Insights into palladium-catalyzed cyanation of bromobenzene: Additive effects on the rate-limiting step

Article abstract of DOI:10.1021/ol8016935

(Chemical Equation Presented) Kinetic studies using reaction calorimetry were conducted under synthetically relevant conditions to study the effect of additives in the cyanation of bromobenzene catalyzed by palladium complexes. This work demonstrates that

Full text of DOI:10.1021/ol8016935

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5325-5328
Insights Into Palladium-Catalyzed
Cyanation of Bromobenzene: Additive
Effects on the Rate-Limiting Step
Frederic G. Buono,* Rama Chidambaram, Richard H. Mueller, and
Robert E. Waltermire
Process Research and DeVelopment, Bristol-Myers Squibb Pharmaceutical Research
Institute, One Squibb DriVe, New Brunswick, New Jersey 08903
Frederic.Buono@bms.com
Received July 24, 2008
ABSTRACT
Kinetic studies using reaction calorimetry were conducted under synthetically relevant conditions to study the effect of additives in the
cyanation of bromobenzene catalyzed by palladium complexes. This work demonstrates that the addition of a catalytic amount of ZnBr2
facilitates the reaction with an elimination of the induction period observed without additive. This study afforded a qualitative assessment of
the effect of water on the rate-limiting step and the apparent reaction order in bromobenzene.
Over the past few years, the metal-catalyzed cyanation of
aryl halides has received much attention as a broad synthetic
method for the preparation of substituted benzonitriles.1
Benzonitriles are important building blocks of natural
products, agrochemicals, and pharmaceutical products with
interesting biological properties.2 Prior studies of palladium-
catalyzed cyanation reactions revealed that catalyst deactiva-
tion was dependent on the concentration of dissolved cyanide
species, which can form unreactive complexes.3 Intensive
efforts to prevent catalyst deactivation and to improve the
reaction have been undertaken. This has usually consisted
of efforts to reduce the solubility of cyanide ions, such as
the use of nonpolar solvents4 or less soluble cyanide reagents
(zinc cyanide5 and potassium ferrocyanide(II)6). Other ap-
proaches to improve the reaction rate include the combination
of various additives (e.g., Bu3SnCl,7 Zn(OAc)28 or Zn dust,
9
Br2 ) and/or the addition of a catalytic amount of water to
(1) (a) Nandurkar, N. S.; Bhanage, B. M. Tetrahedron 2008, 64, 3655–
3660. (b) Ryberg, P. Org. Proc. Res. DeV. 2008, 12, 540–543. (c) Littke,
A.; Soumeillant, M.; Kaltenbach, R. F.; Cherney, R. J.; Tarby, C. M.; Kiau,
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Eaddy, J. F. Tetrahedron Lett. 2007, 2555–2557. (e) Weissman, S. A.;
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Sakakibara, Y.; Ohno, A.; Oka, S.; Hayama, N. Bull. Chem. Soc. Jpn. 1975,
48, 3298–3301.
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Marshall, W. J.; Roe, D. C. J. Am. Chem. Soc. 2008, 130, 4828–4845. (b)
Dobbs, K. D.; Marshall, W. J.; Grushin, V. V. J. Am. Chem. Soc. 2007,
129, 30–31. (c) Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem., Int.
Ed. 2003, 42, 1661–1664.
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2004, 1388–1389.
(2) Kleemann, A. Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical
Substances: Syntheses, Patents, Applications, 4th ed.; Georg Thieme:
Stuttgart, 2001.
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10.1021/ol8016935 CCC: $40.75
Published on Web 11/04/2008
2008 American Chemical Society

the catalytic system.10 Despite this progress, only a few
mechanistic and kinetic studies have been reported to
understand the effect of these additives for the cyanation
process.11 We report herein the kinetic analysis of the
cyanation of bromobenzene with zinc cyanide catalyzed by
palladium complexes in the presence of additives such as
water and/or ZnBr2 (see Scheme 1) using reaction calorim-
etry12 as an in situ monitoring technique under practical
synthetic conditions. These studies provide a basis for
discussion of proposed reaction mechanisms and the efficient
optimization of the cyanation process.
increased for more than 30 min as the substrate concentration
decreased, which would suggest that more active or more
soluble species were formed over the reaction conversion.
