. L. Filleux-Blanchard. M. T. Quemeneur, and G. J.Martin, Chem. Comm., 1968, 8362072 J.C.S. Perkin I1The reaction-time curves are not sigmoid since theformation of the complex, although not instantaneous,is nevertheless much faster than the reaction betweenthe complex and the substrate.Some experimentswere carried out by premixing dimethylf ormamideand phosphorus oxychloride and allowing them toreach the equilibrium before adding the substrate :the results were the same, within experimental error,as those obtained when all the three reagents weremixed at the same time.Reaction with the Dimethy&wmamide-CarbonyJ Chlor-ide Com$Zex.-Carbon dioxide is evolved and theelectrophilic complex, having an unequivocal structure,can be isolated as crystals. The reactions betweenthis complex and the heteroaromatic compounds followZI = K, [Substrate] [Me,N*CHO-COCl, complex] (ii)pure second-order kinetics (ii).The rate constantsand the isomer distribution for the reaction with3-methylthiophen are reported in Table 2 and comparedwith the data obtained in the reaction with POCl,and dimethylformamide. The isomer distribution ispractically the same in the two reactions, showingthat the electrophilic species involved exhibit similarsteric requirements.A difference in k values exists, although not verylarge; it could be ascribable either to different struc-tures of the cations or to different anions bonded tothe same cation Me,NCHCl+ in the ion-pair. Wehope to be able to collect further information whichwill permit us to give a definitive answer to this problem.The reaction with the COC1,-Me,N*CHO complex, inview of its very simple kinetics, appears promising forstudies of s truc ture-reac tivi ty correlations.EXPERIMENTA4LMaterials.-Thiophen, 2-methylthiophen, 3-methyltio-phen, 2-methoxythiophen, and 2-methylfuran were fromprevious studies.Dimethylformamide, l,S-dichloroethane,toluene, and phosphorus oxychloride were fractionatedthrough a Todd column in a nitrogen atmosphere. Com-mercial carbonyl chloride (20% solution in toluene) wasused without further purification.Product A naZysis.-All the substrates examined gave,under kinetic conditions, the expected aldehydes in veryhigh yield, as checked by g.1.c. analysis of the products.Thiophen gave thiophen-2-carbaldehyde, 2-methylthiophengave 5-methylthiophen-2-carbaldehyde, 3-methylthiophengave a mixture of 858% of 3-methylthiophen-2-carb-aldehyde and 14.2% of 4-methylthiophen-2-carbaldehydewith Me,N*CHO-POCl, and, respectively, 86-2 and 13.8%with Me,N.CHO-COCl,.Kinetic Procedures.-Formation and equilibrium constantsof the Me,N*CHO-POC1, complex.Stock solutions of di-methylformamide and phosphorus oxychloride, preheateda t the proper temperature, were mixed and the reactionof complex formation was followed directly in the spectro-photometer by measuring the decrease in dimethylform-amide concentration a t 240 nni. A ten-fold excess ofPOCl, with respect to the dimetliylformamide concen-tration (ca. 1 x 1f.F~) was used and the pseudo-first-orderconstants, graphically evaluated, were converted intosecond-order constants (Table 1) by dividing them by theinitial concentration of POC1, (ca.1 0 - l ~ ) .For the determination of the equilibrium constant,preheated solutions of dimethylformamide and phos-phorus oxychloride in 1,2-dichloroethane were mixed in athermostatted cell, and allowed to reach equilibrium. Theequilibrium concentration of the ' free ' NN-dimethyl-formamide was determined by measuring the absorbancea t 240 nm.Reaction of heteroaromatic substrates with POCl, and di-methylformamide. The reaction mixture for each kineticexperiment was prepared in a 25 ml volumetric flask bydissolving a weighed sample of the heteroaromatic com-pound with ca. 15 ml of 1,2-dichloroethane, then addingthe calculated volumes of stock solutions (in the samesolvent) of dimethylformamide and phosphorus oxychloride,and finally diluting with the solvent to the mark andshaking.The concentrations used were equal for all thethree reagents (ca. 0 . 