Mechanisms and models for homogeneous copper mediated ligand exchange reactions of the type: CuNu + ArX - ArNu + CuX'

CHRISTIANE COUTURE A N D ANTHONY JAMES PAINE' Xeros Re.set~rclz Centre qf C~ot~ntlt~, 2660 Sp~.nkrntln Drive. Mi.ssi.s,snn~u, Ont., Cat~cldt~ U K 2LI

Received January 24, 1984

CHRI~TIANE COUTURE and ANTHONY JAMES PAINE. Can. J. Chem. 63, 1 I 1 (1985). The title reactions arc an important class of copper mediated nucleophilic aromatic substitution processes, which constitute

a useful tool in the molecular design and synthesis of small molecules. We report the results of extensive investigation of these processes, primarily focussing on cyanodeiodination (Arl + CuCN + Cul + ArCN). Among the interesting features of these processes are: (a) an unusual rate equation involving autocatalysis by Cul product; (b) retardation by both excess nucleophile (as KCN) and excess leaving group (as KI), which compete with ArX to complex with CuNu; (c) only cuprous nucleophiles are active (ligand exchanged products from cupric salts arise from prior redox equilibria which form CuNu); (d) the halogen effect is large (kl - 40- 100 kBr - 300-5000 kc,) but the Hammett p value is zero; (c) ortho-alkyl groups do not hinder the reaction (and actually cause mild acceleration by relief of steric strain). Finally, the introduction of an ortho-COO group accelerates the reaction by a factor of 10"- lo5, but the general features of the accelerated reactions are also the same, again indicating a common mechanism, with entropic acceleration by ortllo-carboxylatc. Both kinetic and thermodynamic factors were considered in detail, the latter apparently for the first time. Applications to practical syntheses are considered, and novel mechanistic models for these interesting processes are discussed.

C H R I ~ T I A N E COUTURE et ANTHONY JAMES PAINE. Can. J. Chern. 63, 1 l l (1985). Les rCactions rnentionnies dans Ic titre constituent une classe irnportante de rkactions de substitutions nuclCophiles aro-

rnatiques catalysCes par le cuivre qui sont un outil utile pour la conception molCculaire ct la synthkse des petites molCcules. Nous rapportons les rCsultats d'une Ctude poussCe de ces rkactions au cours de laquelle on a mis I'accent. en premier lieu. sur la cyanodCiodation: (Arl + CuCN + Cul + ArCN). Parrni les caractCristiques interessantes dc ces reactions on peut noter, entre autre, le fait que: (a) ces rkactions prismtent une equation de vitesse inhabituelle qui impliquc une autocatalyse par le Cul qui est produit; (b) la vitcsse de la rkaction est retardte i la fois par un exces de nuclkophile (cornme le KCN) ou de nuclCofuge (comme le KI) qui entre en competition avec le composC ArX pour cornplexer le CuNu; (c) le fait que seuls lcs nuclCophiles cuivreux soient actifs (les produits provenant d'un Cchange de ligands se forrnent au cours d'un Cquilibre rCdox antCrieur qui forrne du CuNu; (d) I'effet des halogenes soit grand (kl = 40 i I00 ku, = 300 i 5000 ko) alors que la valeur p de Harnmett est Cgale i zCro; (e) les groupes alkyles en position ortlzo n'encornbrent pas la reaction (et qu'ils provoquent en fait une legere accelCration grice i une diminution de la contrainte stiriquc). Finalernent l'introduction d'un groupe C O O en position ortho accClere la rCaction par un facteur de 10' i lo5; toutefois les caracttristiques ginCrales des rCactions accClCrCes sont les rn&mes que les autres et ce fait indique I'existence d'un mecanisme cornrnun qui subit une accClCration entropique due i la prCsence du groupe carboxylate en ortlzo. On a considire en detail les facteurs cinktiques et therrnodynamiques; il sernble que ces derniers ont CtC exarnints pour la premiere fois. On considere les applications de ces rkactions dans des syntheses pratiques et on discute de nouveaux modkles rnkcanistiques pour ces reactions intkressantes.

[Traduit par Ic journal]

Introduction [2]. There is evidence that cuprous nucleophile species are Aromatic substitution reactions are important tools in the intermediates in the catalytic reactions, and therefore. these

molecular design and svnthesis of small molecules. Substi- Processes likely share the same mechanism (3-5) . - tution methodologies may be of electrophilic, nucleophilic, or radical character, the last of which is relatively rarely applied to synthetic problems. Electrophilic aromatic substitution (EAS) is the most common, and is supported by a wide litera- ture. Nucleophilic aromatic substitution (NAS) usually re- quires a suitable leaving group, X , plus activation by electron- withdrawing substituents, which stabilize the intermediate negative charge in the classic addition-elimination mechanism (1). Nucleophilic aromatic substitution on unactivated rings is relatively rare, but may be effected in the presence of copper. There are two major classes of copper mediated reactions which are formal nucleophilic aromatic substitutions: copper catalysed reactions (known as Ullmann condensations), where copper is present as the metal, a salt, or an oxide; and copper ligand exchange reactions ( 1 , 2). These reactions are fairly general, and some of the possibilities are shown in eqs. [ I ] and

[I] CuNu + ArX --t CuX + ArNu (ligand exchange)

[2] NuH + ArX % ArNu t HX (catalysis)

Nu = X, CN, SCN, OAc, OH. ArO. ArS, ArSe, ArNH, Ar2N, Ar. . . .

X = 1, Br, CI.