Scheme 1. Cyanation Reaction
Figure 1. ()) Reaction heat flow versus time for the cyanation of
bromobenzene (1.1 M) with Zn(CN)2 (0.7 mmol(s)/mL), Zn (8 mol
%), Pd2(dba)3 (0.5 mol %), and dppf (1.4 mol %) in DMF (5 mL)
with 1.7 vol % water at 95 °C. Comparison of conversion measured
by heat flow calorimetry (0) to the conversion measured by HPLC
(4).
Figure 1 shows a typical reaction heat flow profile as a
function of time for the reaction initiated by addition of
bromobenzene ([ArBr]0 ) 1.1 M) to a reaction vial,
equilibrated thermally for 45 min in a reaction calorimeter
(Omnical, Super CRC) at 95 °C, containing a heterogeneous
mixture of Zn(CN)2 (0.7 equiv or 0.77 mmol(s)/mL solvent)13
and a preformed catalyst mixture of Pd2(dba)3 (0.5 mol %),
dppf (1.4 mol %), and Zn dust14 (8 mol %) in DMF (5 mL)
containing 1.7 vol % of water (equivalent to [H2O] ) 0.8
M).10b Comparison of fraction conversion determined by
reaction calorimetry and from HPLC analysis of samples
extracted over time confirmed that the heat flow profile
provides an accurate measure of the reaction rate.15 The
reaction heat flow versus time reveals that a key feature of
this reaction is an induction period during which the rate
To obtain more information about the reaction kinetics
over time, an experimental protocol involving a series of
three consecutive injections of bromobenzene aliquots to a
single vessel containing all other reagents with an excess of
Zn(CN)2 sufficient to provide full conversion of bromoben-
zene was carried out at 95 °C (Figure 2). As expected, the
first injection exhibited the sudden exotherm observed in the
previous experiment and the subsequent two injections
exhibited a well-behaved positive order rate profile. The
difference of the reaction rates observed between the second
and third injection could be due to a deactivation of catalyst
over time in the presence of a large excess of zinc cyanide.
It was hypothesized that the zinc(II) bromide side product
of the reaction could be the species responsible for the
acceleration of rate observed in the initial phase of the
reaction.16
(9) (a) Seki, M. Synthesis 2006, 18, 2975–2992. (b) Hatsuda, M.; Seki,
M. Tetrahedron 2005, 61, 9908–9917.
(10) (a) Stazi, F.; Palmisano, G.; Turconi, M.; Santagostino, M.
Tetrahedron Lett. 2005, 46, 1815–1818. (b) Maligres, P. E.; Waters, M. S.;
Fleitz, F.; Askin, D. Tetrahedron Lett. 1999, 40, 8193–8195, and ref 8.
(11) (a) Sakakibara, Y.; Sasaki, K.; Okuda, F.; Hokimoto, A.; Ueda,
T.; Sakai, M.; Takagi, K. Bull. Chem. Soc. Jpn. 2004, 77, 1013–1019. (b)
Ellis, G. P.; Romney-Alexander, T. M. Chem. ReV. 1987, 87, 779.
(12) For significant examples of kinetic studies using reaction calorim-
etry, see: (a) Mathew, J. S.; Klussmann, M.; Iwamura, H.; Valera, F.; Futran,
A.; Emmanuelsson, E. A. C.; Blackmond, D. G. J. Org. Chem. 2006, 71,
4711–4722. (b) Blackmond, D. G. Angew. Chem., Int. Ed. 2005, 44, 4302–
4320.
(13) Zn(CN)2 is poorly soluble in DMF. The amount of Zn(CN)2
introduced is noted as mmol of solid Zn(CN)2/mL solvent (mmol(s)/mL).
(14) In the absence of Zn powder, the reaction stalled at low conversion
as observed in refs 8 and 10a. We believe that the zinc dust should play a
role to maintain palladium(0) complexes, avoiding inhibition processes of
the catalyst system.
