The Heck reaction: mechanistic insights and novel ligands

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Polyhedron 19 (2000) 517–520

The Heck reaction: mechanistic insights and novel ligands

Michael Casey *, John Lawless, Colette ShirranChemistry Department, University College Dublin, Belfield, Dublin 4, Ireland

Received 4 October 1999; accepted 6 December 1999

Abstract

The kinetics of the Heck reaction of aryl iodides with methyl acrylate using phosphane ligands were studied. Triphenylphosphane stronglyinhibited the reaction when used in excess over the Pd(0) precatalyst. The rate of reaction was found to be weakly dependent on theconcentrations of both the aryl iodide and the alkene. The results indicate that the migratory insertion step is turnover limiting, with theoxidative addition to the aryl iodide being faster but not negligible. Phosphane sulfane hemilabile ligands were found to give good yields andgood catalyst stability in Heck reactions. q2000 Elsevier Science Ltd All rights reserved.

Keywords: Heck reactions; Palladium; Phosphane; Sulfane; Ligands; Mechanism

1. Introduction

The Heck reaction has developed into an extremely impor-tant synthetic method [1–4]. Nevertheless, there is scope forfurther improvement, for example in developing catalystswhich give greater reactivity or enantioselectivity. We wereinterested in studying ligands containing sulfur donorsbecause, despite their extensive coordination chemistry[5,6], such ligands have not often been applied in transitionmetal catalysis [7–13]. Phosphane ligands are frequentlyemployed in the Heck reaction, so we decided initially tocarry out a semiquantitative kinetic comparison of our newligands with triphenylphosphane. Surprisingly, although theindividual steps of the catalytic cycle have been studied indetail [14–17], very few studies of the kinetics of the Heckreaction using phosphorus ligands have been reported [18–20]. We now report our preliminary observations on thekinetics of Heck reactions of aryl iodides.

2. Experimental

Kinetics runs were carried out by adding a freshly preparedsolution of Pd2dba3PCHCl3 or Pddba2 (0.02–0.05 mmol) inDMF (1 ml) to the reaction mixture consisting of iodoben-zene (1 mmol), methyl acrylate (1.2 equiv.), ligand (0.02–0.08 equiv.), DIPEA (5 equiv.) and pentamethylbenzene

* Corresponding author. Tel.: q353-1-706-2420; fax: q353-3-706-2127;e-mail: [email protected]

(internal standard for GC analysis), in dry DMF (5–20 ml),at room temperature. After stirring for 10 min, the mixturewas heated to the required temperature. All steps were per-formed under an atmosphere of nitrogen. Samples were with-drawn periodically and analysed by GC. All kineticsexperiments were carried out at least twice.

3. Results and discussion

The model Heck reaction studied was the addition ofiodobenzene to methyl acrylate to give methyl cinnamate(Fig. 1). Use of Pd2dba3PCHCl3 and Pddba2 as precatalystsgave essentially identical results. Early runs at 508C, using4% Pd and 8% ligand, revealed an induction period, duringwhich the rate was negligible. During this phase the reactionmixtures remained pale yellow in colour, but they darkenedquickly once product formation had begun, to give wine col-oured solutions. When the reactions got underway the decayof iodobenzene and the formation of methyl cinnamateappeared to be roughly exponential, but the rates decreasedsubstantially towards the end. All of the PhI was consumed,but only ca. 65% yields of product were obtained.

The length of the induction period correlated strongly withthe initial ratio of PPh3 to Pd, varying from ca. 700 min for a4:1 ratio to ca. 30 min for a 1.1:1 ratio. Addition of CuI,which is known to bind to PPh3 [21], caused a significantreduction in the induction period. When Pd(OAc)2/2PPh3

was the catalyst precursor, only a short induction period wasobserved (ca. 30 min). Presumably, 1 equiv. of PPh3 was

M. Casey et al. / Polyhedron 19 (2000) 517–520518


Fig. 1. The model Heck reaction.

Fig. 3. Relative rate of the reaction vs. substrate concentration.