Although these reactions have been known for many de- cades, there has been little systematic investigation of the reac- tion mechanism (2, 6, 7). The literature is characterized by questionable conclusions drawn with only a minimum of data, using relative yield measurements, or final product analyses (e.g. ref. 8) -techniques which cannot distinguish between rate and equilibrium effects (which, as will be shown, are quite important). In order to broaden mechanistic understanding of copper mediated NAS in general, and to improve its scope as a synthetic tool, we have begun by investigating the kinetically

I Presented, in part at the 66th canadian chemical conference, simpler ligand exchange reaction. ln this Case. CUNU is a mea- Calgary, Alberta as paper OR 14-9 (June, 1983). surable reactant, rather than a hypothetical transient inter-

'Author to whom correspondence should be addressed. mediate. In particular we focussed on copper mediated cy-

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112 CAN. J. CHEM.

anodeiodination (replacement of iodide with cyanide using cuprous cyanide) in detail, although we also examined a variety of other nucleophiles and leaving groups to ensure the gener- ality of the work.

Experimental Most substrates and products were commercially available and were

purified by distillation or recrystallization to >99% purity by ana- lytical hplc. 2.4.6-Tri-tert-butylbromobenzene was prepared by the method of Pearson et 01. (9). Sodium salts of aromatic carboxylic acids were prepared by standard methods, and recrystallized from water.

Syt~thesis of2.4.6-tritnethyliodobenzene Following the general procedure of Martin et nl. (10). 2,4,6-tri-

methylbenzene (12.1 g; 0.10 mol), iodine (6.4 g; 0.025 mol), and ammonium persulfate (6.9 g; 0.031 mol) were added to a solvent consisting of acetic acid (135 mL), water (25 mL), and sulfuric acid (6 mL) in a 250-mL round bottom blask. The reaction mixture was stirred and heated at 80°C for 4 h, poured on ice (300 g), and worked up into methylene chloride. The coloured impurities were removed by elution through a short column of silica gel in hexane. The product was isolated from excess starting material by fractional distillation (bp 128"C/13 Tom) ( I Tom = 133.3 Pa) to give a low-melting white crystalline solid (7.1 g; 0.029 mol; 58% yield; mp 29.5-31°C (lit. ( I I ) mp 29-30°C)). 2.4.6-Tri-tert-buty liodobenzene could not be prepared by this method.

Synthesis of 2,4,6-tri-tert-b~ctylbenzonitrile CuCN (0.48 g; 50 mmol) and 2,4,6-tri-tert-butylbromobenzene

(0.20 g; 0.6 1 mmol) were heated in 50 mL DMA at 137°C for 44 days, then cooled and worked up into methylene chloride. The solvent was dried and evaporated to give a green oil which was chromatographed on silica gel, with hexane as eluent, to give impure white crystals (crude yield 0. I0 g; 0.37 mmol; 60% yield). Pure product obtained by crystallization from MeOH (mp 150-151.5"C (lit. (12) mp 15 1 - 152°C)) had ir, 'Hmr, Cmr, and ms consistent with the structure and the literature.

General kinetic method Dimethylacetamide (DMA; Burdick and Jackson Company, Dis-

tilled in Glass grade) was the solvent selected. DMA from alternative suppliers gave the same results. Analytical hplc correction factors (KFs) were determined with reference to internal standard biphenyl (or N,N-diphenylformamide for the carboxylic substrate series), which gave the concentrations of substrate and product directly.

[Compound] =

Area counts compound X KF compound X [Internal STD]

Area counts internal STD

Unfortunately, there was a relatively narrow operating window of reagent concentrations determined by the balance between the limited solubility of the cuprous nucleophiles and the requirement for mod- erately high iodobenzene concentrations to achieve a reasonable con- version rate. These windows were [CUCN]~, = 50- 160 mM and [Phllr, = 15-45 mM. Product cuprous iodide was less soluble and often precipitated from solution. For kinetic analysis, the following re- lationship was assumed: [CuNu], = [CUNU]~, - [ArNu],.

Five or six reactions were usually conducted simultaneously in a temperature controlled oil bath fitted with independent magnetic stir- rers. In a typical reaction CuCN (350 mg; 3.55 mmol) and biphenyl (internal standard; 3 mg; 0.02 mmol) were brought to temperature (usually 137°C) in 20 mL DMA. lodobenzene (100 mg; 0.50 mmol in l .OO mL DMA) was added and 10-20 aliquots (-50 p.L) were taken from the reaction flask over 5- 100% conversion. The aliquots were quenched in 68% CH3CN/H,0, filtered, and analysed by analytical hplc using a Varian 5020 liquid chromatograph. CDS 401 Vista data station, and 8055 auto-sampler (Column: Applied Science 3p. Excal- ibar adsorbosphere C l x or Spherisorb ODs rcverse phase; 150 x 4.6

VOL. 63. 1985

I I

TIME (min)

40

- z E - 30

Z 0 + =x 20-

Z W

X 10-

FIG. 1. Typical reaction profile for cyanodeiodination.

- RUN # 98 A - ~ - A-A-A- A-A-A 6-

TOTAL

-'*\ /*G \* ,*

/*

h. / ' 0

,* \a

/* \. -* Phl f

o..f I I I I & I

TIME (rnin)

0 100 200 300 400 1300 1400

FIG. 2. Second-order kinetic plots for cyanodeiodination.

mm. Mobile phase: typically 68% CH3CN/H,0 (+2% HOAc for carboxylate substrates); 1.5 mL/min. Detection: 254 nm and variable wavelength).

Ana1y.si.s of kinetic results The hplc data were corrected for thermal volume expansion of

DMA (measured to be 1.2 X lo-' K-I) and used to prepare reaction profiles for over 170 runs (example in Fig. I). These profiles were not well fit by the expected second-order kinetic expressions (see Fig. 2), so initial rates were determined over the first 10-30% of reaction from the slope, kt,.,, of plots of -In [ArX] vs. time as follows.