(15) Reproducibility of the reaction heat flow profile versus time has
been checked, and the heat of reaction was in average 26.8 ((1.5) kcal/
mol.
Figure 2. Consecutive reactions with three added aliquots of
bromobenzene (5.9 mmol) to a solution of Zn(CN)2 (11.8 mmol),
Zn (8 mol %), Pd2(dba)3 (0.5 mol %), and dppf (1.4 mol %) in 5.9
mL of DMF/water (1.7 vol %) at 95 °C.
(16) A significant induction period could be attributed to the slow
activation of the catalytic precursors. A solution of Pd2(dba) 3/dppf/Zn was
stirred for 20 min at rt before addition of Zn(CN) 2 and the reaction solution
was equilibrated at 95°C for 45 min; no significant difference in the heat
flow profile was observed with longer equilibration time (1 h). For palladium
complexes activation, see: Shekhar, S.; Ryberg, P.; Hartwig, J. F.; Mathew,
J. S.; Blackmond, D. G.; Strieter, E. R.; Buchwald, S. J. Am. Chem. Soc.
2006, 128, 3584–3591.
Figure 3 shows that with a catalytic amount of ZnBr2 (6
mol %) added initially, the reaction kinetics directly afforded
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Org. Lett., Vol. 10, No. 23, 2008

Addition of ZnBr2 (6 mol %) was again observed to eliminate
the induction period of the reaction (Figure 5b). Interestingly,
under these conditions, the reaction showed a different kinetic
profile, with the reaction rate constant over the course of
the reaction. No effect of palladium catalyst concentration
on the rate of reaction was observed (Figure 5c), while the
reaction rate was found to be dependent on the amount of
Zn(CN)2 introduced at the beginning of the reaction (Figure
5d). This would suggest that the reaction rate is zero order
in bromobenzene concentration and is limited by the dis-
solution of Zn(CN)2 under anhydrous conditions.
Figure 3. Reaction rate versus [ArBr]. Standard conditions: [ArBr]0
) 1.0 M with Zn(CN)2 (()) (1 mmol(s)/mL), (∆) (2 mmol(s)/mL)
and Zn (8 mol %), ZnBr2 (6 mol %), Pd2(dba)3 (0.5 mol %), and
dppf (1.4 mol %) in DMF with 1.7 vol % water at 95 °C.
a kinetic profile without the sudden exotherm. The method-
ology of reaction progress kinetic analysis was employed to
establish the kinetic profile.12 With different zinc cyanide
loadings, the curves of reaction rate versus bromobenzene
concentration overlay, showing that the reaction rate is not
dependent on the amount of zinc cyanide introduced in the
reaction, and exhibit a straight line, indicating that the
reaction rate is dependent on bromobenzene concentration.
Figure 4 shows the reaction rate versus palladium con-
centration. It appears that the reaction is first order in
palladium at low catalyst concentration and negative order
at high catalyst concentration.17 Finally, these experiments
reveal that the reaction rate is first order in bromobenzene
and in palladium (at low catalyst concentration) and zero
order in zinc cyanide and is in alignment with the effects of
Zn dust/Br2 observed in ref 9, which indicates that zinc
bromide formed during the initial phase of the reaction plays
a role in the formation of the more active or more soluble
species.18 Determination of the solubility of cyanide con-
firmed that the addition of ZnBr2 (10 wt %) to a solution of
Zn(CN)2 in wet DMF at 95 °C increased the amount of
dissolved cyanide species by up to 5-fold.19
Figure 5. Reaction rate versus [ArBr] in dry DMF (20 ppm water)
at 95 °C. (5a, )) Standard conditions: [ArBr]0 ) 1.1 M, Zn(CN)2
(2.1 mmol(s)/mL), Zn (8 mol %), Pd2(dba)3 (0.3 mol %), and dppf
(0.8 mol %). (5b, 0) Standard conditions with ZnBr2 (6 mol %);
(5c, ∆) with Pd2(dba)3 (0.5 mol %), dppf (1.4 mol %); (5d, O)
with ZnBr2 (6 mol %) and Zn(CN)2 (0.7 mmol(s)/mL).
