Mechanisms of catalyst poisoning in palladium-catalyzed cyanation of haloarenes. Remarkably facile C-N bond activation in the [(Ph3P) 4Pd]/[Bu4N]+ CN- system

Published on Web 03/13/2008

Mechanisms of Catalyst Poisoning in Palladium-Catalyzed

Cyanation of Haloarenes. Remarkably Facile C-N Bond

Activation in the [(Ph₃P)₄Pd]/[Bu₄N]⁺CN^-System

Stefan Erhardt,^‡Vladimir V. Grushin,*^,†Alison H. Kilpatrick,^‡Stuart A. Macgregor,*^,‡

William J. Marshall,^†and D. Christopher Roe^†

Central Research & DeVelopment, E. I. DuPont de Nemours and Co., Inc., Experimental Station,

Wilmington, Delaware 19880, and School of Engineering and Physical Sciences, William H.

Perkin Building, Heriot-Watt UniVersity, Edinburgh EH14 4AS, U.K.

Received October 30, 2007; E-mail: vlad.grushin-1@usa.dupont.com; s.a.macgregor@hw.ac.uk

Abstract: Reaction paths leading to palladium catalyst deactivation during cyanation of haloarenes (eq 1)

have been identified and studied. Each key step of the catalytic loop (Scheme 1) can be disrupted by

excess cyanide, including ArX oxidative addition, X/CN exchange, and ArCN reductive elimination. The

catalytic reaction is terminated via the facile formation of inactive [(CN)₄Pd]^2-, [(CN)₃PdH]^2-, and

[(CN)₃PdAr]^2-. Moisture is particularly harmful to the catalysis because of facile CN^-hydrolysis to HCN

that is highly reactive toward Pd(0). Depending on conditions, the reaction of [(Ph₃P)₄Pd] with HCN in the

presence of extra CN^-can give rise to [(CN)₄Pd]^2-and/or the remarkably stable new hydride [(CN)₃PdH]^2-

(NMR, X-ray). The X/CN exchange and reductive elimination steps are vulnerable to excess CN^-because

of facile phosphine displacement leading to stable [(CN)₃PdAr]^2-that can undergo ArCN reductive elimination

only in the absence of extra CN^-. When a quaternary ammonium cation such as [Bu₄N]⁺is used as a

phase-transfer agent for the cyanation reaction, C-N bond cleavage in the cation can occur via two different

processes. In the presence of trace water, CN^-hydrolysis yields HCN that reacts with Pd(0) to give

[(CN)₃PdH]^2-. This also releases highly active OH^-that causes Hofmann elimination of [Bu₄N]⁺to give

Bu₃N, 1-butene, and water. This decomposition mode is therefore catalytic in H₂O. Under anhydrous

conditions, the formation of a new species, [(CN)₃PdBu]^2-, is observed, and experimental studies suggest

that electron-rich mixed cyano phosphine Pd(0) species are responsible for this unusual reaction. A

combination of experimental (kinetics, labeling) and computational studies demonstrate that in this case

C-N activation occurs via an S_N2-type displacement of amine and rule out alternative 3-center C-N oxidative

addition or Hofmann elimination processes.

Introduction

complexes, and recently reconfirmed in a targeted research

report.⁵

One of the most efficient modern synthetic routes to aromatic

nitriles is palladium-catalyzed cyanation of the corresponding

haloarenes (eq 1).¹The cyano group is an important functional-

ity²in numerous intermediates, dyes, pharmaceuticals, and

agrochemicals.^1,2A serious drawback of the catalytic cyanation

method is the low tolerance of palladium catalysts to excess

cyanide, one of the two key reagents, in the liquid phase.

This problem has been widely recognized¹since the discovery

of aromatic cyanation, catalyzed by palladium³and nickel⁴

Ar-X + CN^-^{Pd catalyst}8 Ar-CN + X^-

(1)

The mechanism of palladium catalyst poisoning during the

cyanation process (eq 1) needs to be understood to develop

methods to avoid or suppress the catalyst deactivation. Although

it has been found that Zn(CN)₂⁶and K₄[Fe(CN)₆]⁷are less toxic

to the catalyst than KCN and NaCN, very little is known about

how the process is terminated by excess cyanide and the factors

^†DuPont CR&D.

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^‡Heriot-Watt University.

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9

4828

J. AM. CHEM. SOC. 2008, 130, 4828-4845

Palladium-Catalyzed Cyanation of Haloarenes

A R T I C L E S

Scheme 1

Scheme 2

that may influence the poisoning. In 2003, Beller and co-

workers⁸reported that [Bu₄N]⁺CN^-impeded the ability of

[(Ph₃P)₄Pd] to undergo oxidative addition of the aryl halide

substrate in the first step of the process (Scheme 1). A recent

preliminary communication by some of us⁹shows that every

key step of the catalytic loop may be affected by excess cyanide

in solution. In particular, it was demonstrated that the key σ-aryl

palladium halide intermediate takes the desired path to ArCN

if treated with only 1 equiv of cyanide (steps 2 and 3 in Scheme

1) but is easily converted to stable, catalytically inactive

[(CN)₃PdAr]^2-in the presence of excess cyanide (Scheme 2).

Although the dianion [(CN)₃PdPh]^2-may be rendered catalyti-

cally active via Ph-CN reductive elimination to give Pd(0)

species,^10,11this process apparently occurs from a tricoordinate

complex and thus requires predissociation of one of the Pd-

CN bonds.⁹This bond ionization, however, is most efficiently

inhibited by even small quantities of extra free cyanide, which

shifts the equilibrium between [(CN)₃PdPh]^2-and [(CN)₂PdPh]^-

toward the unreactive 4-coordinate species.

[(CN)₃PdH]^2-is linked to the presence of trace water in the

reaction system. Under strictly anhydrous conditions, however,

a new process leading to the formation of [(CN)₃PdBu]^2-has

been identified (eq 3). This reaction is a rare example of

intermolecular nonallylic single C-N bond activation with a

platinum group metal complex.^12-16We also present a compu-

tational study of the mechanism of this unusual C-N activation

reaction displayed by the [(Ph₃P)₄Pd]/[Bu₄N]⁺CN^-system.

The preliminary study has also led to identification of yet

another reaction that may result in palladium catalyst deactiva-

tion if the cyanation process (eq 1) is carried out in the presence

of a quaternary alkylammonium salt as a phase transfer catalyst.

It was found that [(Ph₃P)₄Pd] readily reacts with [Bu₄N]⁺CN^-

in THF at room temperature to produce catalytically inactive

[(CN)₃PdH]^2-(eq 2).

Experimental Studies

C-N Activation in the [(Ph₃P)₄Pd]/[Bu₄N]⁺CN^-System.

The Formation of [(CN)₃PdH]^2-and [(CN)₃PdBu]^2-. As

preliminarily communicated,⁹adding [Bu₄N]⁺CN^-to [(Ph₃P)₄-

Pd] in dry THF resulted in an immediate color change from

(12) Allylic C-N activation with late transition metals is more common,

apparently due to CdC bond precoordination prior to C-N bond cleavage.

For a review of the synthetic use of palladium π-allyl methodology to cleave

the C-N bond of allylamines, see: Guibe, F. Tetrahedron 1998, 54, 2967.

(13) For selected recent reports on metal-assisted allylic C-N bond cleavage,

see: (a) Alcaide, B.; Almendros, P.; Alonso, J. M. Chem.sEur. J. 2006,

12, 2874. (b) Cadierno, V.; Garcia-Garrido, S. E.; Gimeno, J.; Nebra, N.

Chem. Commun. 2005, 4086. (c) Alcaide, B.; Almendros, P.; Alonso, J.

M.; Luna, A. Synthesis 2005, 668. (d) Escoubet, S.; Gastaldi, S.; Bertrand,

M. Eur. J. Org. Chem. 2005, 3855. (e) Alcaide, B.; Almendros, P.; Alonso,

J. M. Chem.sEur. J. 2003, 9, 5793. (f) Aresta, M.; Quaranta, E. J.

Organomet. Chem. 2002, 662, 112. (g) Torrent, M.; Musaev, D. G.;

Morokuma, K. Organometallics 2000, 19, 4402. (h) Aresta, M.; Quaranta,

E.; Dibenedetto, A.; Giannoccaro, P.; Tommasi, I.; Lanfranchi, M.;

Tiripicchio, A. Organometallics 1997, 16, 834.

(14) For chelation-assisted and pincer complex C-N bond activation, see:

Takano, K.; Inagaki, A.; Akita, M. Chem. Lett. 2006, 35, 434. Weng, W.;

Guo, C.; Moura, C.; Yang, L.; Foxman, B. M.; Ozerov, O. V. Organo-

metallics 2005, 24, 3487. Ozerov, O. V.; Guo, C.; Fan, L.; Foxman, B. M.

Organometallics 2004, 23, 5573. Fan, L.; Yang, L.; Guo, C.; Foxman, B.

M.; Ozerov, O. V. Organometallics 2004, 23, 4778. Yamamoto, Y.; Seta,

J.; Murooka, H.; Han, X.-H. Inorg. Chem. Commun. 2003, 6, 202. Morilla,

M. E.; Morfes, G.; Nicasio, M. C.; Belderrain, T. R.; Diaz-Requejo, M.

M.; Graiff, C.; Tiripicchio, A.; Sanchez-Delgado, R.; Perez, P. J. Chem.

Commun. 2002, 17, 1848. Gandelman, M.; Milstein, D. Chem. Commun.

2000, 17, 1603.

In this article, we describe further critical insights into the

mechanisms of palladium catalyst poisoning during aromatic

cyanation. In particular, we show that the formation of

(6) Tschaen, D. M.; Desmond, R.; King, A. O.; Fortin, M. C.; Pipik, B.; King,

S.; Verhoeven, T. R. Synth. Commun. 1994, 24, 887. Since the appearance

of this communication, numerous reports have been published, describing

the successful use of Zn(CN)₂as the source of cyanide for palladium-

catalyzed aromatic cyanation.

(7) Schareina, T.; Zapf, A.; Beller, M. Chem. Commun. 2004, 1388. Schareina,

T.; Zapf, A.; Ma¨gerlein, W.; Mu¨ller, N.; Beller, M. Tetrahedron Lett. 2007,

48, 1087. Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem.sEur. J. 2007, 13,

961. Cheng, Yi-n.; Duan, Z.; Li, T.; Wu, Y. Synlett 2007, 543. Zhu, Y.-Z.;

Cai, C. Eur. J. Org. Chem. 2007, 2401. Polshettiwar, V.; Hesemann, P.;

Moreau, J. J. E. Tetrahedron 2007, 63, 6784. Cheng, Yi-n.; Duan, Z.; Li,

T.; Wu, Y. Lett. Org. Chem. 2007, 4, 352.

(8) Sundermeier, M.; Zapf, A.; Mutyala, S.; Baumann, W.; Sans, J.; Weiss,

S.; Beller, M. Chem.sEur. J. 2003, 9, 1828.

(9) Dobbs, K. D.; Marshall, W. J.; Grushin, V. V. J. Am. Chem. Soc. 2007,

129, 30.

(15) For C-N activation in N-heterocyclic carbene complexes, see: Burling,

S.; Mahon, M. F.; Powell, R. E.; Whittlesey, M. K.; Williams, J. M. J. J.

Am. Chem. Soc. 2006, 128, 13702. Caddick, S.; Cloke, F. G. N.; Hitchcock,

P. B.; de K. Lewis, A. K. Angew. Chem., Int. Ed. 2004, 43, 5824.

(16) Suzuki coupling reactions of aryltrimethylammonium,^16avinyltrimethyl-

ammonium,^16band N-vinylpyridinium salts have been recently reported.

(a) Blakey, S. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125,

6046. (b) Buszek, K. R.; Brown, N. Org. Lett. 2007, 9, 707.

(10) For a recent review of reductive elimination from Pd(II), see: Hartwig, J.

F. Inorg. Chem. 2007, 46, 1936.

(11) For studies of R-CN reductive elimination from Pd(II), see: Marcone, J.

E.; Moloy, K. G. J. Am. Chem. Soc. 1998, 120, 8527. Huang, J.; Haar, C.

M.; Nolan, S. P.; Marcone, J. E.; Moloy, K. G. Organometallics 1999, 18,

297.

9

J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008 4829

A R T I C L E S

Erhardt et al.

yellow to tan, followed by gradual loss of color. After several

hours, a colorless reaction mixture was produced, which

contained ([Bu₄N]⁺)₂[(CN)₃Pd(H)]^2-, PPh₃, Bu₃N, and 1-butene,

as shown in eq 2. The formation of a biphasic liquid-liquid

system was frequently observed toward the end of the reaction,

due to phase segregation of the ionic hydride, a viscous colorless

oil that is only moderately soluble in THF at room temperature.

Monophasic reaction mixtures were obtained at higher dilution.

After this first round of studies, we continued our research

toward a better understanding of the mechanism of this unusual

reaction. By then, our supplies of the Pd(0) complex had been

exhausted and hence the project was continued with a new

sample of [(Ph₃P)₄Pd] (99.9+%) freshly purchased from Strem.

To our surprise, the first experiments with the new [(Ph₃P)₄Pd]

reagent resulted in a slightly different outcome. Whereas the

initial visual signs of the reaction were similar, the resulting

mixture retained homogeneity and exhibited no phase segrega-

tion, even though the ionic hydride was expected to oil out.

The ¹H and ³¹P NMR spectra of the reaction mixture indicated

the presence of free PPh₃and Bu₃N, as before. However, only

small quantities of the hydride [(CN)₃PdH]^2-(<10%) and

1-butene were formed, if any. Instead, a new species,

[(CN)₃PdBu]^2-, appeared to be the main product of the reaction

(eq 3). By comparing eqs 2 and 3, one can see that the

stoichiometry of the two reactions is the same, except that the

old [(Ph₃P)₄Pd] sample reacted to produce [(CN)₃PdH]^2-and

1-butene separately (eq 2), whereas these two molecules came

together to form [(CN)₃PdBu]^2-(eq 3) when the newly pur-

chased [(Ph₃P)₄Pd] was used. The above observations prompted

us to investigate the apparently erratic [(Ph₃P)₄Pd]/[Bu₄N]⁺CN^-

system in more detail, using both experimental and computa-

tional methods. These studies have defined a major route for

palladium catalyst deactivation in the presence of water, even

in trace quantities, and ultimately this may prove to be the

most common mechanism undermining catalytic aromatic

cyanation. For our experimental work, we needed to devise

routes to obtain pure samples of salts of both [(CN)₃PdH]^2-

Figure 1. ¹H (bottom) and ¹H{¹³C} (top) NMR spectra of [(¹³CN)₃Pd(H)]^2-

(trans-J_C-H) 64.9 Hz, cis-J_C-H) 2.6 Hz) in CD₃CN.

Figure 2. ¹³C (top) and ¹³C{¹H} (bottom) NMR spectra of [(¹³CN)₃Pd(H)]^2-

(J_C-C) 5.8 Hz; trans-J_C-H) 64.9 Hz, cis-J_C-H) 2.6 Hz) in CD₃CN.

and [(CN)₃PdBu]^2-

.

with J_C-H) 64.9 and 2.6 Hz, respectively. This signal was

observed as a singlet when the spectrum was acquired ¹³C-

decoupled (Figure 1). In full accord, a doublet and a triplet with

J_C-C) 5.8 Hz appeared in the ¹³C{¹H} NMR spectrum of the

hydride, and both C-H coupling constants were observed with

Preparation, Isolation, and Characterization of Salts of

[(CN)₃PdH]^2-. An independent synthetic method was developed

for [(CN)₃PdH]^2-. Slow addition of a dilute THF solution of

aqueous H¹³CN to [(Ph₃P)₄Pd] in the presence of ca. 2.1 equiv

of [Bu₄N]^{+ 13}CN^-in THF afforded ([Bu₄N]⁺)₂[(¹³CN)₃PdH]^2-

in high yield (eq 4). As mentioned above, this tetrabutyl-

ammonium salt is an oil that partially precipitated out of the

reaction solution. Our previous attempts to obtain an accurate

crystal structure of this hydride as its PPN salt (PPN⁺) [Ph₃-

PNPPh₃]⁺) were unsuccessful due to disorder.⁹In the present

work, we found that reacting ([Bu₄N]⁺)₂[(¹³CN)₃PdH]^2-with

1

the H-decoupler off (Figure 2).¹⁷

A highly accurate X-ray structure of ([Et₄N]⁺)₂[(¹³CN)₃PdH]^2-

(Figure 3) exhibited no signs of disorder in the crystal, possibly

due to hydrogen bonding interactions of the cyano ligands on

palladium with the C-H bonds of the cation (for the CIF file,

see the Supporting Information). The hydride ligand was located

from a difference map and fully refined. The Pd-H bond

distance (1.61 Å) appears to be the longest in the small family

of structurally characterized terminal palladium hydrides.^18,19

This points to the strong trans influence of the cyano ligand,

although this is not as large as that of hydride, the mutually

trans Pd-C1/C3 bonds (1.996(2) Å and 2.000(2) Å, respectively)

being noticeably shorter than Pd-C2 trans to hydride (2.053-

(2) Å). Considering the well-known poor stability of molecular

palladium hydrides,¹⁸the dianion [(¹³CN)₃PdH]^2-is remarkably

stable (see below), despite its long Pd-H bond.