[3] Initial rate = (d[ArCN]/dt),, = kt,.,, + I [ArX],, [CuCN],,"

[4] Initial pseudo first-order rate constant = (d[ArCNlldt

= -d(ln [ArX])/dt = - - k11. ,, + 1 [CuCN It," [ArXIO

The order in CuCN, n, was determined from a log-log plot (Fig. 3) to be 0.64 5 0.04. We have elected to represent the initial rate equation as 312 order (n = 1/2), so the initial 312-order rate constant is given by:

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COUTURE A

Slope =0.64 t 0.04 Intercept = -3.43 t0.04 cc = 0.990

FIG. 3. Determination of the kinetic order in CuCN.

FIG. 4. Activation parameter plots for copper mediatcd cy- anodehalogenations. (Labels A, B, and C correspond to the columns in Table I .)

Unless otherwise noted, all rate constants presented in this work are the initial 312-order rate constants, kl,..llz, in units of L'" mol-'I' s-- ' , and are designated simply as k , without subscripts.

Deterrninntiotz of nctivcltion pnrnrneters Transition state theory gives the relation k = ~(kT/ i i ) [exp

(-Ac"/RT)], where k is the rate constant. K the transmission cocffi- cient, k the Boltzmann constant, and the other symbols have their usual meaning (13). Substitution of AG': by AH.' - TAs', and reor- ganization of this equation leads to the linear relation in eq. [6], where the slope and intercept give the enthalpy and entropy of activation, respectively.

Activation parameter plots are shown in Fig. 4 and the results sum- marized in Table I.

Competitive renctions Some competitive reactions were performed in which the relative

reactivity of A vs. B was obtained by extrapolating the measured

TABLE]. Summary of activation parameters for cyano- dehalogenation

AH* (kcal mol-I) 20 * 1 21 * 3 19 2 1 AS* (cal mol-' K-') -26 ? 2 - 19 ? 5 -12 ? 4

product ratio [P,]/[P,] back to time = 0. and correcting for the initial concentration of A and B as follows: kA/kl, = ([P,:I/[P,]),, x ([B]lr/[A]J", where tn = 1 if A and B were aromatic halides, and tn = 112 if A and B were cuprous nucleophiles.

Results The rote equation

Second-order kinetic plots for cyanodeiodination exhibited upward curvature (see Fig. 2). This curvature is greater in reactions performed with nearly stoichiometric amounts of re- agents (R = [CuCN],,/[Phl],, - I) than in cases where a large excess of CuCN was employed (e.g. R = 8), which become almost pseudo-first order. Interestingly, the R = 1.5 (Run 98) and R = 8 (Run 5 1 ) lines in Fig. 2 appear to have the same initial slope, but the R = 1.5 line diverges upwards with time, indicating significant acceleration.

More than a dozen kinetic models were examined in an attempt to quantitatively describe the kinetics. Of these mod- els, only two could rationalize upward curvature of this type:

[7] Model I : v = k,/? [CuCN]'/'[Phl]; 312 order

RMS error - 1.5%

and (or)

[S] Model 2: v = kl [CuCN] [Phl] + k3 [CUCNII [ ~ h l ] [Cull

RMS error - 0.3%

The 312-order model appears to best describe the initial rate, but the 3rd-order autocatalytic term in [Cull in the second model (eq. [8]) is the only explanation for the slight acceler- ating effect of added Cul (vide irlfra and Table 2), as shown in Run 99 of Fig. 2. Run 99, saturated with added Cul, had an excellent 2nd-order plot (v = k,,h,[CuCN] [Phl], where koh, = kl + k, [Cul],,,). lntegrating the Model 2 rate equation led to the result that -35% of the R = 1.5 reaction proceeded via the 3rd-order term while less than - 12% of the R = 8 reaction went that way. The phenomenon of autocatalysis appears to be general: added CuBr also accelerates cyanodebromination of 2-bromobenzoic acid (for example, when [CuBr] - 16 X [2 BrPhCOOH], cyanodebromination is about twice as fast as in the absence of CuBr).

Other results Reaction rates were compared in the presence and absence of

various added substances, as shown in Table 2. Within experi- mental error, common electron or radical traps I, l-diphenyl- ethylene, 1,4-dinitrobenzene, and I ,6-di-tert-butyl-4-methyl- phenol had no effect on the rate of reaction between iodobenzene and CuCN, even when added in very large excess. Similar results were obtained for reaction of o-bromobenzoic acid with CuCN at 137OC in DMA (7.1 equiv. DNB gave a

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CAN. J . CHEM. VOL. 63, 1985

TABLE 2. Effect of added substances on cyanodeiodination at 137'C in DMA

[ P h x ] ~ Ratio Ratio kr,l Added Substance (mM) [CUCN],~/[P~X],, [addlO/[PhXI~) (k.,dc~/krcl)

None" PhZC=CH2 B HT' DNB" H zO Cu 1

PhCOOH

PhCN

KCN

-

13 10 5.9

5% in DMA c8.1 '

< 1 0 17 17 17 17 12 13 13 10

< 1 0 <2.6"

"Average o f I I runs. "k,,, = 2.75 X 10.' L"' mol I f ' s ' . Error limits refer to standard deviation o f the sample. I ,6-Di-tert-butyl-4-methylphenol (butylated hydroxy[oluene).

" I ,4-Dinitrobenzene. ' Not all the added substance dissolved, so these were saturated solutions.