Fig. 2. Product concentration vs. time.

consumed in reducing the Pd(OAc)2 [22], so that the initialPPh3:Pd(0) ratio was 1:1. When an additional 0.5 equiv. ofPPh3 relative to Pd was added to a reaction mixture after ca.40% product formation, the reaction stopped completely for155 min, after which it continued to completion, albeit at aslower rate. These experiments showed that when thePPh3:Pd ratio exceeds 1:1 the reaction is strongly inhibited.With higher initial ratios, the PPh3 is slowly oxidised by tracesof air, until most of the excess is destroyed, and the overallrate then increases dramatically. We thought that catalystdecomposition might be responsible for the observed curva-ture of the graphs of product concentration against time. Theamount of Pd was therefore increased from 4% to 10%, only11% of PPh3 was employed to keep the induction period to aminimum, and the temperature was reduced to 408C. GCanalysis produced straight line graphs of product concentra-tion versus time, with tailing at the end (Fig. 2). Virtuallyno induction period was observed, but again only ca. 60%yield of methyl cinnamate was obtained. The results sug-gested that the reaction was proceeding with pseudo zeroorder kinetics (constant [Pd]). The reactions of 4-iodotri-fluoromethylbenzene and 4-fluoroiodobenzene with methylacrylate, and the reaction of iodobenzene with styrene, whichwere slower than the model reaction, also showed linearbehaviour.

A series of experiments was performed using 10% Pd and11% PPh3 at 408C, varying the initial concentrations of sub-strates. The rate of reaction in the initial linear phase wascalculated in each case, but we were unable to obtain quan-titatively reproducible rates. To minimise sources of error,the reactions were then carried out in batches of three, pre-pared by dividing one solution of catalyst, ligand, base andone substrate in three, and adding different quantities of thesecond substrate. The three reactions were then treated iden-tically. Although the rate constants still showed some varia-bility, the trends observed within these series of triple

experiments were reproducible (Fig. 3). The initial rate wasfound to be weakly dependent on the concentration of iodo-benzene, with a ca. three-fold rate increase on an eight-foldincrease in [PhI]. A weaker dependence of rate on aryl iodideconcentration was observed for the reaction of 4-iodotrifluo-romethylbenzene with methyl acrylate at 758C. The initialrate increased by a factor of ca. 2 on increasing [acrylate] bya factor of eight and the dependence was suggestive of satu-ration behaviour. The weak dependence on substrate concen-tration is consistent with the approximate straight linekineticsdepicted in Fig. 2, with curvature at high conversions.

In these model reactions only ca. 60% yields of methylcinnamate were obtained even though virtually all the iodo-benzene had been consumed. Benzene seemed a likely by-product as there are reports of reduction of aryl halides underHeck conditions [23,24]. Indeed, GC showed that benzenewas formed and 19F NMR analysis of a 4-fluoroiodobenzenereaction showed that fluorobenzene was the only significantby-product. The reduction can be accounted for by coordi-nation of DIPEA to the PhPdI oxidative addition complex,and b-H elimination of the amine [25,26], thus forming ahydridopalladium(II) species such as 6, which gives benzeneby reductive elimination (Fig. 4). To confirm the proposal,bases which cannot undergo b-elimination were tested. With2,2,6,6-tetramethylpiperidine, DABCO [27] or quinucli-dine, reaction continued to only ca. 30% conversion but theyields of methyl cinnamate based on iodobenzene consumedwere excellent.

Based on these results, we propose a mechanism for themodel Heck reaction that focuses on the ligation of the oxi-dative addition product (Fig. 4). Initially, the Pd(0) bistri-phenylphosphane complex 1 is formed from the Pd(dba)2

[28]. This species is in equilibrium with other Pd(0) com-plexes formed by coordination of other ligands such as dba[28], acrylate, trialkylamine [29] and iodide [30]. Reactionwith iodoarene then gives bisphosphane complex 2(PsDsPPh3) [28] and the alkene coordination step isunfavourable and turnover limiting due to the difficulty ofdisplacing PPh3. The reaction proceeds, if at all at these lowtemperatures, by a slow catalytic cycle. When the phosphaneto Pd ratio is reduced to -2:1 by air oxidation, the oxidativeaddition products may be substitutionally labile monophos-

M. Casey et al. / Polyhedron 19 (2000) 517–520 519


Fig. 4. Proposed mechanism for the model Heck reaction.