-

[Et₄N]⁺BF₄in a THF-acetonitrile mixture resulted in

precipitation of solid ([Et₄N]⁺)₂[(¹³CN)₃PdH]^2-which was

isolated in an analytically pure form in 90% yield and fully

characterized in solution and in the solid state. The Pd-H

resonance at -10.8 ppm (Figure 1) appears as a doublet of

triplets due to the coupling to one trans and two cis ¹³C nuclei

Formation and Characterization of [(CN)₃PdBu]^2-. The

n-butyl complex ([Bu₄N]⁺)₂[(¹³CN)₃PdBu]^2-was prepared by

9

4830 J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008

Palladium-Catalyzed Cyanation of Haloarenes

A R T I C L E S

Figure 4. ¹H NMR spectrum of ([Bu₄N]⁺)₂[(CN)₃PdBu]^2-in THF-d₈.

The low-intensity resonances at 1.7 and 3.6 ppm are residual solvent

peaks.

Figure 3. ORTEP drawing of the palladium hydride dianion of ([Et₄N]⁺)₂

[(¹³CN)₃PdH]^2-with thermal ellipsoids drawn to the 50% probability level.

Selected bond distances (Å) and bond angles (deg): Pd(1)-H(1) 1.61, Pd-

(1)-C(1) 1.996(2), Pd(1)-C(3) 2.000(2), Pd(1)-C(2) 2.053(2), N(1)-C(1)

1.150(2), N(2)-C(2) 1.150(2), N(3)-C(3) 1.149(2), C(1)-Pd(1)-C(3)

174.98(7), C(1)-Pd(1)-C(2) 93.11(7), C(3)-Pd(1)-C(2) 91.91(6).

treating the newly purchased [(Ph₃P)₄Pd] with [Bu₄N]^{+ 13}CN^-

in dry THF or benzene. This reaction (eq 3) was found to

proceed faster at lower concentrations of [(Ph₃P)₄Pd], in full

accord with the results of our subsequent kinetic studies (see

below). At ambient temperature and [[(Ph₃P)₄Pd]] ) 0.5-1.5

× 10^-2mol dm^-3, it took the reaction 1-3 days to go to

completion, whereas for [[(Ph₃P)₄Pd]] ) ca. 8 × 10^-2mol dm^-3

and higher virtually no reaction was observed. The resulting

complex ([Bu₄N]⁺)₂[(¹³CN)₃PdBu]^2-is a viscous oil that is

easily soluble in THF and MeCN but insoluble in benzene and

ether. Attempts to isolate the solid [Et₄N]⁺salt using [Et₄N]⁺

CN^-in an analogous fashion to that employed for [(¹³CN)₃PdH]^2-

failed as a result of the greater solubility of the complex

containing the more lipophilic Pd-Bu moiety. Instead, precipi-

tation of [Et₄N]⁺CN^-was seen (NMR, X-ray; Supporting

Information). Therefore, ([Bu₄N]⁺)₂[(CN)₃PdBu]^2-could only

be characterized in solution. The ¹H NMR spectrum of isolated

([Bu₄N]⁺)₂[(CN)₃PdBu]^2-(Figure 4) displays eight multiplets

arising from the n-butyl groups of two different types, whereas

Figure 5. ¹³C{¹H} NMR spectrum of [(¹³CN)₃PdBu]^2-(J_C-C) 6.8 Hz)

in THF-d₈.

both concentration and solvent dependent. Unambiguous NMR

identification and characterization of the n-butyl palladium

complex and Bu₃N, the other reaction product, was carried out

using a combination of TOCSY and HMBC, and was facilitated

1

by the use of [(CH₃CH₂CD₂CH₂)₄N]⁺¹³CN^-to alleviate H

spectral overlap (see Experimental Section). These studies

confirmed the remarkable selectivity toward the formation of

only the linear, n-butyl palladium isomer and indicated that no

deuterium scrambling occurred during the reaction.

The Dianions [(CN)₃PdH]^2-and [(CN)₃PdBu]^2-are not

Interconvertible under the Reaction Conditions. One might

expect the dianions [(CN)₃PdH]^2-and [(CN)₃PdBu]^2-to be

interconvertible via migratory insertion of 1-butene into the

Pd-H bond and â-elimination from the n-butyl ligand. If these

transformations were feasible, the selectivity toward the forma-

tion of [(CN)₃PdH]^2-and [(CN)₃PdBu]^2-(eqs 2 and 3) could,

in principle, be affected by factors favoring or precluding olefin

removal from the system. Independent experiments, however,

pointed to a striking reluctance of [(CN)₃PdH]^2-and [(CN)₃-

PdBu]^2-to interconvert in THF in the presence of 0.03-1 equiv

of extra cyanide in the form of [Bu₄N]⁺CN^-. Heating the

isolated ([Bu₄N]⁺)₂[(¹³CN)₃PdBu]^2-in THF in the presence

of only 5% of [Bu₄N]^{+ 13}CN^-at 60 °C for 3 h resulted in no

change. Likewise, no transformation was observed upon treat-

ment of ([Bu₄N]⁺)₂[(¹³CN)₃PdH]^2-with 1-butene in THF

containing ca. 1-5% of [Bu₄N]^{+ 13}CN^-first at room temper-

ature and then at 55 °C for 5 h.^20aThus, once formed

[(CN)₃PdH]^2-and/or [(CN)₃PdBu]^2-do not interconvert, and

this is in accord with the selective formation of the n-butyl

palladium isomer and the lack of deuterium scrambling in the

reaction of [(CH₃CH₂CD₂CH₂)₄N]^{+ 13}CN^-with [(Ph₃P)₄Pd] (see

above). Finally, the formation of only [(CN)₃PdBu]^2-and no

NMR-detectable quantities of the hydride were observed when

the reaction of the new [(Ph₃P)₄Pd] with [Bu₄N]^{+ 13}CN^-was

a doublet (144.1 ppm) and a triplet (147.6 ppm) with J_C-C

)

6.8 Hz were observed in the ¹³C NMR spectrum of a ¹³CN

labeled sample (Figure 5). These ¹³C NMR chemical shifts are

(17) The preliminary experiments⁹with ¹³C-enriched cyanide were carried out

with the already new Strem 99.9+% reagent that was reacted with [Bu₄N]⁺

¹³CN^-to give small yet ¹H NMR-detectable quantities of the hydride.

Because in the ¹H NMR spectrum the doublet of triplets (1H, Pd-H)

integrated against the aromatic protons (40H, PPh₃) as ca. 0.6 to 40, it was

concluded that the ¹³C NMR signals at 144.6 and 148.0 ppm observed for

the same reaction solution were from the hydrido species, [(¹³CN)₃PdH]^2-

,

whereas in fact those were from [(CN)₃PdBu]^2-, the main product of the

reaction. The big ¹H NMR integration error is yet another reminder that

one should be careful when quantifying a weak MH multiplet resonance

against CH signals of much higher intensity.

(18) Grushin, V. V. Chem. ReV. 1996, 96, 2011.

(19) Clement, N. D.; Cavell, K. J.; Jones, C.; Elsevier, C. J. Angew. Chem., Int.

Ed. 2004, 43, 1277. Perez, P. J.; Calabrese, J. C.; Bunel, E. E. Organo-

metallics 2001, 20, 337. Wander, S. A.; Miedaner, A.; Noll, B. C.; Barkley,

R. M.; DuBois, D. L. Organometallics 1996, 15, 3360. Leoni, P.;

Sommovigo, M.; Pasquali, M.; Midollini, S.; Braga, D.; Sabatino, P.

Organometallics 1991, 10, 1038. Di Bugno, C.; Pasquali, M.; Leoni, P.;

Sabatino, P.; Braga, D. Inorg. Chem. 1989, 28, 1390. Young, S. J.;

Kellenberger, B.; Reibenspies, Joseph H.; Himmel, S. E.; Manning, M.;

Anderson, O. P.; Stille, J. K. J. Am. Chem. Soc. 1988, 110, 5744. Braga,

D.; Sabatino, P.; Di Bugno, C.; Leoni, P.; Pasquali, M. J. Organomet. Chem.

1987, 334, C46.

9

J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008 4831

A R T I C L E S

Erhardt et al.

repeated at room temperature and with vigorous stirring in a

flame-dried glass tube that was flame-sealed under Vacuum

(<0.001 Torr at -196 °C).^20bThis result indicated that the

difference in the reaction outcomes between the earlier (eq 2)

and more recent (eq 3) experiments cannot be accounted for by

the change in the reaction conditions affecting olefin removal

from the liquid phase.

The Critical Role of Water in the Selective Formation of

[(CN)₃PdH]^2-or [(CN)₃PdBu]^2-. As [(CN)₃PdBu]^2-and

[(CN)₃PdH]^2-were found not to interconvert, the variation in

the reaction outcomes (eqs 2 and 3) was apparently caused by

some difference between the old and new [(Ph₃P)₄Pd] reagents,

because all other chemicals and solvents used throughout this

work were the same.^21aFurthermore, we carried out the reaction

of [Bu₄N]⁺CN^-with two other sources of triphenylphosphine

Pd(0) complexes: another freshly received commercial sample

of [(Ph₃P)₄Pd] (99%; Aldrich) and [(Ph₃P)₃Pd] that was prepared

according to the literature.²²In both cases, the Pd-Bu complex

was formed as the main product (eq 3) and only small amounts

of the hydride were detected: ca. 5% for the Aldrich reagent

and <1% for the prepared [(Ph₃P)₃Pd].

An important result was obtained when the new Strem

99.9+% [(Ph₃P)₄Pd] reagent was treated with [Bu₄N]⁺CN^-in

the presence of a small quantity of water (1-5 equiv per

palladium) that was deliberately added to the system. In this

case, the tan-yellow color that emerged immediately upon

mixing the reagents faded much more rapidly, and after a few

hours the reaction produced ca. 80% of the hydride (eq 2).^21b

Because similar experiments with the same Pd(0) reagent in

the absence of water always produced the butyl complex (eq

3), we propose that the old Pd(0) reagent might have been

contaminated with a small amount of water, which could not

be detected in our standard purity tests.^21cDue to the significant

difference in the molecular weights of [(Ph₃P)₄Pd] (MW )

1155) and H₂O (MW ) 18), the presence of 1 mol equiv of

water in the palladium complex would translate into only ca.

1.5% contamination by weight. As will be discussed in detail

below, cyanide is easily hydrolyzed in the presence of water to

produce HCN, which rapidly reacts with [(Ph₃P)_nPd] to give

[(CN)₃PdH]^2-in the presence of [Bu₄N]⁺CN^-(eq 4). This

explains why the presence or absence of even small quantities

of H₂O can strongly influence the reaction paths for the [(Ph₃P)₄-

Pd]/[Bu₄N]⁺CN^-system, such that [(CN)₃PdH]^2-(eq 2) or

[(CN)₃PdBu]^2-(eq 3) can be formed predominantly or almost

exclusively. Even water absorbed on the walls of the glassware

used for the reaction can cause the formation of some quantities

of [(CN)₃PdH]^2-, no matter how dry all the reagents and the

solvent are.

Reactivity of [(Ph₃P)₄Pd] toward Cyanide in the Presence

of Water and in the Absence of a Quaternary Alkylammo-

nium Cation. As shown above, Pd(0) is highly reactive toward

HCN, a weak acid (pKa ) ca. 9) that is easily generated upon

hydrolysis of the cyanide anion. A series of experiments was

designed to explore the reactivity of [(Ph₃P)₄Pd] toward cyanide

in the presence of water and in the absence of a noninnocent

cation, such as [Bu₄N]⁺. Stirring a solution of [(Ph₃P)₄Pd] in

dry THF with excess K¹³CN for several hours at room

temperature did not result in any reaction. However, once O₂-

free D₂O or H₂O (140 equiv per palladium) was added to the

mixture, the yellow color from the Pd(0) complex began to fade,

and full discoloration was observed within ca. 10 min of agita-

ton, pointing to the disappearance of Pd(0). Analysis of the reac-

tion mixture indicated the presence of free PPh₃(³¹P NMR: s,

-5.5 ppm) and [(¹³CN)₄Pd]^2-(¹³C NMR: s, 131.4 ppm) as

the only P- and ¹³C-containing products. This reaction (eq 5) is

an important path leading to catalyst poisoning in palladium-

catalyzed cyanation of haloarenes,¹a process that is seldom run

under rigorously anhydrous conditions (see Discussion).

(20) (a) It is noteworthy that isolated and purified ([Et₄N]⁺)₂[(¹³CN)₃PdH]^2-

that is insoluble in THF was found to react with ethylene or 1-butene in

acetonitrile, as long as no extra cyanide was present. Both reactions

occurred within ca. 1 hour at room temperature. The reaction with ethylene

produced [(¹³CN)₃PdEt]^{2- 13}C NMR: 144.6, d, J_C-C) 6.8 Hz, 2C; 146.1,

(

t, J_C-C) 6.8 Hz, 1C). At the beginning, the reaction with 1-butene gave

[(Ph₃P)₄Pd] + 4KCN + 2H₂O f

a ca. 3:2 mixture of two species that we formulate as [(¹³CN)₃Pd(n-Bu)]^2-

(

¹³C NMR: 144.4, d, J_C-C) 7.0 Hz, 2C; 146.3, t, J_C-C) 7.0 Hz, 1C) and

K₂[Pd(CN)₄] + 4PPh₃+ 2KOH + H₂(5)

[(¹³CN)₃Pd(sec-Bu)]^{2- 13}C NMR: 145.6, d, J_C-C) 7.3 Hz, 2C; 146.9, t,

(

J_C-C) 7.3 Hz, 1C). As the reaction proceeded, the n-Bu/sec-Bu product

ratio was quickly increasing to reach ca. 20:1 at thermodynamic equilibrium.

This migratory insertion reaction was efficiently shut down by extra cyanide.

After a 1:1 mixture of ([Et₄N]⁺)₂[(¹³CN)₃PdH]^2-and [Bu₄N]^{+ 13}CN^-was

dissolved in 1-butene-saturated MeCN, no reaction was observed for 14

days. Simply dissolving pure ([Et₄N]⁺)₂[(¹³CN)₃PdH]^2-in MeCN resulted

We propose that first the Pd(0) undergoes oxidative addition

with the H¹³CN generated upon the hydrolysis of K¹³CN to form

(21) (a) All of the old Pd(0) reagent had been spent by the time the need emerged

to analyze it for impurities. However, we customarily test the quality of

any newly obtained [(Ph₃P)₄Pd] reagents prior to use in our laboratories.