Me0 Me H COOH NOz -4 CFa

FIG. 5. Hammett plot for cyanodeiodination at 137°C in DMA.

relative rate of 1.2 -+ 0.25 (4 experiments)). An equilibrium was observed for the reaction between iodo-

benzene and cuprous bromide (CuBr + Phl % CuI + PhBr) at 137°C in DMA. Equilibrium was initially observed for a reac- tion, involving stoichiometric amounts of reagents, which stopped at only 85% conversion, and then confirmed by ap- proach to equilibrium from the other direction. Unfortunately, the limited range of accessible compositions made it difficult to determine whether the equilibrium was bimolecular (K, = ([CuI~I[PhBr])/([CuBr:l[PhI])) or 312-order (K3/? = ([Cul]'" x [Ph~r])/([CuBr]"~[Ph1])). Equilibrium constants calculated for 5 runs performed at different compositions averaged 14 &

3 for K?, and 6.5 -+ 1.4 for K3/2 A single run of the same 1/Br exchange in sodium ortho-halobenzoates was performed at 53"C, giving K? - 6.3 and K,/? - 3.1. Cyanodeiodination, in contrast, goes to 3 9 . 9 9 % conversion.

The effect ofpara-substituent on reactions of the type ArI + CuCN + ArCN + Cul was negligible (the Hammett plot in Fig. 5 has a p value of -0.02 * 0.08), and ortho-methyl or even -tert-butyl groups have very little effect, causing a mild

SCHEME I. ortho-Substituent effects on cyanodehalogenation at 137°C in DMA.

acceleration, as reflected in the data in Scheme 1 . The relative- ly large error in the reaction rate for 2,4,6-tri-tert-butylbromo- benzene is due to side reactions, apparently dealkylation, which destroy the mass balance.

Ortho- and para-diiodobenzene react sequentially, first form- ing the monosubstituted iodobenzonitrile, which builds up to 40-60% yield before conversion into the disubstituted product. Rate data for fits of these reaction profiles (not shown) are as follows: for p-diiodobenzene, k, (first substitution) = 1.24 x lo-' and k2 (second substitution) = 5.26 X for o- diiodobenzene, k, = 5.48 x and k, = 5.99 x L'/' m o ~ - l / ? s- ' at 137°C in DMA. These rate constants were deter-

mined by Runge-Kutta fits of the reaction profiles (RMS error -2-3%), and are not initial rate constants.

In contrast to the relatively minor impact of all para- substituents and ortho-methyl, -tert-butyl, -iodo, and -cyan0 groups, there is an enormous ortho-carboxylate effect, and a

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COUTURE A N D PAlNE 115

TABLE 3. Rclativc reactivity of somc cupsous nuclco- &..- philcs in dciodinations

[Phl]~ Ratio COOH CuNu" ( r n M ) [CUNU]II/[P~I]~, kral * 10%

1.0 1.0 2400 ( l o 4 - lo5 3 ) ( ~ . ~ s x I o - ~ L ' ~ rno~-'~s-') CuSPh" 13.3 7.5 7.5

CUB? 18-53 0.4-7 6.2 CUCN' 18-46 2-8 I .O CuCl 12.0 8.1 0.78 CuOAc" 15.3 8.5 <0.0 13"

"All CuNu species, except CuSPh and CuOAc, seemed completely soluble in DMA. The relative reactivity shown in the table assumes complete solubility.

" Average of 5 runs. ' Average of I I runs. k,,, = 2.75 x 10 ' Lti2 m o l t / ' s ~ ~ ' "Yield of - 15% after 6 days.

TABLE 4. Comparison of bromodeiodination yields with CuBr and CuBrzn

[Br2I0 24-Hour yield Reagent (M) Ratio [Cu],/[PhI], of PhBr (%)

SCHEME 2. Relativc ratcs of cyanodchalogcnation at 137°C in DMA. CuBr - 0.53 91 CuBrz - 0.49 3 1 CuBr 0.16 0.54 9.5 CuBrz 0.13 0.48 7

large halogen leaving group effect, as summarized in Scheme 2. The data in the scheme has been rendered to a common temperature, and the bracketted value for sodium 2-iodobenzoate has been estimated from the trend in the bromo series.

"All runs with [PhIIo = 0.045 M; at T = 135°C.

nals at the beginning of a cyanodeiodination reaction, they were due to -2% Cu" initially present in the CuCN (a com- mon impurity in cuprous salts). The fact that cyanodeiodination of o- and p-diiodobenzene clearly occurs with the detectable buildup and decay of substantial amounts of the monocyano intermediate species also rules out the SRN1 chain mechanism (14a, c).

The reactivity of several cuprous salts was compared to CuCN to explore the effect of the nucleophile on the rate, and the results for nucleodeiodination are summarized in Table 3. Both CuBr and CuBr2 react with Phl to form PhBr (Table 4). 'The addition of excess Br2 to either reaction effectively inhibits the exchange, indicating an equilibrium of the type CuBrz cj CuBr + 112 Brz, where only CuBr is active in the ligand exchange reaction. The rate equatiorz

Second-order kinetics normally prevail for exchange reac- tions run under homogeneous condition^,^ but Fig. 2 shows that second-order plots had upward curvature, consistent with the observed mild catalysis by cuprous iodide. Because n , the order in CuCN, at 0.64, was closer to 112 than to 1, and because the mechanistically significant relative rates were insensitive to variations in tz , all results have been reported in terms of a simpler 312-order rate equation ( n = 112) for the irzitial rate.