Fig. 5. Product concentration vs. time for the ligands 8 and 9.

phane complexes such as 3, 4, and 5 [19,31] in which onephosphane is replaced by more weakly coordinating ligands.Alkene coordination is now fast and the equilibrium favoursthe alkene complex 7. The approximate pseudo zero orderkinetics are consistent with this, and prove also that oxidativeaddition is a relatively fast step (although it seems to besufficiently slow to influence the rate weakly). Any of theother steps may be turnover limiting, but the migratory inser-tion is likely to be the slowest of these. As the reaction nearscompletion, continued phosphane oxidation and catalystdecomposition may be contributing to the departure fromlinearity. To our knowledge, this is the first detailed study ofthe kinetics of this prototypical Heck reaction using phos-phane ligands at atmospheric pressure. It indicates that foraryl iodides, alkene coordination is turnover limiting withG2 equiv. of PPh3, whereas migratory insertion is turnoverlimiting with 1 equiv. of phosphane. The mechanisticproposalis consistent with previous work, especially with its emphasison the need for a weak ligand/vacant site to facilitate alkenecoordination [14,19]. An induction period in the Heck reac-tion [23] and inhibition by phosphane have been reported[20,32,33]. A fast reaction cycle involving monoligatedcomplexes has also been invoked in a very recent paper byvan Leeuwen and co-workers [19], but with their very bulkyphosphorus amidite ligand the reaction was first order withrespect to alkene (styrene).

We also studied the kinetics of reactions using tri-o-tolyl-phosphane, which Heck showed to be the ligand of choice inmany cases [34]. The use of 1–4 equiv. of P(o-Tol)3 withboth iodobenzene (408C) and 4-iodotrifluoromethylbenzene(708C) gave high conversion, with no more than a briefinduction period, and pseudo zero order kinetics up to 60%conversion. The contrast with PPh3 is striking and the resultssuggest that Pd[P(o-Tol)3]2 forms sterically hindered oxi-dative addition complexes (2, PsDsP(o-Tol)3) in which

one phosphane is readily displaced by other ligands includingalkene [31,34].

With these mechanistic insights, we decided to study aseries of heterobidentate phosphane/sulfane ligands 8–10.We hoped that these hemilabile ligands [35] would formactive catalysts, as alkene coordination could take place bydisplacement of a weakly coordinating sulfane rather than astrongly coordinating phosphane. Ligand 8 was tested usinga 1:1 Pd:ligand ratio at 808C. Product formation clearly fol-lowed pseudo zero order kinetics until the conversion reachedca. 75% and the yield was ca. 100%. Ligand 9 gave verysimilar results under the same conditions (Fig. 5), althoughan induction period of ca. 95 min was observed. Ligand 10gave much faster reaction, but the yield of cinnamate wasonly ca. 65%.

Clearly PS ligands are viable in the Heck reaction. Thereactions were relatively fast, high conversionswereachievedand yields of methyl cinnamate were high, except for ligand

M. Casey et al. / Polyhedron 19 (2000) 517–520520


10 with the propane backbone. When the catalyst is a palla-dium complex containing PS ligands, the sulfur donor atomof the oxidative addition product (2, PDschelating phos-phanosulfane) is easily displaced by the alkene. The ligandsgive better catalyst stability and higher yields than PPh3,presumably because the dissociated S moiety of the hemila-bile ligand can recoordinate to stabilise the other complexesin the cycle, and to prevent competitive coordination of theamine. Ligand 10 gives faster reactions and lower yields thanligands 8 and 9, presumably because it gives a less stable six-membered chelate. Reactions using these ligands are not asfast as those using 1 equiv. PPh3 or P(o-Tol)3, where theconcentration of the Pd-alkene complex should be the high-est. To our knowledge, the use of hemilabile ligands in theHeck reaction has not been reported, although they have beenused in related reactions involving insertion of alkenes[36,37]. Ligand 9 seemed to give the best results so it wasinvestigated further. The reaction of styrene, in the presenceof ligand 9, was performed at 908C. An induction period ofca. 90 min was observed, the reaction rate was slow (ca. 1000min to reach completion) and excellent pseudo zero orderkinetics were observed. High conversion was obtained (ca.95%) but the yield was relatively low (ca. 70%), albeit muchhigher than using PPh3. Bromobenzene was reacted withmethyl acrylate employing 9 as ligand (2.4 equiv.) at thehigher temperature of 1108C. The reaction was slow (ca. 20h at 1108C), it ceased at 40% consumption of PhI, and theyield of methyl cinnamate was only 35%. Although thesepreliminary results are not as impressive as others reportedrecently [19], we believe that PS ligands offer considerablepotential and deserve further investigation.

Acknowledgements

We are very grateful to Enterprise Ireland for financialsupport (Basic Research Project No. SC/1996/435), and toJohnson-Matthey for a gift of palladium salts.

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The Heck reaction: mechanistic insights and novel ligands