This standard test includes reacting [(Ph₃P)₄Pd] with PhI in benzene and

analyzing the resulting solution by ³¹P NMR. Integration of the singlets

from the products, trans-[(Ph₃P)₂Pd(Ph)I] (22.3 ppm, 1 equiv) and free

PPh₃(-5.5 ppm, 2 equiv) determines the composition of the Pd(0)

compound in terms of the PPh₃to palladium ratio. The amount of Ph₃PO

impurity in the sample is easily estimated by integrating its ³¹P NMR singlet

(usually around 25-28 ppm) against those from [(Ph₃P)₂Pd(Ph)I] and PPh₃.

Judging by this test, both the old and new Pd(0) reagents were found to

have the expected stoichiometry, [(Ph₃P)₄Pd], and appeared to be pure,

containing Ph₃PO in only trace amounts that were hardly ³¹P NMR-

detectable. (b) In the presence of water, the two reaction paths (eqs 2 and

3) compete, which results in the formation of both [(CN)₃PdBu]^2-and

[(CN)₃PdH]^2-. The [(CN)₃PdBu]^2-to [(CN)₃PdH]^2-product ratio was found

to strongly decrease with an increase in the concentration of [(Ph₃P)₄Pd].

At [[(Ph₃P)₄Pd]] > 0.08 mol dm^-3with 1-5 equiv of H₂O per palladium,

the reaction produces almost exclusively [(CN)₃PdH]^2-and only barely

observable amounts of [(CN)₃PdBu]^2-. This is in accord with the results

of our kinetic studies of reaction 3 (see below), which show that the rate

of formation of [(CN)₃PdBu]^2-varies inversely with [Pd(0)]. Reaction 2

leading to the hydride [(CN)₃PdH]^2-is not as dependent on [(Ph₃P)₄Pd]

concentration. (c) We cannot rule out the possibility of contamination of

the old Pd(0) reagent with not only water but also some other impurities

that, like H₂O, cannot be detected by the PhI test.^21a

in rapidly self-decelerating decomposition to palladium black, [(¹³CN)₄Pd]^2-

,

free cyanide, and H₂(¹H NMR: s, 4.6 ppm). The resonance from the H₂

disappeared after another gas, N₂, ethylene, or 1-butene had been bubbled

through the solution. The previously described⁹decomposition of (PPN⁺)₂

[(CN)₃PdH]^2-in MeCN occurred similarly, except HCN rather than H₂

was detected among the products. Apparently, in both cases the first step

is the reversible ionization of the Pd-CN bond trans to hydride, followed

by reductive elimination of HCN. Depending on the conditions, the HCN

released may react with the as yet unreacted hydride to produce H₂and

[(¹³CN)₄Pd]^2-. Intuitively, the bulky, poorly coordinating organic cation

should not influence the reactivity of HCN. In nonaqueous aprotic media,

however, it apparently may do so, due to tight ion pairing (see below) that

can involve specific interactions between the counterions. The Pd-CN

ionization and sequential HCN reductive elimination should result in

[Pd(CN)]^-which decomposes to palladium metal and CN^-. Therefore, free

cyanide is generated upon decomposition, which shifts the equilibrium

between the unstable tricoordinate [(CN)₂PdH]^-and stable tetracoordinate

[(CN)₃PdH]^2-toward the latter, thus decelerating and eventually terminating

the decomposition process. The stability of the hydride and its lack of

reactivity toward olefins in THF is accounted for by much more difficult

Pd-CN ionization in the medium of considerably lower polarity. (b)

Interestingly, when the reaction under Vacuum was repeated in a flask that

had not been flame-dried and using a teflon stopcock instead of flame

sealing (i.e., under less rigorously anhydrous conditions), both [(CN)₃PdBu]^2-

and [(CN)₃PdH]^2-were produced (see Experimental Section). This indicated

that the [(Ph₃P)₄Pd]/[Bu₄N]⁺CN^-system might be highly sensitive to

microscopic quantities of water, as has now been established (see below).

(22) Giannoccaro, P.; Sacco, A.; Vasapollo, G. Inorg. Chim. Acta 1979, 37,

L455.

9

4832 J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008

Palladium-Catalyzed Cyanation of Haloarenes

A R T I C L E S

an unstable¹⁸phosphine palladium hydride, conceivably [(Ph₃P)₂-

Pd(H)(¹³CN)]. The latter would then react with another equiv

of H¹³CN to give rise to [(Ph₃P)₂Pd(¹³CN)₂] and H₂, just as

many [L_nPd-H] complexes react with HX to give H₂and [L_n-

Pd-X].¹⁸Finally, the phosphine ligands on palladium would

be easily displaced with excess cyanide,⁹resulting in stable

tetracyanopalladate, the final product. Support for this proposal

came from the detection of a hydrido palladium intermediate

that was formed immediately upon treating a THF-d₈solution

of [(Ph₃P)₄Pd] with a ca. 2-fold excess of aqueous H¹³CN. This

species displayed a signal in the hydride region of the ¹H NMR

spectrum (-8.7 ppm, d, J_H-C) 56.2 Hz) and was also detected

by ¹³C NMR (141.5 ppm, a singlet; a doublet with J_H-C) 56.2

Hz with the proton decoupler off). Other ¹H and ¹³C NMR data

were consistent with the presence of H¹³CN²³and H₂(4.5 ppm,

s).²⁴As the reaction occurred, well-shaped colorless crystals

formed, which were identified as trans-[(Ph₃P)₂Pd(CN)₂] by

NMR and X-ray analysis.²⁵

We also considered the reaction of K¹³CN with [(Ph₃P)₄Pd]

and H¹³CN in the presence of 18-crown-6 in THF. The main

product was again [(¹³CN)₄Pd]^2-(¹³C NMR); however, the

formation of ([K‚18-crown-6]⁺)₂[(¹³CN)₃PdH]^2-in ca. 20-

30% yield was also seen. The balance between the formation

of [(CN)₄Pd]^2-and [(CN)₃PdH]^2-is clearly dependent on the

nature of the cation, because with [Bu₄N]⁺¹³CN^-the clean

production of [(CN)₃PdH]^2-was observed (see above). The

formation of both species could involve an initial HCN oxidative

addition to [(Ph₃P)₄Pd] to produce a phosphine Pd(II) cyano

hydride [(Ph₃P)_nPd(H)(CN)]. The latter could then undergo PPh₃

displacement with cyanide,⁹leading to [(CN)₃PdH]^2-. This path

was favored for the [Bu₄N]⁺CN^-reagent, a highly reactive

source of cyanide with a weakly coordinating counterion. How-

ever, when KCN‚18-crown-6 was used, the reactivity of cyanide

was diminished due to its interactions with the potassium cation.

As a result, PPh₃/CN^-exchange leading to [(CN)₃PdH]^2-was

slower and the HCN that was still present could successfully

compete for the reaction with the [(Ph₃P)_nPd(H)(CN)] species

to give H₂and [(CN)₄Pd]^2-, as shown in eq 5.

Figure 6. First-order kinetic plot for the formation of [(¹³CN)₃PdBu]^2-at

5 °C (∆), 10 °C ()), 20 °C (0), 30 °C (O), and 40 °C (3) in THF-d₈. Data

acquisition at 5 °C was continued out to 65.6 h.

then to 8 (entries 1-3).²⁶In fact, slightly slower rates were

observed at higher concentrations of the cyanide salt. To

determine if the tetrabutylammonium cation and the cyanide

anion, both involved in the reaction, had counterdirecting effects

on rate, kinetic run 3 was repeated with half of the concentration

of cyanide but with the same concentration of [Bu₄N]⁺(entry

4). The similar rate constants in these two experiments provided

a clear indication of no counterdirecting effects involved and,

overall, the rate of the reaction appears to be relatively

unaffected by changes in [Bu₄N]⁺¹³CN^-concentration. In

contrast, lowering the concentration of [(Ph₃P)₄Pd] by a factor

of 2 resulted in approximately twice as fast a reaction, regardless

of the reagent ratio (entries 1, 5, and 6). Using [(Ph₃P)₃Pd] in

place of [(Ph₃P)₄Pd] led to a slightly faster rate. It is well-known

that in solution [(Ph₃P)₄Pd] is ca. 100% dissociated to [(Ph₃P)₃-

Pd] and PPh₃and that these species are involved in fast exchange

at ambient temperature.²⁷Larger quantities of extra phosphine

inhibited the reaction more noticeably. For instance, in a separate

semiquantitative experiment it was found that adding 6 equiv

of PPh₃decelerated the reaction of [(Ph₃P)₄Pd] under the

standard conditions (Table 1, entry 1) by a factor of ca. 4.

Studying the kinetics of the formation of [(¹³CN)₃PdBu]^2-

in the temperature range from 5 to 40 °C (Figure 6) allowed

for the determination of the activation parameters of the reaction.

The activation enthalpy and entropy were determined by direct

nonlinear least-squares fitting of these parameters to the Eyring

equation k₁) (k_BT/h) exp(∆S^q/R) exp(-∆H^q/RT) using the

temperature and rate constant data in Table 2. This gave the

Kinetic Studies on the Formation of [(CN)₃PdBu]^2-. To

gain insight into the unusual C-N activation reaction leading

to the formation of [(¹³CN)₃PdBu]^2-(eq 3), the kinetics of this

process was studied by ¹³C NMR using the new [(Ph₃P)₄Pd]

reagent and [Bu₄N]^{+ 13}CN^-. Details of these runs are presented

in the Experimental Section. The reaction was >95% selective

toward the formation of [(¹³CN)₃PdBu]^2-and exhibited first-

order kinetics, as clearly indicated by the linearity of the

logarithmic plots for product formation (Figure 6).

parameter estimates (25 °C) ∆G^q) 22.7 ( 0.1 kcal mol^-1

∆H^q) 26.3 ( 0.7 kcal mol^-1, ∆S^q) 12 ( 2 cal mol^-1deg^-1

,

In the first series of experiments (Table 1), it was established

that for the same concentration of [(Ph₃P)₄Pd] (1.7 × 10^-2mol

dm^-3) reaction rates varied insignificantly upon changing the

molar ratio of [Bu₄N]^{+ 13}CN^-to [(Ph₃P)₄Pd] from 4 to 3 and

and E_a) 26.9 ( 0.7 kcal mol^-1

.

The kinetic isotope effect (KIE) associated with the C-N

activation was studied by reacting [(Ph₃P)₄Pd] with [(C₄D₉)₄N]⁺

¹³CN^-or [(CH₃CH₂CD₂CH₂)₄N]^{+ 13}CN^-(Table 3 and Figure

S2 in the Supporting Information). For the fully deuterated

cation, a modest KIE of k_H/k_D) 1.6 was measured at 20 °C.

An even lower value of 1.3 was measured when [(CH₃CH₂CD₂-

CH₂)₄N]^{+ 13}CN^-was used for the reaction.

(23) For the literature NMR data for H¹³CN, see: Olah, G. A.; Kiovsky, T. E.

J. Am. Chem. Soc. 1968, 90, 4666.

(24) Only one broad singlet (14.5 ppm, ∆ν_1/2) 150 Hz) was observed in the

³¹P NMR spectrum. This signal is believed to be from trans-[(Ph₃P)₂Pd-

(H)(CN)] in fast exchange with free PPh₃. Analogous hydrido cyano nickel

complexes stabilized by tertiary phosphines and phosphites have been shown

to undergo such exchange that is fast on the NMR time scale, causing

removal of H-P coupling: Druliner, J. D.; English, A. D.; Jesson, J. P.;

Meakin, P.; Tolman, C. A. J. Am. Chem. Soc. 1976, 98, 2156.

(25) A crystal structure of trans-[(Ph₃P)₂Pd(CN)₂]‚CH₂Cl₂has been reported:

Hua, R.; Gota, M.; Tanaka, M. Anal. Sci. 2001, 17, 469.

(26) The lowest [Bu₄N]^{+ 13}CN^-to [(Ph₃P)₄Pd] molar ratio of 3 used in the kinetic

runs was dictated by the stoichiometry of the reaction (eq 3).

(27) Mann, B. E.; Musco, A. J. Chem. Soc., Dalton Trans. 1975, 1673.

9

J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008 4833

A R T I C L E S

Erhardt et al.

Table 1. Kinetic Data for Reaction 3 in THF-d₈at 20 °C

Pd(0)

[Pd],

mol dm^-

[Bu₄N^{+ 13}CN⁻],

k

×

s^-

10⁵,

3

1

entry

complex

mol dm^-

additive (concentration)

1

2

3

4

5

6

7

[(Ph₃P)₄Pd]

[(Ph₃P)₃Pd]

1.7 × 10^-2

0.8 × 10^-2

1.7 × 10^-2

7.0 × 10^-2

5.2 × 10^-2

14.0 × 10^-2

7.0 × 10^-2

3.5 × 10^-2

7.0 × 10^-2

5.95 ( 0.19

6.49 ( 0.19

4.65 ( 0.20

4.01 ( 0.11

10.94 ( 0.24

9.24 ( 0.22

6.65 ( 0.16

[Bu₄N]⁺BF₄^-(7.0 × 10^-2mol dm^-3

)

Table 2. VT Kinetic Data for Reaction 3 in THF-d₈at [(Ph₃P)₄Pd]

) 1.7 × 10^-2mol dm^-3

1

temp,

°C

k, s^-

5

5.34 ( 0.23 × 10^-6

1.21 ( 0.04 × 10^-5

5.95 ( 0.19 × 10^-5

2.97 ( 0.08 × 10^-4

1.19 ( 0.07 × 10^-3

10

20

30

40

Table 3. KIE for Reaction 3 ([(Ph₃P)₄Pd] ) 1.7 × 10^-2mol dm^-3

)

in THF-d₈at 20 °C

3

1

cyanide source (7.0

×

10^-2mol dm^-

)

k ×

10⁵, s^-

[Bu₄N]^{+ 13}CN^-

5.95 ( 0.19

3.52 ( 0.10

4.39 ( 0.12

[(C₄D₉)₄N]^{+ 13}CN^-

[(CH₃CH₂CD₂CH₂)₄N]^{+ 13}CN^-

Figure 7. ORTEP drawing of [K‚18-crown-6]⁺[(Ph₃P)Pd(CN)(O₂)]^-with

thermal ellipsoids drawn to the 50% probability level. Selected bond

distances (Å) and bond angles (deg): Pd(1)-C(2) 1.981(6), Pd(1)-O(1)

1.990(3), Pd(1)-O(2) 2.016(3), Pd(1)-P(1) 2.253(1), O(2)-O(1) 1.441-

(4), O(2)-K(1) 2.697(3), O(1)-K(1) 2.784(3), C(2)-Pd(1)-O(1) 154.6-

(2), C(2)-Pd(1)-O(2) 112.5(2), O(1)-Pd(1)-O(2) 42.2(1), C(2)-Pd(1)-

P(1) 93.5(1), O(1)-Pd(1)-P(1) 111.9(1), O(2)-Pd(1)-P(1) 154.0(1),

N(2)-C(2)-Pd(1) 177.4(5).

The presence of a KIE was confirmed by independent

semiquantitative experiments. A solution of [(Ph₃P)₄Pd] in THF-

d₈was divided into two equal parts, of which one was reacted

with 4 equiv of [Bu₄N]^{+ 13}CN^-and the other with 4 equiv of

[(C₄D₉)₄N]^{+ 13}CN^-. At room temperature, it took the reaction

involving the deuterated cation about twice as long to go to

completion, as was judged by full color loss and confirmed by

¹³C NMR. Analysis of the two reaction solutions by ¹³C NMR

revealed that the signals from the cyano ligand on palladium

trans to n-C₄H₉and n-C₄D₉were sufficiently separated for

integration. This led to another experiment, in which 1 equiv

of [(Ph₃P)₄Pd] was reacted with a solution of 10 equiv of

[Bu₄N]^{+ 13}CN^-and 10 equiv of [(C₄D₉)₄N]^{+ 13}CN^-. After this

reaction had gone to completion, the KIE was estimated at ca.

2 by integrating the triplet resonances from the [(¹³CN)₃Pd-

(C₄H₉)]^2-and [(¹³CN)₃Pd(C₄D₉)]^2-, as shown in Figure S3 in

the Supporting Information. This experiment ruled out the

possibility that the difference in reaction rates observed in the

other experiments was due to some impurities in the samples

of [Bu₄N]^{+ 13}CN^-and [(C₄D₉)₄N]^{+ 13}CN^-, rather than the actual

KIE.