More than a dozen kinetic models were tested on individual runs, with the best fits obtained by two-term equations of the form v = k, [PhI][CuCN]" + k2 [Phll[Cul][CuCN]" for rz = 1 /2 or 1 (RMS error -0.3%). One possible interpretation of n = 112 could be reversible dissociation of inactive, largely dimeric Cu,CN,:

Discussion Full reaction profiles, similar to the example in Fig. I , were

determined by analytical hplc, using an internal standard to test for the maintenance of a mass balance. Except where noted, the reactions were clean, and went to >99.99% conversion, with no side reactions detectable (hydrodehalogenation to form ben- zene: <0.5%; Ullmann coupling to form biphenyl: <0.02%). Mass balance failure occurred with some ortho-carboxylate systems and with 1,3,5-tr.1-tert-butylbromobenzene. These ~roblems were attenuated somewhat bv the use of initial rates.

Among the major identifiable classes of proposed mech- anisms for copper mediated NAS reactions are the concerted mechanism, the benzyne mechanism, the SRN1 radical chain - -

K Phl [g] Cu2CN2 = 2 CuCN + PhCN + CUX

inactive active

mechanism (14), other non-chain electron transfer or radical mechanisms, and other forms of catalysed addition-elimi- nation mechanisms. The concerted mechanism has frequently been proposed in the face of lack of evidence for any inter- mediates (particularly benzyne or radical ions (6, 7)). For ex- ample, the benzyne mechanism has been clearly ruled out by thewell-known retention of position of substitution on the ring. Our unoriginal observation that copper mediated NAS is not inhibited by normal radical or electron traps rules out the SRN 1 mechanism (14) and any non-chain electron transfer or radical

'Bacon and Hill found second-order kinetics to prevail in most copper mediated ligand exchange processes (using R - 2- lo), except for cyanodeiodination, where their second-order rate constant also increased with timc (6). They did not attempt to explain the obser- vation.

mechanism involving "free" radicals or radical ion inter- mediates. Furthermore, although we did observe weak esr sig-

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CAN. J . CHEM. VOL. 63, 1985

TABLE 5. Results of competitive reactions performed in DMA at 137OC. The ratio of absolute rate constants (determined from ordinary experiments) is shown in the last column for comparative purposes

Reaction k,~ k,~ competitors Ratio [ArI],,, Ratio ~ A I ~ B k ~ l k ~

A B Co-reagent [A]o/[B]~ (mM) R = [CUNU]~/[A~I]~ Competition Absolute

CuBr CuCN PhI 0.86 40.0 1.1 0.85 42.3 1.1 0.90 16.5 8.0 1.02 17.4 7.4

if the extent of dissociation is small. CuCN may dimerize at low temperatures, or in the solid state (15); however, at 137°C in DMA solution, dissociation should be extensive for entropy reasons. Detailed curve fitting of reaction profiles to general kinetic models allowing this dissociation, with K as a second adjustable parameter, gave worse results than the two-term models above. Furthermore, if CuCN actually dimerizes in solution, some consideration of potential Cu,lCN species would be required, further complicating the quantitative anal- ysis. For all these reasons, the rate equation was not pursued further, and the following discussion relies on the initial rate measurements using the empirical 312-order rate equation. Fortunately, the broad conclusions drawn from these results are independent of the precise form of the initial rate equation. Furthermore, the impact of the third-order term describing Cul autocatalysis could be attenuated significantly by comparing initial rates for reactions run with excess cuprous cyanide ([CuCN\lIo/[Phl],, - 8, which approaches pseudo-first-order ki- netics).

One of the interesting features of the SRN1 mechanism in particular, and chain reactions in general, is the observation that relative rates measured in competitive reactions are very much different than relative rates determined by the ratio of absolute rate constants (14b). We applied this test of mech- anism to these reactions (Table 5). In competition of p-nitro and p-methyliodobenzenes for cuprous cyanide, the com- petitive rate ratio was about the same as the ratio of absolute rate constants (2.05 vs. 1.65; both 2 15%). However, when CuBr and CuCN competed for iodobenzene, the competitive rate ratio was smaller than the absolute rate ratio (1-2 vs. 6-7). Since Cul catalyses CuCN reactions, the combination of two cuprous nucleophile species in the same solution may give rise to complex interaction effects, making it doubtful that this rate ratio discrepancy indicates a chain component to the reac- tion mechanism. The role of cuprous iodide autocatalysis may be assistance for removal of halide ion in the rate-limiting step, forming Cu1,- as a superior leaving group.

Effect of other added substances Basic mechanistic information may often be garnered from

the effect various substances have on reaction rates. There is a rather strong solvent effect on copper mediated ligand ex- change reactions which has been attributed to the ability to dissolve and solvate the cuprous species (6). For example, the rate in DMA was one-half that in DMF. The cuprous nucleo- philes are insoluble in solvents like hydrocarbons, chloro-

carbons, ethers, etc., so there is no reaction in those solvents. Table 2 lists the impact of various substances added at 10 to 20 times the initial iodobenzene concentration. 5% Water in DMA accelerates the reaction about 60%, probably a solvent effect. Benzoic acid, methyl benzoate, and benzonitrile have essen- tially no effect on cyanodeiodination. The absence of any effect with PhCOOH appears to contradict results of Cohen on reac- tion of o-iodo-N,N-dimethylbenzamide with CuCl and CuCN, where benzoic acid diverts the reaction to hydrodehalogenation (8). Unfortunately, Cohen gives no details on which to base a discussion of this difference. Interestingly, the addition of either excess nucleophile, in the form of KCN, or excess leav- ing group, as KI, retards the rate significantly. This observation effectively rules out any dissociative mechanisms, which should show common ion effects.