1 ~ ) . The flask was placed in athermostatic bath and 2 ml samples were removed a tintervals and quenched in water. After a t least 2 h(time necessary to complete the hydrolysis) theacid was titrated with 0- 1M-sodium hydroxide solution(Bromocresol Green). A typical kinetic run is reportedin Table 3. For the determination of the total order ofTABLE 3Formylation of 2-methylthiophen ; typical kinetic run[2-Methylthiophen] = [Me,NCHO] = [POCl,] =0- 1 6 7 ~ ; temperature 58-0 "Ct / 0.0985~- 70 1 0 3 ~ , ~ , 104k2min NaOH (ml) Reaction 102x l2 moP s-1 1 mol-1 s-10 13.60165 13.15 13.2 2.20 1.91 3.27310 12.78 24.1 4.02 1.70 3.60416 12.52 3 1.8 6.31 1-89 3.411195 11.85 51.5 8.60 1.73 3.471435 11.70 55.8 9.32 1.78 3.501855 11.62 58.4 9-75 1-62 3.502665 11.38 65.4 10.09 1.64 3-52Average k, = 3.47 x lo-* 1 mol-l s-l; tangent method.Average k , = 3.71 x 10-4 1 mob1 sl; integration method.the reaction, several experiments (with equimolecularconcentrations of the reactants) were carried out, theabsolute initial concentration being varied.The orderwas then calculated from the Noyes equation (9). Forn = 1 + [(log t'g - log $)/(log C - log C')] (9)the determination of the partial orders, the concentrationof dimethylformamide or the substrate was changed overa ten-fold range, the concentration of the other two re-agents being kept constant.The orders were determinedby the differential method from the plots of log Ax/Atagainst log a, where a is the initial concentration of thereagent considered. The order with respect to POC1,was determined by difference from the total order. Formyl-ation of 2-methoxythiophen follows second-order kinetics:a typical run is reported in Table 4.Reaction with the carbonyl chloride-dimethy2fornzalnidecomplex. Chloromethylenedimethylammonium chloride[Me,N:CHCl]+Cl- was synthesised in a flask equipped wit1972 2073a mechanical stirrer, a condenser, a dropping funnel, andan inlet tube for nitrogen. All operations were carriedTABLE 4Formylation of 2-methoxythiophen ; typical kinetic run[B-Methoxythiophen] = [Me,N*CHO] = [POCl,] =0.115~; temperature 25.0 "Ctimin045901552153004200.0978~- %NaOH (ml) Reaction9.509.30 8- 78.90 21.38.70 33.88.48 43.58.28 51-08.08 60.2Average k, = 4.81 x1 0 4 ~ ~10% 1 mol-l s-l1.00 4-8 12.45 4.443.86 4.626-00 5.045.85 4.906.92 5-0810-4 1 mal-1 s-l.out under nitrogen. A solution of carbonyl chloride(20% in toluene) in slight excess with respect to dimethyl-formamide was added dropwise with stirring t o an ice-cooled solution of dimethylformamide in toluene.After complete evolution of carbon dioxide [check withBa(OH),] the white precipitate was washed thoroughlywith anhydrous toluene and filtered off with reducedpressure.Kinetic stock solutions in 1,2-dichloroethane were pre-pared by dissolving the complex in the same apparatusused for the preparation in order to avoid contact withmoisture.The reactions of thiophen derivatives with (Me,N:CH-Cl]+Cl- were carried out in a volumetric flask, by use of aprocedure similar to that described in the previous para-graph. A ten-fold excess of substrate was used and thereaction was followed by titrating the acid present in thewater-quenched mixture. Total hydrolysis requires h.Consiglio Nazionale delle Ricerche is thanked for financial[2/646 Received, 20th Alavch, 19721support