Low-Temperature ¹³C and ³¹P NMR Studies of the

[(Ph₃P)₄Pd]/[Bu₄N]^{+ 13}CN^-System. To gain insight into the

nature of the reactive Pd(0) species that are formed upon mixing

[(Ph₃P)₄Pd] and [Bu₄N]⁺¹³CN^-in THF, we attempted their

characterization. Unfortunately, despite repeated attempts we

were unable to isolate any of these mixed cyano-phosphine Pd-

(0) complexes for an X-ray study, although in the course of

this work an unusual dioxygen adduct, [K‚18-crown-6]⁺

[(Ph₃P)Pd(CN)(O₂)]^-, was characterized crystallographically

(Figure 7).²⁸Therefore, the [(Ph₃P)₄Pd]/[Bu₄N]^{+ 13}CN^-system

was studied by low-temperature ¹³C and ³¹P NMR. The two

reagents in a 1:4.7 palladium to CN ratio were dissolved in a

mixture of THF and THF-d₈at -78 °C, and the resulting solid-

free, tan-yellow solution was immediately placed in an NMR

probe at -80 °C. The spectra were acquired with sufficient delay

to ensure integration accuracy. Both ¹³C and ³¹P NMR spectra

were recorded in the sequence -80, -60, 0, and -20 °C. The

(28) Preparing concentrated solutions of [(Ph₃P)₄Pd] and [Bu₄N]⁺CN^-in THF

at 0 °C and then cooling them to -25 °C and below commonly resulted in

precipitation of yellow crystals, which, unfortunately, were never of X-ray

quality. The choice of cations and solvents for the reaction of [(Ph₃P)₄Pd]

with cyanide is very limited. For instance, [Et₄N]⁺CN^-is insoluble in

THF but soluble in MeCN, whereas [(Ph₃P)_nPd] (n ) 3, 4) is soluble in

THF but insoluble in acetonitrile. Although KCN is poorly soluble in THF

in the presence of 18-crown-6, it was found to dissolve readily upon addition

of [(Ph₃P)₄Pd]. After THF solutions containing [(Ph₃P)₄Pd], KCN, and 18-

crown-6 in a 1:2:2 ratio had been prepared at room temperature and then

kept at -25 °C overnight or slowly evaporated, yellow plates of [(Ph₃P)₄-

Pd]‚THF (X-ray) and tiny white needles of [KCN‚18-crown-6] precipitated

out. The crystallization process was obviously driven by the poor solubility

of [KCN‚18-crown-6] rather than by any enhanced stability of mixed

phosphine cyanide anions at lower temperatures. Upon collection of one

of the yellow plates of [(Ph₃P)₄Pd]‚THF for X-ray analysis, the entire

mixture was exposed to air. Six hours later, the appearance of some new,

faint amber needle-shaped crystals was noticed. One of those was studied

by X-ray diffraction to reveal an interesting structure of a palladium complex

containing one PPh₃, one CN^-, and one O₂molecule bound to the metal

(Figure 7). Both oxygen atoms also form contacts to the potassium cation

inside the crown. The O-O bond distance of 1.441(4) Å is within the range

of 1.37-1.48 Å observed for other structurally characterized dioxygen

complexes of palladium: Yoshida, T.; Tatsumi, K.; Matsumoto, M.;

Nakatsu, K.; Nakamura, A.; Fueno, T.; Otsuka, S. New J. Chem. 1979, 3,

761. Stahl, S. S.; Thorman, J. L.; Nelson, R. C.; Kozee, M. A. J. Am.

Chem. Soc. 2001, 123, 7188. Clegg, W.; Eastham, G. R.; Elsegood, M. R.

J.; Heaton, B. T.; Iggo, J. A.; Tooze, R. P.; Whyman, R.; Zacchini, S. J.

Chem. Soc., Dalton Trans. 2002, 3300. Miyaji, T.; Kujime, M.; Hikichi,

S.; Moro-oka, Y.; Akita, M. Inorg. Chem. 2002, 41, 5286. Aboelella, N.

W.; York, J. T.; Reynolds, A. M.; Fujita, K.; Kinsinger, C. R.; Cramer, C.

J.; Riordan, C. G.; Tolman, W. B. Chem. Commun. 2004, 1716. Konnick,

M. M.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2004, 126, 10212.

Adjabeng, G.; Brenstrum, T.; Frampton, C. S.; Robertson, A. J.; Hillhouse,

J.; McNulty, J.; Capretta, A. J. Org. Chem. 2004, 69, 5082. Yamashita,

M.; Goto, K.; Kawashima, T. J. Am. Chem. Soc. 2005, 127, 7294.

9

4834 J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008

Palladium-Catalyzed Cyanation of Haloarenes

A R T I C L E S

Table 4. Variable Temperature ³¹P and ¹³C NMR Data for a

Solution of [(Ph₃P)₄Pd] (6.7 × 10^-3mol dm^-3) and [Bu₄N]^{+ 13}CN^-

(31.6 × 10^-3mol dm^-3) in THF/THF-d₈(3:1)^a

as aggregates of tight ion pairs. The lack of observable ³¹P-

¹³C coupling in the NMR spectra limited significantly the

amount of structural information that could be extracted from

these experiments.

equiv per Pd (³¹P NMR)

equiv per Pd (¹³C NMR)

free PPh₃

bound PPh₃

(21 ppm)

free CN^-

bound CN^-

entry

T,

°

C

(−5 ppm)

(167 ppm)

(ca. 159 ppm)

Computational Studies

1

2

3

4

5

6

-80

-60

0

1.4

1.7

2.6

2.3

4

3.9

4.1

0.7

0.8

0.6

C-N Bond Activation in the [(Ph₃P)₄Pd]/[Bu₄N]⁺CN^-

System under Anhydrous Conditions. Density functional

theory (DFT) calculations have been carried out to assess

possible mechanisms for the C-N bond activation reaction

exhibited by the [(Ph₃P)₄Pd]/[Bu₄N]⁺CN^-system. In the

majority of our calculations, [Bu₄N]⁺has been simplified to

[Me₃NEt]⁺, whereas PPh₃is replaced with PH₃. A number of

test calculations with PPh₃and various larger [R₄N]⁺cations

have also been performed to assess the role of steric bulk (see

below). Two general processes for the reaction of the [R₄N]⁺

species with a metal fragment, L_nM, have been considered,

namely, (a) Hofmann elimination or (b) oxidative addition

(Scheme 3). Within these two classes, Hofmann elimination may

occur in either an anti or syn fashion, while oxidative addition

may proceed via a concerted 3-membered process or an S_N2-

type displacement of amine. Note that oxidative addition yields

the observed metal-alkyl product directly, whereas Hofmann

elimination links to a metal hydride. In principle, the alkyl

product could then be produced by this latter route via

subsequent alkene migratory insertion.

2-Coordinate Models. The initial choice of the model for

the reactive metal fragment, L_nM, is based on the data in Table

4, which indicate [(PPh₃)₂Pd(CN)]^-to be the dominant species

at -60 °C but that warming facilitates further PPh₃dissociation.

Our initial focus will therefore be on the 2-coordinate

[(PH₃)Pd(CN)]^-model species. A 3-coordinate complex acting

as the actiVe species cannot be ruled out, however, especially

given the role proposed for such species in the oxidative addition

of aryl halides.^31-33A second set of calculations was therefore

carried out with [(PH₃)₂Pd(CN)]^-. One further issue is that in

THF anionic palladium-cyano species would be expected to

form ion pairs and aggregates with [NR₄]⁺cations.³⁰To reflect

this, our starting model reactant in the [(PH₃)Pd(CN)]^-/[Me₃-

NEt]⁺system will be the ion pair, 1, the computed structure of

which is shown in Figure 8.

4.0 (coalescence)

-20^b

-40

-60

2.7

2.4

2.0

1.3

1.6

2.0

^aThe molar ratio of Pd/PPh₃/CN^-) 1:4:4.7 (see text). ^bKept at -20

°C for 48 h prior to further studies (entries 4-6).

sample was then stored at -20 °C for 48 h, after which time

the study was resumed to obtain the data at -40 °C and then

again at -60 °C. No C-P coupling was observed throughout

the experiment in the temperature range of 0 to -80 °C.²⁹The

lack of multiplicity for the observed signals was most unfor-

tunate because it strongly impeded unambiguous interpretation

of the composition and structure of the mixed phosphine cyanide

Pd(0) species. Nonetheless, some conclusions could be drawn

from the integration data for the free and coordinated PPh₃and

¹³CN^-(Table 4).

As can be seen from Table 4, of the total of 4.7 equiv of

cyanide per palladium present in the system, approximately one

remained coordinated to the metal, regardless of the temperature.

At least two Pd-CN species could be observed, as judged by

the appearance of two signals around 159 ppm in the ¹³C NMR

spectra. While the linewidths, exact chemical shifts, and relative

intensities of the two resonances varied at different temperatures,

the two together consistently integrated against the singlet from

the free cyanide (167 ppm) as 0.6-0.8 to 3.9-4.1. In contrast,

the coordinated PPh₃(21 ppm) to free PPh₃(-5 ppm) ratio

varied throughout the experiment. The degree of PPh₃binding

was different at -60 °C after this temperature was approached

from ca. -80 °C an hour or so after the sample was prepared,

and later on, after the sample had been warmed to 0 °C, kept at

-20 °C for 2 days, and finally cooled back. Apparently,

exposure of the sample to higher temperatures led to more

efficient phosphine loss from the metal. The free to coordinated

phosphine ratio of 1:1 observed at -60 °C toward the end of

the experiment is indicative that, on average, only two PPh₃

ligands were bound to palladium at that point, along with one

cyanide. Importantly, even less than two PPh₃molecules per

palladium appeared to be coordinated at -20 and -40 °C

(entries 4 and 5 in Table 4).

Within 1, the individual ions show their expected linear and

tetrahedral geometries, although a slight bending of the

[(PH₃)Pd(CN)]^-moiety at palladium and C1 is computed (P-

Pd-C1 ) 176.7°, Pd-C1-N1 ) 172.4°). This presumably

arises from the attractive electrostatic interaction between the

two species and indeed N1, in particular, is computed to carry

a significant negative charge (-0.46) that attracts the δ⁺methyl

The VT NMR studies indicated that a solution of [(Ph₃P)₄-

Pd] and [Bu₄N]⁺CN^-in THF is a complex system that involves

temperature-dependent and not necessarily fast equilibria be-

tween various mixed phosphine cyanide Pd(0) species. While

stoichiometry considerations along with the VT NMR data

(Table 4) suggest that [(Ph₃P)₂Pd(CN)]^-is likely to be the main

species present when the system is roughly equilibrated at

-60 °C, care should be exercised when proposing structures

of the actual complexes in the solution. Like conventional

quaternary ammonium salts in media of low polarity,³⁰ionic

phosphine cyanide Pd(0) species are expected to exist in THF

(30) See, for example: (a) Ivashkevich, A. N.; Kostynyuk, V. P. Zh. Fiz. Khim.

1991, 65, 948 and references cited therein. (b) Everaert, J.; Persoons, A. J.

Phys. Chem. 1981, 85, 3930. (c) Barker, C.; Yarwood, J. Faraday Symp.

Chem. Soc. 1977, 136. (d) Mo, H.; Wang, A.; Wilkinson, P. S.; Pochapsky,

T. C. J. Am. Chem. Soc. 1997, 119, 11666.

(31) For selected original reports, see: (a) Amatore, C.; Jutand, A.; Suarez, A.

J. Am. Chem. Soc. 1993, 115, 9531. (b) Jutand, A.; Mosleh, A. Organo-

metallics 1995, 14, 1810. (c) Amatore, C.; Carre, E.; Jutand, A.; M’Barki,

M. A. Organometallics 1995, 14, 1818. (d) Amatore, C.; Carre, E.; Jutand,

A.; M’Barki, M. A.; Meyer, G. Organometallics 1995, 14, 5605.

(32) For reviews, see: Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 576,

254. Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314.

(33) For computational studies, see: (a) Kozuch, S.; Shaik, S.; Jutand, A.;

Amatore, C. Chem.sEur. J. 2004, 10, 3072. (b) Amatore, C.; Jutand, A.;

Lemaitre, F.; Ricard, J. L.; Kozuch, S.; Shaik, S. J. Organomet. Chem.

2004, 689, 3728. (c) Kozuch, S.; Amatore, C.; Jutand, A.; Shaik, S.

Organometallics, 2005, 24, 2319.

(29) Cooling the sample to -90 and further to -100 °C resulted in broader

lines, apparently due to higher viscosity.

9

J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008 4835

A R T I C L E S

Scheme 3

Erhardt et al.

hydrogens and results in a number of short inter-ion contacts.³⁴

Both of these effects are slightly exaggerated in the gas-phase

geometry, and solution-phase optimization leads to a somewhat

looser structure where the shortest inter-ion contact is 2.29 Å

(N1‚‚‚H3) and the [(PH₃)Pd(CN)]^-moiety is closer to linear

(P-Pd-C1 ) 178.7°, Pd-C1-N1 ) 177.3°). Similar structural

changes are also seen when comparing gas-phase and solution-

phase optimized geometries for other species in this study (see

Experimental Section).

The four transition states for C-N activation derived from 1

are shown in Figure 9. In the Hofmann elimination reactions

via TS1_antiand TS1_synconcerted C-N and C-H bond activation

occur, and in both cases rather late transition-state structures

are computed with short Pd‚‚‚H1 distances below 1.65 Å,

elongated N1‚‚‚C3 distances, and a shortening of the C2-C3

bond that indicates the onset of double-bond character in the

putative alkene moiety. The anti and syn processes entail barriers

of around 24 kcal/mol in the gas phase, which increase to 30

kcal/mol upon solvent correction. The increased barriers com-

puted in THF reflect the reduced dipoles of TS1_antiand TS1_syn

compared to ion pair 1, and as a result the PCM stabilization is

greater for the reactant than for the transition states. The

reduction in the dipole arises from a more even charge

distribution in the transition states. In particular, for TS1_antiand

TS1_synthe incipient protonation of the metal center markedly

lowers the negative charge on palladium from -0.46 in 1 to

around 0 in the transition states. Similar effects account for the

increased barriers computed in solution via TS1_SN2and TS1_conc

below.

For the oxidative addition processes, concerted C-N activa-

tion via TS1_concis computed to entail a prohibitively high barrier

of almost 34 kcal/mol in the gas phase, which increases to 38.4

kcal/mol upon solvent correction. The latter value can be

compared with a computed barrier of 18.6 kcal/mol for C-N

activation in an allyl-ammonium cation by [(PH₃)₂Ni].^13gThe

substantially lower barrier in the nickel case may arise from

precoordination of the allylic double bond, which facilitates

C-N cleavage. Certainly, without this feature concerted activa-

tion appears to be untenable, and the very long distances

between the Pd, C3, and N2 reactive centers in TS1_concare

suggestive of excessive steric strain in this structure.

(34) During the course of our studies, a number of alternative structures for 1

were located which feature different orientations of [Me₃NEt]⁺relative to

[Pd(CN)(PH₃)]^-. Of these, 1 is the most stable, although the alternative

structures are all within 1.5 kcal/mol.

Figure 8. Computed reactant ion pair [(PH₃)Pd(CN)]^-‚[Me₃NEt]⁺(1) with

selected distances in Å.

9

4836 J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008

Palladium-Catalyzed Cyanation of Haloarenes

A R T I C L E S

Figure 9. Computed transition state geometries for C-N activation in the [(PH₃)Pd(CN)]^-‚[Me₃NEt]⁺ion pair (1) with selected distances in Å. Energies

(kcal/mol) are given relative to 1 for the gas phase (plain text) and in THF solution (italics).

Figure 10. Computed solvent-corrected reaction profiles (kcal/mol) for C-N activation in 1.