Other features Scheme 2 summarizes the impact of halogen on cy-

anodehalogenation reactions. For both ordinary and o-COOH substituted systems, aryl iodides are about 40- 100 times more reactive than aryl bromides, which, in turn, are more reactive than aryl chlorides. This series parallels leaving group ability of the halide ions (I- > B r > C1-), and has been interpreted as indicative of rate limiting CX rupture (5,6). I t is noteworthy that the opposite order of reactivity is observed for unmediated nucleophilic aromatic substitution, proceeding via the well known addition-elimination mechanism with rate limiting at- tack by the nucleophile on the activated aromatic ring (16). In contrast to the relatively large aromatic halide leaving group effect, the cuprous nucleophile effect is quite small for soluble cuprous salts (Table 3), again consistent with rate limiting breakdown of an intermediate.

There is mounting evidence that only cuprous ion is active in copper mediated reactions, although cupric reagents may sometimes give product (5, 17)."n the case of ligand exchange obierved with cupric bromide, the formation of bromobenzene from iodobenzene was traced to a redox equilibrium (eq. [ I 2]), followed by subsequent reaction of cuprous bromide (eq. [13]). Crude thermodynamic estimates indicate that eq. [I21 is proba- bly thermoneutral at 140°C (AHu -9 kcal mol-' (18) but ASo -20 cal mol-' K-' gives AGO -0).

[I21 CuBrz = CuBr + 112 Brz

[I31 CuBr + Phl --, PhBr + CuI

Also A. J . Paine, unpublished data.

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AND PAlNE 117

The Hammett p value for cyanodeiodination was found to be zero, within experimental error, for 7 parcl-substituents (Fig. 5). Copper mediated reactions typically have p values in the range 0- 1 (6, 7 , 19). This is also in marked contrast to un- mediated nucleophilic aromatic substitution, where electron withdrawing groups like nitro are required to stabilize the incip- ient negative charge as it develops on the ring during attack by the nucleophile, leading to p values of 3-5 (7, 20). Clearly the copper mediation results in a mechanism which completely avoids the build-up of negative charge.

The effect of ortho-alkyl groups on the reaction was probed with the idea that steric retardation might indicate a concerted mechanism, because the transition state would be very crowded. Interestingly, both o-methyl and o-tert-butyl groups demonstrate a mild steric acceleration, perhaps indicative of relief of steric strain in the transition state. Thus. the overall absence of steric retardation appears to speak against a fully concerted mechanism.

ortho-Carboxylate effect In spite of the fact that electronic substituent effects and

ortho-alkyl steric effects are small, there is a widely recognized ortho-carboxylate effect (1, 2, 6): sodium ortho-iodobenzoate reacts -lo4- lo5 times faster than iodobenzene (Scheme 2). p-Carboxylate has no effect, and the ortho salt is about 40- 100 times more reactive than the free acid. The trend is the same in the bromo and chloro series as well. Of particular interest here is whether the ortho-carboxylate acceleration occurs via the same basic mechanism or by a completely new mechanism. This problem was considered in detail, and the general features of the ortho-acid series were found to parallel those in the simple haloaromatic series in all aspects: the rate equation, the halogen effect, the effect of added substances, cuprous iodide autocata~~sis, etc. Thus we conclude that the accelerated reac- tions must have essentially the same mechanism. What then accounts for the huge rate difference?

It appears that the difference is primarily in the activation entropy. The plot of activation parameters in Fig. 4 shows that iodobenzene, ortho-bromobenzoic acid, and sodium ortho- bromobenzoate reactions with cuprous cyanide give three es- sentially parallel lines (same AH') with different intercepts, AS* (see Table 1). The ASt obtained for the reaction of io- dobenzene with CuCN is --26 entropy units, typical of second-order reactions, and is associated with the need for the reagents to diffuse together. On the other hand, a much more entropically neutral AS' - - 12 eu for reaction of bromo- carb6xylate with CuCN suggests that the two reagents are already substantially associated in the ground state (perhaps by complexation of cuprous ion in the vicinity of the halide leav- ing group). On the other hand, the enthalpy of activation, corresponding to the bond breaking and forming steps, is the same as for the normal copper mediated reaction (19-2 1 kcal).

Thermodynamics and reversibility Thus far. the discussion has considered the results of kinetic

measurements and presented some pseudo-thermodynamic pa- rameters. It is also useful to examine the thermodynamic pa- rameters, particularly with regard to potential reversibility of these processes. Table 6 shows the reaction enthalpies, AH0, calculated for generalized bimolecular copper ligand exchange equilibria of the type shown, using the relatively rare literature data on these compounds (18). Although they are quite crude, these appear to be the first such thermodynamic estimates, presently limited to the cases X, Y = F, C1, Br, 1, CN, N,, and

TABLE 6. Estimated reaction enthalpies for assumed bimolecular li- gand exchange reactions. (The standard states are the solid and liquid phases for the cuprous and aromatic species, respectively. The units

are kcal mol ' .)

A H' CUX + PhY - PhX + CUY

NUCLEOPHILES

0 Feasible (AH' 5 0)

Possible (0 5 AH' 5 7)

to solid or liquid standard states. 'The resulting table of 21 possible ligand exchange reactions is useful for correlation and prediction. For example, equilibrium constants, Kc,, may be estimated using the relation AH0 - -RT in Kc, (assuming AS0 - 0). If AH is too large (>5 kcal mol-I) then the reaction is predicted to be too endothermic to be feasible. If AH is nega- tive, then the reaction becomes thermodynamically possible (but may still be kinetically slow). Synthetically useful reac- tions must be thermodynamically downhill, and, indeed, cyanodehalogenation is found to be so. In cases where AH - 0 , reversible equilibria may result, lowering the synthetic yield. For example, Table 6 predicts possible equilibria for CI/Br or Br/I exchange, which was tested in the latter case, measuring AH0 = -2.15 kcal mol-' (vs. prediction of -4 +- 2 in Table 6). This appears to be the first fully established case of reversibility in these reactions and it reinforces the notion that the proposed mechanism must have a symmetrical, high energy intermediate or transition state, which does not dis- tinguish between the nucleophile and the leaving group.