In contrast, in the S_N2 oxidative addition process [(PH₃)-

Pd(CN)]^-can attack from the less hindered face of the ethyl

moiety and the resultant transition state, TS1_SN2, is much more

accessible (E ) +17.2 kcal/mol in the gas phase, rising to +19.8

kcal/mol in solution). TS1_SN2exhibits a classical trigonal

bipyramidal geometry at C3, with the C3-N2 bond lengthening

to 2.05 Å, while the Pd‚‚‚C3 distance is 2.61 Å. These values

suggest a relatively early transition state, and this notion is in

line with the S_N2 mechanism being clearly the most kinetically

accessible process of all of those considered from 1, as

summarized in Figure 10. Figure 10 also emphasizes the far

greater stability of the 3-coordinate palladium-alkyl species

formed via oxidative addition over the alternative palladium-

hydride formed via Hofmann elimination. The release of both

NMe₃and C₂H₄makes this latter process more favored

entropically. However, the computed free energies indicate that

oxidative addition remains more stable (∆G ) -7.1 kcal/mol

cf. ∆G ) +1.4 kcal/mol for Hofmann elimination). The

computed ∆G^qvalues are less affected and are all within 1.7

kcal/mol of the enthalpies reported in Figure 10.

3-Coordinate Models. The computed structure of the most

stable form of the ion pair [(PH₃)₂Pd(CN)]^-‚[Me₃NEt]⁺, 2, is

9

J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008 4837

A R T I C L E S

Scheme 4

Erhardt et al.

displayed in Figure 11 and shows the position of the [Me₃NEt]⁺

cation relative to the CN^-ligand to be very similar to that

described above in 1. C-N activation in 2 will lead directly to

4-coordinate products in which the new hydride or alkyl ligand

may be trans to either PH₃or CN^-(T_Pand T_CN, respectively,

Scheme 4). There are therefore, in principle, a total of eight

possible reaction pathways stemming from ion pair 2.

For the T_Ppathways, all four possible C-N activation

reactions have been fully characterized, and the trends that

emerge are very similar to those found previously with the

2-coordinate model. Thus, the most accessible process involves

the S_N2 attack of palladium at C3 and this proceeds via TS2_SN2

(T_P) with a gas-phase activation energy of +17.8 kcal/mol or

+23.6 kcal/mol in solution (Figure 12). The structure of TS2_SN2

(T_P) shows that the {P₂Pd(CN)} core distorts to a T-shaped

geometry to accept the ethyl group trans to P2. This additional

PH₃stays bound during the C-N activation process (Pd-P2

the T_Ptransition states (p ) 6-7 D). The PCM stabilization is

therefore greater for 2, leading to the relative destabilization of

the T_Pstructures. In contrast, for TS2_SN2(T_CN) p ) 18.2 D,

and this leads to a greater PCM stabilization than for 2 and a

relative stabilization of TS2_SN2(T_CN) upon solvent correction.

This different behavior of TS2_SN2(T_CN) can also be related to

its structure in which the CN^-ligand is much more exposed

than in any of the other transition states as a result of the loss

of the stabilizing electrostatic interactions with the [Me₃NEt]⁺

cation. This ‘desolvation’ of the CN^-ligand accounts for the

larger gas-phase activation barrier compared to that computed

for TS2_SN2(T_P). For the same reason, however, resolvation of

the exposed CN^-group through the PCM correction then

produces an enhanced stabilization for TS2_SN2(T_CN) and drops

the energy of this species below that of TS2_SN2(T_P). It is

important to stress that this result does not reflect the strategy

of correcting gas-phase optimized energies with a single-point

) 2.43 Å). Otherwise, the structure is very similar to TS1_SN2

,

PCM correction, as full optimization of both 2 and TS2_SN2(T_CN

)

although the key Pd‚‚‚C3 and C3‚‚‚N2 distances are slightly

longer in the 3-coordinate model. Relative energies (with

solvent-corrected values in italics) for the remaining transition

states follow the trend TS2_anti(T_P) (+21.7/26.1 kcal/mol) <

TS2_syn(T_P) ) (+23.3/+29.8 kcal/mol) < TS2_conc(T_P) (+32.7/

39.1 kcal/mol). Full structural details for these processes are

given in the Supporting Information.

in THF solvent produced essentially the same activation barrier

(see Experimental Section and the Supporting Information).

The three lowest-energy routes for C-N activation in 2 are

summarized in Figure 13, which shows that both S_N2 processes

entail lower barriers than the lowest Hofmann elimination

pathway via TS2_anti(T_P). Moreover, the 4-coordinate pal-

ladium-alkyl products are significantly more stable than the

analogous palladium-hydrides. As in the reactions of 1, entropy

will tend to make the Hofmann elimination products more

accessible than what is implied in Figure 13. However, the

computed relative free energies of the products show that cis-

For the T_CNprocesses, despite repeated efforts,³⁵it has only

proven possible to locate the S_N2 transition state, TS2_SN2(T_CN

)

(Figure 12). The behavior of this species is rather different from

the T_Ptransition states. For example, unlike TS2_SN2(T_P) where

an incipient square-planar geometry was seen, in TS2_SN2(T_CN

)

the ethyl group is forced to approach from above the trigonal

{P₂Pd(CN)} unit. The resultant structure exhibits a ‘D_2d’

geometry (P1-Pd-P2 ) 136.7°; C1-Pd-C3 ) 134.3°) and

also features an agostic interaction with the C2-H1 bond

(Pd‚‚‚H1 ) 2.07 Å; C2-H1 ) 1.14 Å). Moreover, TS2_SN2

(T_CN) is unique in being stabilized relative to the ion-pair

reactant upon PCM solvent correction. This result reflects the

computed dipole moments, p, of the various stationary points

involved. For 2, p ) 11.5 D, a much higher value than any of

(35) Although linear transits for the other T_CNprocesses produced promising

guess geometries, subsequent transition state optimizations failed, converg-

ing instead onto 2- or 3-coordinate product geometries or TS_SN2(T_CN).

This may reflect the intrinsic difficulty in distorting the {Pd(CN)P₂} core:

a T_CN[Pd(CN)(PH₃)₂]^-geometry (i.e. with P1/P2-Pd-C1 fixed at 90°)

lies 9.8 kcal/mol above optimized [Pd(CN)(PH₃)₂]^-, whereas the T_Pform

(P1-Pd-P2 ) P1-Pd-C1 ) 90°) is only 1.8 kcal/mol higher in energy.

In addition, for Hofmann elimination the product, trans-[Pd(CN)(PH₃)₂H],

is relatively high in energy (+14.7 kcal/mol, see Figure 13) and, although

this does not rule out this process, it does suggest that any transition state

is unlikely to be lower in energy than TS_SN2(T_CN). In addition, based on

the trends computed for the reactions of 1 and 2 (via the T_Pstructures) we

would expect the S_N2 mechanism to be the most accessible of the T_CN

pathway.

Figure 11. Computed reactant ion pair [(PH₃)₂Pd(CN)]^-‚[Me₃NEt]⁺(2)

with selected distances (Å) and angles.

9

4838 J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008

Palladium-Catalyzed Cyanation of Haloarenes

A R T I C L E S

Figure 12. Computed S_N2 transition states for C-N activation in [(PH₃)₂Pd(CN)]^-‚[Me₃NEt]⁺(2) with selected distances (Å) and angles. Energies (kcal/

mol) are given relative to 2 for the gas phase (plain text) and in THF solution (italics).

Figure 13. Computed solvent-corrected energy profiles (kcal/mol) for the lowest-energy C-N bond activation reactions of ion pair 2. The energy of

trans-[(PH₃)₂Pd(CN)H] is also included for comparison, although no direct pathway to this species could be located.

[(PH₃)₂Pd(CN)Et] is still the most accessible species (G )

-14.4 kcal/mol compared to around -7 kcal/mol for trans-

[(PH₃)₂Pd(CN)Et] and cis/trans-[(PH₃)₂Pd(CN)H]). Thus, es-

sentially the same conclusion can be drawn from both the 2-

and 3-coordinate models: C-N activation will occur via an

S_N2 process to give directly a palladium-alkyl species, whereas

the alternative Hofmann elimination/alkene insertion route is

higher in energy. Interestingly, the lowest-energy processes from

1 and 2 both have activation barriers of ca. 19 kcal/mol in THF

and so the identity of the active species cannot be distinguished

on that basis. To probe this issue further, the energy for the

formation of 2 from 1 was computed. This was found to be

slightly exothermic (∆E ) -3.7 kcal/mol, solvent corrected),

although the unfavorable loss of entropy makes the phosphine

addition endergonic (∆G ) +5.8 kcal/mol). On this basis, ion-

pair 1 containing a 2-coordinate {(PR₃)Pd(CN)^-} moiety is most

likely to be present in solution, and this would react via an S_N2-

type pathway through a transition state such as TS1_SN2. Once

intermediates such as cis- or trans-[(PH₃)₂Pd(CN)Et] have been

formed,subsequentPH₃/CN^-substitutiontogivecis-[(PH₃)Pd(CN)₂-

Et]^-and then [Pd(CN)₃Et]^2-appears to be very favorable, the

solvent-corrected energies associated with these steps being

-26.7 and -19.1 kcal/mol respectively.

∆E ) -1.9 kcal/mol, ∆G ) +12.4), and these values are

virtually unchanged when the full [Bu₃NBu]⁺[Pd(CN)(PPh₃)]^-

model is considered (∆E ) -1.7 kcal/mol, ∆G ) +12.1).

Although it should be stressed that the effects of forming ion-

pair aggregates³⁰have not been taken into account in this

analysis,³⁶these results do suggest the dominant presence of

2-coordinate {(PR₃)Pd(CN)^-}. The C-N bond activation transi-

tion states TS1_SN2and TS1_antihave also been computed for

various [(PR₃)Pd(CN)]^-/[R′NR′′₃]⁺models. The results show

that increased steric bulk on PR₃(R ) H, Ph), the reacting alkyl

chain (R′ ) Et, Bu), and the spectator alkyl chains (R′′ ) Me,

Bu) all serve to reduce the preference for TS1_SN2over TS1_anti

However, even for the full [(PPh₃)Pd(CN)]^-/[BuNBu₃]⁺model,

TS1_SN2remains over 3 kcal/mol lower in energy than TS1_anti

.

Taken together, these results suggest an intrinsic electronic

preference for S_N2-type oxidative addition over E2-type Hof-

mann elimination in the [(PPh₃)Pd(CN)]^-/[BuNBu₃]⁺system,

a preference that is counteracted to some extent by steric effects.

See the Supporting Information for full details.

(36) Equally, we cannot preclude the possibility of further PPh₃/CN^-substitution

to form bis-cyano active species. To assess this, all four reaction pathways

were computed for the ion pair [Pd(CN)₂]^2-‚[Me₃NEt]⁺and a similar trend

for the activation barriers (kcal/mol, after solvent correction) was com-

puted: TS_SN2(+14.6) < TS_syn(+17.2) < TS_anti(+19.1) < TS_conc(+33.0).

Full details are given in the Supporting Information. These barriers are

slightly lower than those computed from mono-cyano 1 and reflect the

greater nucleophilic/basic character of the dianionic reactant. However, the

key point is again that the S_N2 process is most favorable.

To ensure that these conclusions are not biased by our choice

of model system, we have performed a number of additional

test calculations with larger model species. The energies of PPh₃

addition to [Me₃NEt]⁺[Pd(CN)(PPh₃)]^-are very similar to those

described above for the PH₃model (solvent corrected values:

9

J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008 4839

A R T I C L E S

Erhardt et al.

Scheme 5

Discussion

In this section, we will first discuss the two distinct mech-

anisms governing the two unusual C-N activation reactions of

[(Ph₃P)₄Pd] with tetrabutylammonium cyanide (eqs 2 and 3).

In the presence of small quantities of water, the [(Ph₃P)₄Pd]/

[Bu₄N]⁺CN^-system reacts to give [(CN)₃PdH]^2-(eq 2), a

process that involves cyanide hydrolysis to HCN in the first

step. As will be shown, this non-organometallic C-N activation

can be catalytic in H₂O. Under anhydrous conditions, an

alternative path produces [(CN)₃PdBu]^2-(eq 3) via S_N2-type

C-N bond cleavage of [Bu₄N]⁺with mixed cyano phosphine

Pd(0) species. Having discussed the C-N activation reactions,

we will analyze other transformations leading to palladium

catalyst deactivation during the reaction of haloarenes with

cyanide (eq 1) and possible strategies on how to avoid or

minimize the catalyst deactivation problem.

ally added to the reaction of the old sample of [(Ph₃P)₄Pd] did

not seem to have a dramatic effect.⁹Furthermore, deliberate

addition of H₂O to a solution of [Bu₄N]^{+ 13}CN^-and the newly

obtained, anhydrous [(Ph₃P)₄Pd] in THF led to the formation

of [(CN)₃PdH]^2-, whereas in the absence of water [(CN)₃PdBu]^2-

was exclusively produced from the same, anhydrous Pd(0)

reagent under otherwise identical conditions.³⁹

Mechanisms of Reactions of Pd(0) with CN^-in the

Presence of Moisture. With regards to palladium catalyst

activity and stability, these reactions are of particular importance

because practical palladium-catalyzed cyanation of aryl halides

(eq 1) is seldom run under rigorously anhydrous conditions.

Unless the standard organometallic Schlenk-line or drybox tech-

niques are employed, ingress of some quantities of water into

the cyanation reaction medium is almost unavoidable. Even if

the substrate and the solvent are dry, a brief exposure of hygro-

scopic NaCN, KCN, and other ionic cyanides to air prior to

use inevitably leads to the presence of water in the reaction

medium. This, in turn, produces HCN due to facile hydrolysis

of the cyanide anion. Our experiments demonstrate that zero-

valent palladium complexes are highly reactive toward HCN.

As shown in eq 5, [(Ph₃P)₄Pd] readily and irreversibly reacts

with HCN that is generated upon hydrolysis of KCN in the

presence of excess cyanide to produce catalytically inactive tetra-

cyanopalladate. This reaction involves phosphino-hydrido inter-

mediates formed via HCN oxidative addition to Pd(0), which

react with another molecule of HCN and then with CN^-to

produce [(CN)₄Pd]^2-. However, at low concentrations of HCN

and high enough concentrations of active cyanide the phosphine

palladium hydride species can undergo facile ligand exchange

to produce [(CN)₃PdH]^2-. This is the case when [(Ph₃P)₄Pd] is

reacted with slowly added or generated HCN in the presence

of excess [Bu₄N]⁺CN^-(eq 4). As HCN emerges from

hydrolysis to be quickly and irreversibly consumed via oxidative

addition to Pd(0), hydroxide is generated in equimolar quantities.

Provided the overall amount of water in the medium is small,

the OH^-produced is weakly hydrated. Such hydroxide is highly

basic and hence can³⁷easily react with the tetrabutylammonium

cation to follow the classical Hofmann elimination path.³⁸As a

result, the amine and olefin are formed, along with a molecule

of water, which can then hydrolyze another cyanide anion and

so forth, thus acting as a catalyst for reaction 2 (Scheme 5).

The catalysis shown in Scheme 5 is likely the reason for the

occurrence of reaction 2 in the earlier experiments⁹with the

old [(Ph₃P)₄Pd] sample, which we suspect was wet (see above).³⁹

That would also explain why small quantities of H₂O intention-

It is also worth noting that the amount of water in the system

should be within certain limits to efficiently catalyze the reaction

shown in Scheme 5. Larger quantities of water would certainly

promote cyanide hydrolysis but would also inevitably result in

a more hydrated form of OH^-of diminished basicity, which is

less capable of deprotonating [Bu₄N]⁺. This explains why

smaller amounts of water are particularly efficient at catalyzing

reaction 2. In the presence of larger quantities of water, the

palladium hydride can still be formed but the Hofmann

elimination would be strongly inhibited.

Mechanisms of the Reaction of [(Ph₃P)₄Pd] with [Bu₄N]⁺

CN^-under Anhydrous Conditions (Eq 3). While resulting

in very similar outcomes, reactions 2 and 3 are governed by

totally different mechanisms. Obviously, in the absence of

water, no hydroxide is produced to react with [Bu₄N]⁺via

classical Hofmann degradation (Scheme 5). The results of our

experimental and computational studies of the formation of

[(CN)₃PdBu]^2-(eq 3) are consistent with the Beringer-Gindler

kinetic theory of reactions involving cations and anions in

equilibrium with ion pairs which undergo irreversible decom-

position.⁴⁰This kinetic model was successfully used by Bering-

er’s group in a series of studies of the reactions of diaryliodo-

nium salts with charged nucleophiles.^41-43When most of the

ions are associated in ion pairs, the reaction displays first-order

kinetics.⁴⁰For instance, Ph₂I⁺reacts with Cl^-to give PhI and

PhCl by first-order kinetics in less ionizing DMF but by second

order, and much more slowly, in strongly ionizing water.^42,44

When [(Ph₃P)_nPd] is treated with [Bu₄N]⁺CN^-, ligand

exchange occurs to produce tetrabutylammonium salts of mixed

cyano phosphine Pd(0) anions. In low-polar solvents, these

species are expected to exist in the form of tight ion pairs

(39) The 99% purity stipulated by the manufacturer of the old [(Ph₃P)₄Pd] reagent

allows for the presence of up to 1% of H₂O. A ca. 99:1 [(Ph₃P)₄Pd] to

H₂O weight ratio translates into 30-40 mol % of water that may be present

(even without any further contamination) to act as a catalyst for the hydride

formation (Scheme 5). It is worth emphasizing, once again, that the PhI

test performed on the old [(Ph₃P)₄Pd] sample had indicated that otherwise

the reagent was pure (see above and footnote 21a). This information is

provided as a cautionary note that some Pd(0) reagents, while being free

from Pd(II), extra phosphine, phosphine oxide, and so forth, might still

contain small quantities of water. Although in the vast majority of cases

such slight contamination with water would not influence significantly the

performance of the Pd(0) reagent, certain transformations can be affected

dramatically, as clearly demonstrated in this work.

(37) Landini, D.; Maia, A.; Rampoldi, A. J. Org. Chem. 1986, 51, 3187 and

5475.

(38) (a) Hofmann, A. W. Ann. Chem. Pharm. 1851, 78, 253; Ber. Dtsch. Chem.

Ges. 1881, 14, 659. (b) For an interesting review of this and closely related

contributions of August Wilhelm von Hofmann, see: Alston, T. A. Anesth.

Analg. 2003, 96, 622.

(40) Beringer, F. M.; Gindler, E. M. J. Am. Chem. Soc. 1955, 77, 3200.

(41) Beringer, F. M.; Gindler, E. M. J. Am. Chem. Soc. 1955, 77, 3203.

(42) Beringer, F. M.; Geering, E. J.; Kuntz, I.; Mausner, M. J. Phys. Chem.

1956, 60, 141.

(43) Beringer, F. M.; Mausner, M. J. Am. Chem. Soc. 1958, 80, 4535.

9

4840 J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008

Palladium-Catalyzed Cyanation of Haloarenes

A R T I C L E S

Scheme 6

associated in clusters, like conventional quaternary ammonium

salts.³⁰For instance, K_Dfor tetrabutylammonium picrate in

benzene has been estimated at only 6.5 × 10^-18(25 °C).^30bThe

first-order kinetics exhibited by the reaction of [Bu₄N]⁺CN^-

with [(Ph₃P)_nPd] is therefore in full accord with a mechanism

involving the formation and collapse of an ion pair comprised

of a cyano phosphine Pd(0) anion and [Bu₄N]⁺. The extreme

complexity of the [Bu₄N]⁺CN^-/[(Ph₃P)_nPd]/THF system stems

from the aggregate,³⁰solvation, and ligand-exchange (VT NMR)

dynamics involved, with conceivable contributions from the rich

coordination modes and uncommon bonding abilities of cya-

nide⁴⁷which might bridge two metal centers by means of both

σ- and π-bonding.⁴⁸Nonetheless, the molecular mechanistic

model below is coherent with both experimental and compu-

tational results obtained in this work.

The results of our mutually complementing experimental and

computational studies are fully consistent with C-N oxidative

addition rather than the Hofmann elimination/alkene insertion

reaction path for C-N activation, resulting in the butyl-

palladium complex (eq 3). Indeed, the exclusive formation of

the linear isomer and the lack of deuterium scrambling in the

reaction of [(CH₃CH₂CD₂CH₂)₄N]⁺CN^-supports C-N oxida-

tive addition rather than Hofmann elimination. Once formed,

[(CN)₃PdBu]^2-does not undergo â-elimination under the

reaction conditions, that is, in the presence of extra cyanide.

Accordingly, [(CN)₃PdH]^2-does not undergo migratory inser-

tion of olefins (ethylene, 1-butene) in the presence of free CN^-

even at elevated temperatures. Furthermore, the modest KIE

of ca. 1.3-1.6 observed at 20 °C for [(C₄D₉)₄N]^{+ 13}CN^-and

character, regardless of the composition of the mixed cyano

phosphine Pd(0) anion.

A Summary of Catalyst Deactivation Paths in Palladium-

Catalyzed Cyanation of Aryl Halides. Our studies reveal a

number of previously unidentified reaction pathways (Scheme

6) leading to the widely acknowledged catalyst deactivation

during haloarene cyanation.

In the presence of even small amounts of water, hydrolysis

of cyanide occurs to generate HCN, which can compete with

the ArX substrate for oxidative addition to the Pd(0) catalyst⁵⁰

and thus impair the catalysis. The beneficial effects of some

bases^1,8and HCN scavengers such as alumina⁵¹might be due

to their ability to somewhat suppress the hydrolysis of CN^-

and/or lower the concentration of HCN in the system. Depending

on the current concentrations of both water and cyanide, the

activity of the latter, the solvent, and temperature used, the

reaction may lead to [(CN)₄Pd]^2-(eq 5) or [(CN)₃PdH]^2-(eq

2 and Scheme 5). Both dianions are catalytically inactive.

However, reducing the Pd(II) back to Pd(0) would reactivate

the catalyst. This explains why running aromatic cyanation in

the presence of a reducing agent such as zinc has a tremendous

beneficial effect on such parameters as turnover number and

frequency, overall conversion, and yield.^52,53The dianionic

hydride [(CN)₃PdH]^2-could also be rendered active Pd(0) via

reductive elimination of HCN. This reductive elimination,

however, requires predissociation of one cyano ligand to form

tricoordinate [(CN)₂PdH]^-and is therefore efficiently suppressed

by excess cyanide in the system.

[(CH CH₂CD₂CH₂)₄N]^{+ 13}CN^-is not necessarily in accord with

3

C-H bond cleavage in the rate-limiting step.⁴⁹The C-H‚‚‚Pd

agostic interaction found in the computational study for TS2_SN2

(T_CN) and the slightly more “electropositive” character of

deuterium as compared to protium (among other factors⁴⁹) may

account for the observed KIE and its magnitude. As for the

intimate mechanism of the C-N oxidative addition, our

computational studies point to its S_N2 rather than 3-center

(44) Another example is the reaction of Ph₂I⁺with PhO^-to produce PhI and

PhOPh.⁴¹While being second order in 1:1 dioxane-water favoring free

ions, the reaction approached first order at higher dioxane-water ratios

promoting ion pairing. Interestingly, this work could have resulted in the

discovery of phase-transfer catalysis. In their publication, Beringer and

Gindler wrote, “Exploratory runs showed that while the reaction in water

had a convenient rate at 80°, the kinetics were complicated by the fact that

the finely dispersed second phase of insoluble reaction products effected a

considerable acceleration of the reaction. In a typical run a zeroth order

plot is linear from about 3-70% reaction. The reaction caused by the second

phase cannot be equally distributed throughout the second phase, for the

bulk of this second phase increased at least 20-fold during this portion of

the reaction. Possibly surface effects are operative, small drops being

initially formed but coalescing to larger drops having a smaller surface-

volume ratio... To maintain homogeneity, dioxane-water mixtures were used

in all subsequent runs.”⁴¹Lewis and Stout⁴⁵also noticed that the rates of

the reaction of Ph₂I⁺with aqueous hydroxide were sensitive to the second

phase of PhI, Ph₂O, and other products that were forming as the reaction

proceeded. Apparently, in both cases^41,45the emerging organic phase

triggered the phenomenon of phase-transfer catalysis, with the iodonium

cation acting as both a reacting electrophile and a phase-transfer agent.⁴⁶

(45) Lewis, E. S.; Stout, C. A. J. Am. Chem. Soc. 1954, 76, 4619.

(46) Grushin, V. V.; Tolstaya, T. P.; Lisichkina, I. N. IzV. Akad. Nauk, Ser.

Khim. 1982, 2175. Grushin, V. V.; Kantor, M. M.; Tolstaya, T. P.;

Shcherbina, T. M. IzV. Akad. Nauk, Ser. Khim. 1984, 2332. Grushin, V. V.

Acc. Chem. Res. 1992, 25, 529 and references cited therein.

The problem of catalyst deactivation due to HCN generation

from the cyanide reagent persists when the process is run in

protic solvents, such as alcohols, glycols, etc. Any proton source

in the catalytic system is a potential danger to the palladium

catalyst due to the facile formation of HCN via protonation of

(49) Melander, L.; Saunders, H. W., Jr. Reaction Rates of Isotopic Molecules;

Wiley: New York, 1980.

(50) Although no quantitative data have been obtained, HCN appears to

oxidatively add to [(Ph₃P)₄Pd] much more easily than most reactive

haloarenes, such as PhI. The difference in reactivity can be qualitatively

estimated from the fact that [(Ph₃P)₄Pd] reacts with PhI within minutes at

room temperature, whereas the reaction of [(Ph₃P)₄Pd] with HCN occurs

within the time of mixing at ca. 0 °C.

(47) Beck, M. T. J. Indian Chem. Soc. 1977, 54, 19.

(48) Our VT NMR studies of the [Bu₄N]⁺CN^-/[(Ph₃P)₄Pd]/THF system suggest

that under certain conditions only ca. 1 equiv of coordinated PPh₃and 1

equiv of coordinated CN^-are present per 1 equiv of palladium (Table 4,

entry 4). Although it is hardly conceivable that the species observed is

[(Ph₃P)Pd(CN)]^-, the latter might be present in small concentrations due

to equilibrium with oligomeric {[(Ph₃P)Pd(CN)]^-}_n, in which the cyano

ligands bridge the palladium centers.

(51) Dalton, J. R.; Regen, S. L. J. Org. Chem. 1979, 44, 4443.

(52) See, for example: Okano, T.; Iwahara, M.; Kiji, J. Synlett 1998, 243. Okano,

T.; Kiji, J.; Toyooka, Y. Chem. Lett. 1998, 5, 425.

9

J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008 4841

A R T I C L E S

Erhardt et al.

basic cyanide. The most economical and widely used sources

of cyanide for reaction 1 are KCN and NaCN. These ionic salts

are hygroscopic, highly soluble in water, easily hydrolyzable,

and hence most potentially poisonous to the palladium catalyst.

Zinc cyanide⁶and K₄[Fe(CN)₆],⁷both of which have been

extensively used¹for reaction 1, are considerably less capable

of producing free CN^-and consequently deactivating the catalyst.

In practical synthesis, aromatic cyanation with KCN or NaCN

is seldom run in an aprotic solvent under rigorously anhydrous

conditions. The solubility of KCN and NaCN in such systems

is often insufficient for the catalytic reaction to occur at a desired

rate. As cyanide is lipophilic, phase-transfer catalysis might be

a particularly good technique to solve this problem.¹However,

most commonly used phase-transfer catalysts are quaternary

alkylammonium salts which, as we show in this work, can easily

react with zerovalent palladium complexes in the presence of

cyanide even under rigorously anhydrous conditions (eq 3). This

leadstocatalystdeactivationduetotheformationof[(CN)₃PdAlk]^2-.

In fact, Anderson and co-workers⁵⁴have reported that the

otherwise efficient ArX cyanation system Pd(0)/CuI/NaCN/THF

lost its activity upon replacement of the NaCN with [Bu₄N]⁺

CN^-. Therefore, crown ethers should be preferred phase-transfer

catalysts for this process. It is noteworthy, however, that crown

ethers are often hygroscopic and therefore may be another source

of water (and hence HCN) that would ultimately deactivate the

palladium catalyst due to the reactions described above. Some

nonhygroscopic metal compounds capable of forming ate

cyanide complexes such as Cu(I)^54-56and Sn(IV)⁵⁷for CN

transfer to palladium have been shown to efficiently promote

palladium-catalyzed aromatic cyanation with alkali metal cya-

nides in aprotic solvents of low polarity.

[(CN)₃PdPh]^2-(Scheme 2).⁹The high selectivities of these

reactions, taking into consideration the detection limits (NMR),

suggest that the rate constants for I^-/CN^-exchange, Ph₃P/CN^-

exchange, and Ph-CN reductive elimination decrease in the

order k_I/CN> k_P/CNg k_RE× 10².⁹Therefore, if an aromatic

cyanation reaction requires a phase-transfer agent, its concentra-

tion should be comparable to that of the palladium catalyst used,

in order to avoid high [CN^-] to [Pd] ratios.

Conclusions

Mechanisms of palladium catalyst deactivation during cya-

nation of haloarenes (eq 1) have been for the first time identified

and studied in detail. The key results of our investigations are

presented in Scheme 6 showing that the process can be

terminated at every step of the catalytic loop.

The presence of moisture in the reaction medium is one of

the greatest dangers for the catalysis employing readily ionizable

sources of cyanide that easily generate HCN upon hydrolysis.

It has been demonstrated that phosphine-stabilized Pd(0) is

highly reactive toward HCN, undergoing transformations to

catalytically inactive [(CN)₄Pd]^2-and/or [(CN)₃PdH]^2-. There

are some ways to avoid this. Running the process under

rigorously anhydrous conditions in an aprotic solvent would

eliminate the problem but may be unrealistic in practice. Even

if moisture is thoroughly avoided, the low solubility^3dof alkali

metal cyanides in most nontoxic aprotic solvents suitable for

the catalysis, such as THF and MeCN, might require use of a

phase-transfer agent. However, care is required in the choice

of the phase-transfer catalyst as we have shown here that

quaternary ammonium cations such as [Bu₄N]⁺undergo N-Alk

bond cleavage with [(Ph₃P)_nPd] in the presence of cyanide to

give catalytically inactive [(CN)₃PdAlk]^2-. This uncommon

C-N bond activation is remarkably facile, readily occurring

even at room temperature and being particularly fast at low

concentrations of the Pd(0). Both experimental and theoretical

studies of this reaction have pointed to the involvement of mixed

cyano phosphine Pd(0) anions undergoing C-N oxidative

addition of the S_N2 type.

Even if all of the above-described problems dealing with

catalyst deactivation prior to the Ar-X oxidative addition step

are avoided by using rigorously anhydrous conditions and no

quaternary ammonium salts, the process may still be terminated

at steps 2 and 3 of the loop (Scheme 6).⁹The σ-aryl palladium

intermediate from step 1 takes the desired path to ArCN only

if no large excess CN^-is present; otherwise, R₃P/CN^-ligand

exchange competes with the Ar-CN reductive elimination to

give catalytically inactive [(CN)₃PdAr]^2-. Indeed, [(Ph₃P)₂Pd-

(I)Ph] reacted with an equimolar amount of CN^-to give PhCN

and Pd(0), whereas fast addition of 4-6 equiv of cyanide to

the same phenyl iodo complex gave rise exclusively to stable

The X/CN exchange (step 2) and reductive elimination (step

3) of the loop (Scheme 6) can be easily disrupted by excess

cyanide due to facile phosphine displacement with CN^-, leading

to [(CN)₃PdAr]^2-. Being reluctant to undergo Ar-CN reductive

elimination in the presence of extra CN^-, this dianionic

palladium aryl is another dead end for the catalytic process,

unless catalyst reactivation is somehow achieved, for example

via reduction to Pd(0). In light of our studies, the well-known

beneficial effect of a reducing agent such as zinc on palladium-

catalyzed aromatic cyanation is readily accounted for by catalyst

reactivation via reduction to active Pd(0) of the products of the

(53) (a) The highly beneficial effect of a reducing agent on aromatic cyanation

is often believed to be due to catalyst recuperation from poisoning by

oxygen that is damaging to Pd(0).^53b,cIndeed, the O₂-induced catalyst

deactivation is likely the main reason to use a reductant for aromatic

cyanation with Zn(CN)₂,^53b-da poorly soluble salt that is resistant to

hydrolysis. However, when easily hydrolyzable KCN or NaCN is used in

the presence of water, the catalyst is most efficiently poisoned by the

resultant HCN which is apparently much more reactive toward Pd(0) than

O₂. Our own experience with catalytic aromatic cyanation with alkali metal

cyanides indicates that water can be detrimental to the catalysis even under

rigorously O₂-free conditions. (b) Chidambaram, R. Tetrahedron Lett. 2004,

45, 1441. (c) Martin, M. T.; Liu, B.; Cooley, B. E.; Eaddy, J. F. Tetrahedron

Lett. 2007, 48, 2555. (d) For selected reports, see: Jin, F.; Confalone, P.