The thermodynamic data in Table 6 show the following leaving group order: 1 > Br > C1(> N, > CN > F); where the last 3 are usually endothermic. This series agrees with the kinetic leaving group ability. The thermodynamic nucleophilic reactivity is in the reverse order (obviously), but the kinetic nucleophile effects (SPh r Br > CN - C1, Table 3) are much smaller than the kinetic leaving group effects. This series dif- fers from the kinetic nucleodebromination results of Bacon (6): C1 > Br > I > CN - SPh > SCN. Thus, it is evident that both thermodynamic considerations (AH < 0) and kinetic consid- erations (k,,, > kArBr) are required to design practical syntheses using copper mediated NAS.

Reaction mechanism Any proposed mechanism must account for the following:

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CAN. J . CHEM. \

PhNu + CUX

$ or intermediate

SCHEME 3 . lntimate electron transfcr mechanism for copper mediated NAS.

the halogen effect; the lack of para-substituent effect; the neg- ligible ortlio steric effect; entropic acceleration by ortho- carboxylate (but not by para-carboxylate); absence of radical chains or free radicals; cuprous iodide autocatalysis; and the retarding effect of potassium cyanide and postassium iodide. Finally, any proposed mechanism must obey the Principle of Microscopic Reversibility, and because of the symmetry of the ligand exchange, must involve a symmetrical transition state or intermediate which does not distinguish between the incoming nucleophile and the leaving group. It is in fact quite difficult to propose a chemically reasonable mechanism consistent with all these requirements, and this may explain why the literature abounds with concerted mechanisms. However, at this stage, we propose two fairly reasonable working hypotheses which are offered to stimulate further research.

Intimate electron transfer mechanism The first alternative to a fully concerted mechanism is a

special kind of electron transfer mechanism. More and more nucleophilic reactions arc found to involve electron transfer instead of nucleophilic attack. In this system, however, the absence of any effect of electron traps means that electron transfers which do occur must be very rapidly reversible, or rapidly product generating, sc that no "free" radical ions escape the solvent cage. Thus, a mechanism also capable of account- ing for many of the results is shown in Scheme 3: cuprous nucleophile and aromatic halide drift around in solution until they come together in an encounter complex in a solvent cage. Such complexes have lifetimes of 500- I000 vibrations, during which time the action inside the large dotted area in the scheme must occur.

Suppose there were an electron transfer from the cuprous nucleophile to the aromatic halide. Such a transfer should be to the IS* orbital, as opposed to a n * orbital, because diiodo substrates first give monosubstituted products (a classical test to rule out the SRN I electron transfer mechanism (14a, c)). This

radical ion then gives up a halide ion to form a cupric odd- electron species and a phenyl radical, still trapped in the same solvent cage. Presumably the interaction between these prox- imate unpaired electrons stabilizes the complex, and perhaps leads to bonding, giving rise to the possibility of the tri- substituted organocopper intermediate shown in the top centre of the scheme.' Whatever the form of the symmetrical inter- mediate shown in the central box, it merely reverses the for- mation process to give the ligand exchanged material.

This associative mechanism for ligand exchange has the advantage that leakage of phenyl radical can explain the ben- zene which is sometimes observed as a hydrodehalogenation side product (2). Also, cupric copper might further oxidize the phenyl radical to a cation, perhaps accounting for dealkyation in tert-butylated substrates. An electron transfer mechanism of this type might have less rigid stereochemical requirements than a concerted mechanism. Both K1 and KCN retard the reaction by competing with ArX as ligands for the cuprous ion. Finally, the entropic role of the ortho-carboxylate substituent in this mechanism would be to complex the cuprous and cupric ions in the vicinity of the halide, thereby extending the lifetime of the encounter complex in the solvent cage, and increasing the probability of reaction. (The etzthalpic role of ortho- carboxylate, if any, would be to stabilize the transition state by complexation with the copper.) On the other hand, the prob- lems with this mechanism are: (a) the need for intimacy of electron transfer; and (b) the need for electron transfer to the a:': vs. nl: orbital.

~i-Complexed organocuprate intermediates Another mechanism capable of rationalizing many of the

experimental results is a refined version of Weingarten's pro- posal (5) involving n-complexed organocuprate intermediates (eq. [14]). The key intermediate in this process is the h6, 18-electron complex between the cuprous nucleophile and the 6 n-electrons of the aryl halide (cuprous ion is cl,,). From this complex, intramolecular attack of the nucleophile gives the tetrahedral intermediate, where the negative charge that would otherwise be borne in the ring, is neutralized by the 16-electron n-complexed copper atom, which sucks all of the excess elec- tron density out of the ring (hence no substituent effect). The rate determining step would be loss of halide, followed by rapid collapse to final products.

This mechanism offers a ready explanation for the retarding effect of KCN and KI, which are known to form higher coordi- nate anions (Cu(CN),- or CuCNI- (21)) which would be inac- tive in this model because they already have 14 electrons, and therefore cannot form the necessary h6 18-electron complex.

This mechanism appears to be supported by parallels to nucleophilic aromatic substitution reactions in stable iron, chromium, molybdenum, and manganese arene carbonyl com- plexes known in the literature (5, 22). In fact, the tetrahedral

' A referee has noted that thermodynamic E" values for electron transfer from cuprous species to iodobenzenes arc -2 eV (i.e. at least twice as great as the enthalpy of activation of the ligand exchange process). However, the E" values refer to separated ions in solution, and stabilization within the cage (particularly if bonding is involved) could lower the activation energy from the E" value.