N. Tetrahedron Lett. 2000, 41, 3271. Ramnauth, J.; Bhardwaj, N.; Renton,

P.; Rakhit, S.; Maddaford, S. P. Synlett 2003, 14, 2237. Erker, T.; Nemec,

S. Synthesis 2004, 23. Hatsuda, M.; Seki, M. Tetrahedron 2005, 61, 9908.

Littke, A.; Soumeillant, M.; Kaltenbach, R. F., III; Cherney, R. J.; Tarby,

C. M.; Kiau, S. Org. Lett. 2007, 9, 1711.

catalyst poisoning [Pd(CN)₄]^2-, [(CN)₃PdH]^2-, [(CN)₃PdAr]^2-

and [(CN)₃PdAlk]^2-(Alk = Bu in this work).

,

Finally, some conclusions drawn from our work may apply

to nickel-catalyzed cyanation of aryl halides, albeit the nickel

catalysis has its own characteristic features and problems.⁵⁸

Experimental Section

(54) Anderson, B. A.; Bell, E. C.; Ginah, F. O.; Harn, N. K.; Pagh, L. M.;

Wepsiec, J. P. J. Org. Chem. 1998, 63, 8224.

(55) Allentoff, A. J.; Markus, B.; Duelfer, T.; Wu, A.; Jones, L.; Ciszewska,

G.; Ray, T. J. Labelled Compd. Radiopharm. 2000, 43, 1075.

Caution: Cyanides and HCN are highly toxic! All chemicals were

purchased from Aldrich, Fluka, and Strem chemical companies, except

K¹³CN (99% ¹³C), n-C₄D₉I (98% D), and CH₃CH₂CD₂CH₂Br (99.3%

D) that were obtained from Icon Isotopes, Cambridge Isotopes, and

CDN Isotopes, respectively. The solvents were dried using standard

(56) For the use of CuCN as a source of cyanide in palladium-catalyzed aromatic

cyanation, see: Sakamoto, T.; Ohsawa, K. J. Chem. Soc., Perkin Trans. 1

1999, 2323.

(57) Yang, C.; Williams, J. M. Org. Lett. 2004, 6, 2837.

9

4842 J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008

Palladium-Catalyzed Cyanation of Haloarenes

A R T I C L E S

techniques and stored over freshly calcined molecular sieves (4 Å) in

a glovebox. All manipulations were carried out under nitrogen in a

glovebox, except as noted otherwise. NMR spectra were obtained with

a Bruker Avance DRX400 and Varian Unity Inova systems operating

at 400 and 500 MHz, respectively. A Bruker-CCD instrument was used

for single-crystal X-ray diffraction studies. Microanalyses were per-

formed by Micro-Analysis, Inc., Wilmington, Delaware.

immediately sealed with a Teflon-threaded stopper. The contents were

vigorously stirred at 85 °C (oil bath) for 24 h, after which the tube

was allowed to cool to room temperature and unsealed. The reaction

mixture was treated with water (10 mL) and extracted with CH₂Cl₂(5

× 5 mL). The combined extracts were filtered through cotton wool,

and the clear, colorless filtrate was evaporated and treated with ether.

The white crystals were separated, washed with ether, and dried under

vacuum. The yield of [(CH₃CH₂CD₂CH₂)₄N]⁺Br^-was 0.51 g (97%

calculated on NH₃). ¹H NMR (CD₂Cl₂, 25 °C), δ: 1.0 (t, 3H, J ) 7.4

Hz, CH₃), 1.45 (q, 2H, J ) 7.4 Hz, CH₂), 3.3 (s, 2H, CH₂-N).

Synthesis of [(CH₃CH₂CD₂CH₂)₄N]^{+ 13}CN^-. A solution of NaOH

(0.15 g; ca. 3.7 mmol) in water (3 mL) was added to a solution of

AgNO₃(0.31 g; 1.8 mmol) in water (3 mL). The precipitated Ag₂O

was thoroughly washed with water and then with D₂O (5 × 1 mL). To

the still wet Ag₂O was added [(CH₃CH₂CD₂CH₂)₄N]⁺Br^-(0.24 g; 0.7

mmol), D₂O (2 mL), and the mixture was thoroughly triturated in a

mortar with a pestle for 30 min. After the mixture was filtered through

a nylon membrane, the clear filtrate was treated with K¹³CN (0.11 g;

1.7 mmol), evaporated at room temperature under N₂, and treated with

THF (20 mL). Granulated anhydrous CaSO₄was added at stirring to

absorb the water, after which the product was isolated and purified as

described above for [Bu₄N]⁺¹³CN^-. The yield of [(CH₃CH₂CD₂-

CH₂)₄N]^{+ 13}CN^-was 0.18 g (89%). ¹H NMR (THF-d₈, 25 °C), δ: 1.0

(t, 3H, J ) 7.4 Hz, CH₃), 1.4 (q, 2H, J ) 7.4 Hz, CH₂), 3.5 (s, 2H,

CH₂-N). ¹³C NMR (THF-d₈, 25 °C), δ: 165.0 (s).

Preparation of [Bu₄N]^{+ 13}CN^-. A mixture of [Bu₄N]⁺OH^-‚30H₂O

(4.00 g; 5 mmol), K¹³CN (0.40 g; 6.1 mmol), and THF (12 mL) was

stirred under N₂for 10 min. Anhydrous CaSO₄in granules was added

while stirring to fully absorb the small amount of the bottom aqueous

phase. The THF phase was separated. The solids were thoroughly

washed with THF (3 × 10 mL). All THF solutions were combined

and dried with fresh anhydrous CaSO₄under N₂for 3 h and then filtered

and evaporated under N₂. The residual oily material solidified on stirring

with dry ether. After the ether was decanted off, the solid was dried

under vacuum (0.01 Torr) at 30 °C for 12 h and brought to a glovebox

without exposure to air. The material was dissolved in dry THF (15

mL), and the solution was vigorously stirred with powdered K¹³CN

(0.10 g) for 24 h. The solution was filtered, evaporated to a viscous

oil, and treated with ether. The solid was recrystallized three times

from anhydrous THF-ether, dried under vacuum (0.01 Torr) at

30 °C for 60 h, and stored in the glovebox. The yield was 1.25 g (92%).

¹³C NMR (THF-d₈, 25 °C), δ: 165.0 (s).

Synthesis of [(n-C₄D₉)₄N]⁺I^-. A 30 mL thick-walled glass tube

was charged with a magnetic stir bar, n-C₄D₉I (5.00 g; 25.9 mmol),

LiOH‚H₂O (0.75 g; 17.9 mmol), and MeCN (5 mL). Aqueous NH₃

(28%; 0.36 mL) was added, and the tube was immediately sealed with

a Teflon-threaded stopper. The contents were vigorously stirred at 85

°C (oil bath) for 2 h, after which the tube was allowed to cool to room

temperature and unsealed. The reaction mixture was treated with water

(50 mL) and extracted with CH₂Cl₂(5 × 20 mL). The combined extracts

were filtered through cotton wool, and the clear, colorless filtrate was

evaporated and treated with ether. The white crystals were separated,

washed with ether, and dried under vacuum. The yield of [(n-C₄D₉)₄N]⁺

I^-was 2.00 g (92% calculated on NH₃, 76% calculated on n-C₄D₉I).

Synthesis of [(n-C₄D₉)₄N]⁺¹³CN^-. A solution of NaOH (0.25 g;

ca. 6.2 mmol) in water (5 mL) was added to a solution of AgNO₃(0.51

g; 3 mmol) in water (5 mL). The precipitated Ag₂O was thoroughly

washed with water and then with D₂O (5 × 2 mL). To the still wet

Ag₂O was added [(n-C₄D₉)₄N]⁺I^-(1.00 g; 2.5 mmol), D₂O (10 mL),

and the mixture was thoroughly triturated in a mortar with a pestle for

20-30 min. After the mixture was filtered through a nylon membrane,

the clear filtrate was treated with K¹³CN (0.51 g; 7.7 mmol), evaporated

at room temperature under N₂to a few milliliters, and treated with

THF (100 mL). Granulated anhydrous CaSO₄was added at stirring to

absorb the water, after which the product was isolated and purified as

described above for [Bu₄N]^{+ 13}CN^-. The yield of [(n-C₄D₉)₄N]^{+ 13}CN^-

was 0.65 g (86%). ¹³C NMR (THF-d₈, 25 °C, δ): 165.0 (s).

Preparation of H¹³CN. A 25 mL round-bottom flask was charged

with a magnetic stir bar and 85% H₃PO₄(5 mL). Finely ground

K¹³CN (1.5 g; 22.7 mmol) was added at -78 °C, and the flask was

immediately connected to a vacuum-transfer system, which was

evacuated at ca. 0.03 mm Hg. After the Schlenk-type receiver was

immersed in an acetone-dry ice bath, the H₃PO₄-K¹³CN mixture was

allowed to warm to room temperature with the stirrer on. After 3 h of

stirring at room temperature, the cold receiver was disconnected under

N₂, evacuated, closed, and while still cold quickly brought to the

glovebox, where it was allowed to warm to room temperature. Analysis

of the colorless liquid (1.1 g) by ¹H and ¹³C NMR indicated that it was

1

a solution of H¹³CN in H₂O (ca. 1:2 molar ratio). H NMR (THF-d₈,

25 °C), δ: 3.2 (s, ca. 4H, H₂O), 5.4 (d, 1H, J ) 260.6 Hz, H¹³CN).

¹³C NMR (¹H-decoupler off, THF-d₈, 25 °C), δ: 112.0 (d, J_C-H) 260.6

Hz).²³This H¹³CN solution was stored in a tightly capped GC-MS vial

placed inside a closed 20 mL scintillation vial at -25 °C inside the

glovebox.

Synthesis of ([Et₄N]⁺)₂[(¹³CN)₃Pd(H)]^2-

. To a cold (ca.

0 °C) solution of [Bu₄N]⁺¹³CN^-(145 mg; 0.5 mmol) was added

[(Ph₃P)₄Pd] (220 mg; 0.2 mmol), and then, at vigorous stirring, a cold

solution of the aqueous H¹³CN (see above; 20 µL) in THF (6 mL) was

slowly added dropwise over the period of 15-20 min. After full

discoloration, the addition of the H¹³CN solution was stopped at once.

The resulting emulsion of ([Bu₄N]⁺)₂[(¹³CN)₃Pd(H)]^2-in THF was

homogenized by addition of 5-6 drops of MeCN. To this homogeneous

Synthesis of [(CH₃CH₂CD₂CH₂)₄N]⁺Br^-.⁵⁹A 15 mL thick-walled

glass tube was charged with a magnetic stir bar, CH₃CH₂CD₂CH₂Br

(1.00 g; 7.2 mmol), LiOH‚H₂O (0.28 g; 6.7 mmol), and MeCN (1.2

mL). Aqueous NH₃(28%; 0.1 mL) was added, and the tube was

mixture, a solution of [Et₄N]⁺BF₄(78 mg) in MeCN (1.5 mL) was

-

added at agitation. After stirring for 10 min, THF (5 mL) was added,

and the cloudy mixture was kept at -20 °C overnight. The white

precipitate was separated, washed with THF, and recrystallized twice

from MeCN-THF. The yield of ([Et₄N]⁺)₂[(¹³CN)₃Pd(H)]^2-was 73

(58) (a) For instance, HCN formation upon cyanide hydrolysis or solvolysis

readily explains limited reproducibility^4dof nickel-catalyzed aromatic

cyanation in ethanol.^4a,b(b) Oxidative addition of Ar-X to Ni(0) is often

complicated by radical reactions^58cand homocoupling,^58despecially for X

) I and Br. Also, Ni(0) is known^58eto undergo Ar-CN oxidative addition,

which makes the final step of the catalytic loop reversible. These features

provide additional problems to nickel-catalyzed cyanation. (c) See, for

example: Foa, M.; Cassar, L. J. Chem. Soc., Dalton Trans. 1975, 2572.

Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101, 6319 and 7547. (d)

See, for example: Semmelhack, M. F.; Helquist, P. M.; Jones, L. D. J.

Am. Chem. Soc. 1971, 93, 5908. Amatore, C.; Jutand, A. Organometallics

1988, 7, 2203. (e) See, for example: Garcia, J. J.; Brunkan, N. M.; Jones,

W. D. J. Am. Chem. Soc. 2002, 124, 9547 and references cited therein.

(59) For alternative ways of making this and other site selectively deuterated

tetrabutylammonium cations, see: Heinsen, M. J.; Pochapsky, T. C. J.

Labelled Compd. Radiopharm. 2000, 43, 473.

mg (90% calculated on [Et₄N]⁺BF₄^-). H NMR (MeCN-d₃, 25 °C),

1

δ: -10.8 (dt, 1H, trans-J_C-H) 64.9 Hz, cis-J_C-H) 2.6 Hz, Pd-H),

1.3 (tt, 24H, J_H-H) 7.3 Hz, J_N-H) 1.9 Hz, CH₃), 3.3 (q, 16H, J_H-H

) 7.3 Hz, CH₂). ¹³C NMR (MeCN-d₃, 25 °C), δ: 7.9 (s, CH₃), 53.3 (t,

J_N-C) 3.2 Hz, CH₂), 137.7 (d, 2C, J_C-C) 5.8 Hz, mutually trans-

CN), 146.6 (t, 1C, J_C-C) 5.8 Hz, CN trans to H). See also Figure 2.

Anal. Calcd for C₁₆¹³C₃H₄₁N₅Pd: C, 51.5; H, 9.2; N, 15.6. Found: C,

51.4; H, 9.1; N, 14.4.

Preparation and Characterization of ([Bu₄N]⁺)₂[(CN)₃Pd-

(Bu)]^2-. (a) A solution of [(Ph₃P)₄Pd] (24 mg; 0.02 mmol) and [Bu₄N]⁺

CN^-(17 mg; 0.06 mmol) in benzene (1 mL) was kept at room

9

J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008 4843

A R T I C L E S

Erhardt et al.

temperature for 6 days. The slightly yellow benzene solution was

separated from the colorless oil, which was then washed with benzene,

quickly dried, redissolved in THF-d₈, and analyzed by ¹H NMR (Figure

4). This experiment was repeated using [(Ph₃P)₄Pd] (124 mg; 0.11

mmol) and [Bu₄N]⁺CN^-(117 mg; 0.44 mmol) in benzene (6 mL) to

obtain the product in quantities sufficient for microanalysis. After

washing with benzene and drying under vacuum (0.01 Torr at 30 °C

for 24 h), the resultant complex in the form of a viscous, colorless oil

(66 mg) retained ca. 0.5 equiv of benzene, as judged by the analytical

data. Anal. Calcd for C₃₉H₈₁N₅Pd‚0.5C₆H₆: C, 65.9; H, 11.1; N, 9.2.

Found: C, 65.9; H, 11.2; N, 9.4. (b) The experiment was repeated using

[Bu₄N]⁺¹³CN^-to obtain the ¹³C NMR spectrum shown in Figure 5.

(c) After the reaction of [(Ph₃P)₄Pd] with [(CH₃CH₂CD₂CH₂)₄N]⁺

CN^-used in the kinetic study (Table 3) had gone to completion, NMR

characterization of the reaction products was carried out using a

combination of TOCSY and HMBC. The reaction components identi-

fied in this way are assigned as [(¹³CN)₃PdCH₂CD₂CH₂CH₃]^2-C(1)

8.75/1.11 (δ ¹³C/δ ¹H), C(2) 36.77 (δ ¹³C only), C(3) 29.02/1.31, C(4)

14.74/0.86, CN (trans) 147.59, CN (cis) 143.86; [(CH₃CH₂CD₂CH₂)₄N]⁺

C(1) 59.40/3.53, C(2) 24.32 (δ ¹³C only), C(3) 20.40/1.50, C(4) 14.12/

1.03; and (CH₃CH₂CD₂CH₂)₃N C(1) 54.64/2.35, C(2) 29.87 (δ ¹³C

only), C(3) 21.12/1.32, C(4) 14.24/0.91.

vigorous stirring in portions of 30, 20, and 20 µL within 5 min. The

yellow color faded, and full discoloration was observed after ca. 10

min of agitation, pointing to the disappearance of Pd(0). The colorless

THF solution was separated from the viscous droplets of the aqueous/

inorganic phase and analyzed by ³¹P NMR to indicate the presence of

only free PPh₃(s, -5 ppm). Analysis of the inorganic phase in D₂O

(0.7 mL) by ¹³C NMR revealed the presence of only two CN-containing

species, free ¹³CN (s, 165.6 ppm) and [Pd(¹³CN)₄]^2-(s, 131.4 ppm).

Reaction of [(Ph₃P)₄Pd] with H¹³CN. The aqueous H¹³CN (see

above; 2.5 µL) was added to a solution of [(Ph₃P)₄Pd] (16 mg; 0.014

mmol) in THF-d₈(0.8 mL) placed in a 5 mm NMR tube. NMR spectra

of the solution were recorded 10 min after sample preparation. In the

¹H NMR spectrum, a hydrido resonance was observed (-8.7 ppm, d,

J_H-C) 56.2 Hz), along with the doublet resonance from H¹³CN (5.2

ppm, d, J_H-C) 261.0 Hz),²³and a weak resonance from the already

formed H₂(4.5 ppm, s). In the ¹³C NMR spectrum, the cyano hydride

resonated at 141.5 ppm as a singlet and a doublet (J_H-C) 56.2 Hz)

with the proton decopuler on and off, respectively. In addition to this

signal and four resonances from PPh₃, the ¹³C NMR spectrum also

displayed an intense doublet from H¹³CN (111.5 ppm, J_H-C) 261.0

Hz).²³The ³¹P NMR spectrum displayed only one broad singlet (14.5

ppm, ∆ν_1/2) 150 Hz). The hydride is formulated as trans-[(Ph₃P)₂-

Pd(H)(CN)] in fast exchange with free PPh₃(resulting in loss of H-P

coupling, see above), which is known to be the case with analogous

hydrido cyano nickel complexes stabilized by tertiary phosphines and

phosphites.²⁴As the reaction occurred, H₂was produced and well-

shaped colorless crystals of X-ray quality formed after several hours,

which were identified as trans-[(Ph₃P)₂Pd(CN)₂] by NMR and X-ray

analysis. NMR data for the precipitated crystals of trans-[(Ph₃P)₂Pd-

(¹³CN)₂] (CD₂Cl₂, 25 °C), δ: ¹H: 7.5 (m, 12H, m-Ph), 7.55 (m, 6H,

p-Ph), 7.75 (m, 12H, o-Ph); ¹³C: 130.8 (t, J_C-P) 15.5 Hz); ³¹P: 24.8

(t, J_C-P) 15.5 Hz).

Kinetic Measurements and VT NMR Studies. One-dimensional

¹³C NMR and kinetic data were acquired on a Varian Unity Inova

system operating at 500 MHz. Chemical shift referencing was obtained

by setting the downfield THF solvent peak to 67.4 ppm. For conven-

ience, the kinetic data were obtained by placing the transmitter at 150

ppm (between the [Bu₄N]^{+ 13}CN^-starting material and [(¹³CN)₃Pd(Bu)]^2-

product) and restricting the spectral width to 8 kHz. An acquisition

time of 2 s was used in conjunction with a recycle delay of 6 s and a

90° pulse width. Typical signal averaging involved 64 transients for a

total acquisition time of approximately 8 min for each kinetic time

point. The activation enthalpy (∆H^q) and entropy (∆S^q) were determined

by direct nonlinear least-squares fitting of these parameters to the Eyring

equation (k₁) (k_BT/h) exp(∆S^q/R) exp(-∆H^q/RT)) using the temper-

ature and rate constant data in Table 2. This fitting procedure gave the

parameter estimates (25 °C) ∆G^q) 22.7 ( 0.1 kcal mol^-1, ∆H^q)

26.3 ( 0.7 kcal mol^-1, ∆S^q) 12 ( 2 cal mol^-1deg^-1, and E_a) 26.9

( 0.7 kcal mol^-1. The stated uncertainties represent 95% confidence

limits and were obtained using an estimated error in temperature of 2

°C and an estimated error in the rate constants as obtained from

exponential fitting of the raw kinetic data. Conditions for low-

temperature ³¹P and ¹³C NMR studies (Table 4) were established from

T1 relaxation measured at -70 °C by inversion recovery experimenta-

tion. In each case, to ensure accurate integration, the total recycle time

was set to 7.5 s, >5 times the longest measured T1 of 1.3 s, with

inverse-gated decoupling to suppress NOE and a 45° pulse width.

Reaction of [(Ph₃P)₄Pd] with [Bu₄N]⁺¹³CN^-in THF under

Vacuum. (a) Immediately after a mixture of [(Ph₃P)₄Pd] (35 mg; 0.03

mmol) and [Bu₄N]^{+ 13}CN^-(32 mg; 0.12 mmol) was dissolved in THF

(2 mL), the resulting solution was separated into two halves of 1 mL

each. One of the portions was placed in a 20 mL vial and kept

undisturbed inside the drybox. The other half was placed in a freshly

flame-dried 6 mL glass tube equipped with a Teflon-coated magnetic

stirbar, stoppered with a high-vacuum glass stopcock, and brought out

of the drybox. The tube was immediately evacuated at -196 °C and

after two freeze-pump-thaw cycles flame-sealed under vacuum

(<0.001 Torr at -196 °C). The mixture was warmed up to room

temperature and vigorously stirred. Full discoloration was observed after

ca. 1.5 days. Both mixtures remained homogeneous throughout the

1

reaction. Analysis of the mixtures by H and ¹³C NMR in MeCN-d₃

after evaporation of the THF solvent indicated that both reactions pro-

duced [(¹³CN)₃PdBu]^2-and no observable quantities of [(¹³CN)₃PdH]^2-

.

(b) After a mixture of [(Ph₃P)₄Pd] (38 mg; 0.03 mmol) and [Bu₄N]⁺

¹³CN^-(35 mg; 0.13 mmol) was dissolved in THF (2 mL), the resulting

solution was separated into two halves of 1 mL each. One of the

portions was placed in a 20 mL vial and kept undisturbed inside the

drybox. The other half was placed in a 50 mL round-bottom flask (that

had not been flame-dried), equipped with a Teflon stopcock, brought

out of the glovebox, cooled to -196 °C, and evacuated at 0.015 Torr.

The still cold flask was stopcock-sealed under vacuum, after which it

was warmed up to room temperature, brought back to the glovebox,

and vigorously stirred. Full discoloration was observed after 1 day for

the agitated reaction mixture under vacuum and after 2 days for the

reaction at normal pressure. At full conversion, the mixture produced

by the reaction under vacuum was a biphasic liquid-liquid system,

whereas a homogeneous mixture resulted from the reaction under

normal pressure. Analysis of the reaction mixtures by ¹³C NMR in

MeCN-d₃after evaporation indicated that the undisturbed reaction at

normal pressure produced [(¹³CN)₃Pd(Bu)]^2-as the main product and

<1% of [(¹³CN)₃Pd(H)]^2-, whereas the reaction under vacuum led to

both [(¹³CN)₃Pd(Bu)]^2-and [(¹³CN)₃Pd(H)]^2-in a ca. 1:1 ratio.^20b

Reaction of [(Ph₃P)₄Pd] with KCN in the Presence of Water. A

solution of [(Ph₃P)₄Pd] (29 mg; 0.025 mmol) in THF (1.5 mL) was

prepared. The ³¹P NMR spectrum of this solution was recorded to

exhibit a broadened singlet at (14.6 ppm, ∆ν_1/2) ca. 70 Hz), in full

accord with the literature data. To this solution was added K¹³CN (32

mg; 0.48 mmol) as a fine powder, and the mixture was stirred under

N₂for 2 h. This resulted in neither color change nor any observable

reaction, as judged by ³¹P NMR of the yellow THF solution over the

white solid of the K¹³CN. N₂-saturated D₂O was added via syringe at

Crystallographic Studies. A summary of the crystallographic

data for ([Et₄N]⁺)₂[(CN)₃Pd(H)]^2-, [K‚18-crown-6]⁺[(Ph₃P)Pd-

(CN)(O₂)]^-, [Et₄N]⁺CN^-, and trans-[(Ph₃P)₂Pd(CN)₂] is given in Table

5. The CIF files are presented in the Supporting Information section.

Computational Details. All DFT calculations were run with

Gaussian 03⁶⁰and employed the BP86 functional. Lanl2dz pseudopo-

(60) Frisch, M. J.; et al. Gaussian 03, revision C.02; Gaussian, Inc.: Wallingford,

CT, 2004.

9

4844 J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008

Palladium-Catalyzed Cyanation of Haloarenes

A R T I C L E S

Table 5. Summary of Crystallographic Data for ([Et₄N]⁺)₂[(CN)₃Pd(H)]^2-, [K‚18-crown-6]⁺[(Ph₃P)Pd(CN)(O₂)]^-, [Et₄N]⁺CN^-, and

trans-[(Ph₃P)₂Pd(CN)₂]

([Et₄N]⁺)₂

[(CN)₃Pd(H)]²

[K·18-crown-6]⁺

[(Ph₃P)Pd(CN)(O₂)]^-

-

[Et₄N]⁺CN^-

[(Ph₃P)₂Pd(CN)₂]

empirical formula

FW

C₁₉H₄₁N₅Pd

445.97

C₃₅H₄₇KNO₉PPd

802.21

C₂₇H₆₀N₆

468.81

C₃₈H₃₀N₂P₂Pd

682.98

cryst color

form

cryst system

space group

a (Å)

b (Å)

c (Å)

R (deg)

â (deg)

colorless

square prism

monoclinic

P2(1)/c

19.696(4)

8.3139(16)

14.012(3)

90

96.275(2)

90

2280.7(8)

4

colorless

needle

colorless

irregular block

monoclinic

P2(1)/n

12.025(3)

20.710(4)

14.224(3)

90

123.980(14)

90

2937.4(11)

4

colorless

irregular block

triclinic

monoclinic

P2(1)/c

11.550(3)

8.4259(19)

38.732(8)

90

96.543(4)

90

3744.8(15)

4

P1h

9.1134(8)

9.7354(8)

10.2226(9)

110.8770(10)

93.0840(10)

108.0970(10)

791.57(12)

1

γ (deg)

V (Å³)

Z

density (g/cm³)

1.299

0.825

1.423

0.701

1.06

0.063

1.433

0.717

abs µ (mm^-1

)

F(000)

944

1664

1056

348

cryst size (mm³)

T (°C)

0.50 × 0.18 × 0.18

0.38 × 0.08 × 0.02

0.32 × 0.32 × 0.27

0.24 × 0.24 × 0.20

-100

scan mode

detector

ω

Bruker-CCD

28.32

Bruker-CCD

27.18

Bruker-CCD

26.37

Bruker-CCD

28.33

θ

_max(deg)

no. observed refs

no. unique refs

R_merge

29 852

5672

0.038

35 613

8311

0.092

35 142

5992

0.064

12 835

3903

0.031

no. params

238

421

317

198

R indices[I > 2σ(I)]^a

wR2 ) 0.055,

R1 ) 0.024

wR2 ) 0.059,

R1 ) 0.030

1.06

wR2 ) 0.111,

R1 ) 0.054

wR2 ) 0.131,

R1 ) 0.106

1.06

wR2 ) 0.168,

R1 ) 0.062

wR2 ) 0.195,

R1 ) 0.094

1.05

wR2 ) 0.062,

R1 ) 0.025

wR2 ) 0.063,

R1 ) 0.027

1.07

R indices (all data)^a

S ^b

max diff peak,

hole (e/Å³)

0.31, -0.43

0.72, -0.71

0.68, -0.28

0.96, -0.43

^aR1 ) ∑||F_o| - |F_c||/∑|F_o|, wR2 ) {∑[w(F_o²- F²_c)²]/∑[w(F_o²)²]}^1/2(sometimes denoted as R_w2). ^bGOF ) S ) {∑[w(F_o²- F²_c)²]/(n - p)}^1/2, where n

is the number of reflections, and p is the total number of refined parameters.

tentials and basis sets were used for palladium and phosphorus⁶¹with

an additional set of d-orbital polarization functions on P (ú ) 0.387).⁶²

For the [(PH₃)_nPd(CN)]^-/[EtNMe₃]⁺model (n ) 1, 2), 6-31G** basis

sets were used for all other atoms.⁶³For the larger model systems,

[(PPh₃)_nPd(CN)]^-/[R′NR′′₃]⁺, R′ ) Et, Bu; R′′ ) Me, Bu, additional

substituent carbon and hydrogen atoms were described with a 6-31G

basis set. All gas-phase optimized stationary points were fully

characterized via analytical frequency calculations as either minima

(all positive eigenvalues) or transition states (one imaginary eigenvalue),

and IRC calculations were used to confirm the minima linked by each

transition state. Relative energies quoted in the text incorporate a number

of different terms. Standard gas-phase energies include a correction

for zero-point energies. A solvent correction is then added to incorporate

stabilization arising from solvent polarity (THF, ꢀ ) 7.58) as calculated

via the polarized continuum model (PCM) approach.⁶⁴Finally, the T∆S

term (298.15 K, 1 atm) derived from the gas-phase frequency

calculations was included to give the solvent-corrected free energies

given in the text. To check the strategy of applying a single-point PCM

correction to a gas-phase optimized geometry, a number of stationary

points were fully optimized, incorporating the PCM solvation effect.

These test calculations showed that the computed energetics of C-N

activation to be unaffected, and full details are given in the Supporting

Information. Computed charges mentioned in the text are derived from

a Mulliken population analysis.

Acknowledgment. This is DuPont CR&D Contribution No.

8799. We thank Drs. Vladimir I. Bakhmutov (Texas A&M

University), Kenneth G. Moloy (DuPont), Albert L. Casalnuovo

(DuPont), Ronald J. McKinney (DuPont), and David L. Thorn

(Los Alamos National Laboratory) for discussions. Ms. Laurie

A. Howe (DuPont) is thankfully acknowledged for assistance

with selected VT NMR experiments.

(61) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299.

(62) Ho¨llwarth, A.; Bo¨hme, M.; Dapprich, S.; Ehlers, A. W.; Gobbi, A.; Jonas,

V.; Ko¨hler, K. F.; Stegmann, R.; Veldkamp, A.; Frenking, G. Chem. Phys.

Lett. 1993, 208, 237.

(63) (a) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56,

2257. (b) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28,

213.

(64) Cance`s, M. T.; Mennucci, B. B.; Tomasi, J. J. Chem. Phys. 1997, 107,

3032.

Supporting Information Available: Full ref 60 and further

details of computational, KIE (PDF), and crystallographic (CIF)

studies. This material is available free of charge via the Internet

at http://pubs.acs.org.

JA078298H

9

J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008 4845

Article Doi

Mechanisms of catalyst poisoning in palladium-catalyzed cyanation of haloarenes. Remarkably facile C-N bond activation in the [(Ph3P) 4Pd]/[Bu4N]+ CN- system

DOI: 10.1021/ja078298h

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