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COUTURE A N D PAINE 119

intermediate in eq. [I51 has been isolated and characterized by X-ray crystallography (22c). Cuprous h%omplexes are rare (23), but not unknown (24). Unfortunately, the arene carbonyl complexes undergo NAS with the following leaving group order: F > C1 > Br, opposite to that observed here (22). To account for this apparently conflicting order of reactivity, com- plexation of CuNu and ArX would have to be favoured in the order 1 .> Br 9 CI, in order to overcome the reactivity prefer- ence of the complex. If that were so, one would expect a larger substituent effect in general, because h" complexation should see the halide as just another substituent. Thus, this inconsis- tency diminishes the value of the parallel to other transition metal arene complexes.

There are some minor problems with microscopic revers- ibility in the simple picture in eq. [14], but they can be over- come if the stereochemical integrity at the ips0 carbon is allowed to scramble by reversible halide loss.

There are two possible explanations for the ortho- carboxylate effect in this reaction, both based on anchimeric assistance (25). The ortho-carboxylate may displace halide first, facilitating attack by cyanide (eq. [16]), or the carbox- ylate might assist removal of iodide, without ips0 scrambling, through formation of a transient carboxyl hypoiodite (eq. [17]).

CuCN t

[I6] e1 COO- - & q C 0 - *CN coo-

+ Cul

Neither of these possibilities is well supported at present: the first because of the strained 4-membered ring p-lactone inter- mediate (-25 kcal uphill (26)); and the second because of the extra electron density pushed into the rlng upon formation of the hypoiodite. Furthermore, any anchimeric assistance mech- anism is inconsistent with the increaser1 (less negative) entropy of activation observed for ord~o-carboxylate systems. AS' should decrerlse for anchimeric assistance because of the loss of entropy on forming the 4- or 5-membered ring transition state or intermediate (AS: y,,,,,,,,,, - -( 10- 15) eu (26)). so the primary neighbouring group effect in this kind of reaction should be on AH'. Attractive though these anchimeric assis- tance explanations are for the ortho-carboxylate effect, they seem to be inconsistent with the observed activation parameter data.6

Thus, the problems with the n-complexed organocuprate

'I t may be that this inconsistency arises from the comparison of iodo and bromo aromatics in Fig. 4. A more accurate comparison would employ the same halogen.

intermediate mechanism are: (a) questionable parallels to NAS in other transition metal arene complexes; and (b) the inability to rationalize the ortho-carboxylate effect.

Fitzal cotnmetzts Both of these mechanisms implicitly assume that CuNu is

monomeric in solution. This is a crucial requirement for the uc.tive species in the n-complexed organocuprate proposal, but may be relaxed for the intimate electron transfer mechanism. Although the assumption is both reasonable and common, the problems with defining the rate equation serve as a reminder that this was an assumption, and may not be true.

A key mechanistic question is the nature of the initial inter- action of ArX with CuNu: is it halogen complexation or n-type complexation'? An obvious way to attempt to measure the reia- tive affinity of cuprous ion for X or Ar in ArX would be through a systematic study of the solubility of cuprous salts in various ArX (e.g. PhH, PhI, PhBr, PhCI, 2,4,6-tri-tert-butyl- bromobenzene, etc.). If solubility were assumed a direct con- sequence of complexation, then trends in the solubilities would indicate the site of complexation. Attractive as this idea might seem, cuprous iodide was found to be insoluble in io- dobenzene, for example, with a probable solubility of <lo-" M, indicating an enthalpy barrier to dissolution and complex- ation of > -RT In ([Cul]/[PhI]) = 9.6 kcal mol-' at 25°C. (Compare to A H " - 2.9 kcal for Cul in acetonitrile (35 g/kg solution (2 I))). These enthalpy numbers are c~ott~po~site figures, accounting for overcoming lattice energy ontl forming the com- plex, but the lattice energy term is the same for dissolution in either solvent, so complexation of CuI with PhI is >6.7 kcal more endothermic than complexation with CH,CN. Thus it is not surprising that there is no reported spectroscopic evidence for complexed intermediates in these exchange reactions.

Although the 170 runs reported here probably constitute the most thorough investigation of copper mediated ligand ex- change reactions to date, they are not adequate to completely specify the operable mechanism. Two working hypothesis mechanisms have emerged which should be further tested and refined. Further progress on this complex issue requires: a clarified rate equation from a clearer definition of the copper species in solution (monomer/dimer/oligomer and solvation siate); more accurate thermodynamic estimates (particularly experimental data on other CuNu species); a better ~~nravelling of entropy and enthalpy rate effects (via more accurate activa- tion parameters); and measurement of association equilibria of CuNu with ArCOO-. Furthermore, theoretical calculations may have some relevant input. The n-complexation mech- anism may be tested by intramolecular reactions (systems which are sufficiently inflexible that CuNu cannot lie over the aromatic ring of ArX).'

Neither of the proposed mechanisms is completely satis- factory. Perhaps there is a combination process where initial halogen-copper complexation evolves into h%omplexation. Given the plethora of mechanisms for unmediated NAS (28), it is possible that more than one mechanism operates in medi- ated reactions as well. These very interesting and useful pro- cesses pose an extremely complex and difficult problem, but new light has been shed on the issue and promising research directions identified.

In fact, some intramolecular reactions arc known (23. 27), but to interpret the results requires good models for intcrmolccular rates. Some of the known examples involve substrates which appear to be sufficiently flexible to position CuNu over the aromatic ring anyway.

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120 CAN. J . CHEM. VOL. 63. 1985

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