Figure 6 shows the role of water on the rate-limiting step
by varying amounts of water (20 ppm to 1.7 vol %). With
0.2 vol % water, the reaction rate appears to be zero order
and significantly increased compared to the 20 ppm experi-
ment. With 1.2 vol % water, the reaction rate has a complex
order of [ArBr] between zero and first order where the time
to achieve high conversion is approximately 4-fold faster
than under anhydrous conditions (see Supporting Inform-
ation). Further addition of water (1.7 vol %) slowed down
the reaction rate, which appears to be first order in bro-
mobenzene. Overall these studies demonstrate a significant
impact of water on reaction order and on the rate-limiting
step of the reaction.
Scheme 2 shows a simplified mechanism of Pd-catalyzed
cyanation with successive steps: (a) oxidative addition of
aryl halide to the Pd(0) catalyst,20 (b) dissolution of Zn(CN)2,
(c) transmetalation to form ArPdCN, (d) reductive elimina-
tion and regeneration of catalyst. The mechanistic points
(17) The order observed at high palladium concentration would support
the presence of an inactive palladium dimer. The authors would like to
acknowledge one of the referees for their comments and suggestions on
the interpretation of the catalyst order.
(18) Another possible role of zinc bromide, mentioned by one of the
referees, is that it could presumably act as Lewis acid, facilitating halide
abstraction from an oxidative addition intermediate.
Figure 4. Reaction rate at 50% conversion versus [Pd2(dba)3].
[ArBr]0 ) 1.1 M, Zn(CN)2 (0.77 mmol(s)/mL), Zn (6 mol %), ZnBr2
(6 mol %), Pd2(dba)3 (0.1-1.0 mol %), and dppf (0.3-3.0 mol %)
in DMF/water (1.7 vol %) at 95 °C.
(19) Solubility of Zn(CN)2 in DMF/water (1 vol %) at 95 °C was
determined by ionic chromatography: 0.654 mg/mL, equivalent to [CN-]
) 0.025 M if all cyanide species in solution are free cyanide ions. With
added ZnBr2 (10 wt %) solubility is 3.491 mg/mL equivalent to [CN-] )
0.13 M. In ref 10a, Zn(CN)2 solubility in dry DMF at 80°C was 0.180
mg/mL ([CN-] ) 0.007 M).
To further evaluate the effect of water, experiments were
conducted with varying concentrations of zinc bromide and
zinc cyanide under anhydrous conditions (20 ppm water).
Org. Lett., Vol. 10, No. 23, 2008
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Scheme 2. Proposed Reaction Mechanism
Figure 6. Influence of water on the reaction rate at 95 °C. [ArBr]0
) 1.1 M, Zn(CN)2 (0.77 mmol(s)/mL), Zn (8 mol %), ZnBr2 (6
mol %), Pd2(dba)3 (0.3 mol %), dppf (0.8 mol %) in DMF
containing water ()) 20 ppm ([H2O] ) 0.01 M), (×) 0.2 vol %
([H2O] ) 0.10 M), (0) 1.2 vol % ([H2O] ) 0.55 M), (∆) 1.7 vol
% ([H2O] ) 0.80 M).
In summary, this work affords some mechanistic insights
into the effect of additives8-10 in the cyanation reaction of
bromobenzene catalyzed by palladium complexes. The
addition of ZnBr2 may facilitate the reaction initially by
increasing the concentration of dissolved cyanide ions, likely
by formation of a more active, more soluble, noninhibitory
mixed zinc species. This kinetics study highlights the
complex and opposing role that water could play in the
kinetic regime of this heterogeneous palladium-catalyzed
reaction. Deconvoluting these effects will aid in obtaining
true mechanistic understanding in these reactions. Further
studies to establish the overall kinetics and modeling are
underway and will be reported in due course.
revealed by our kinetic studies are that the initial charge of
a catalytic amount of ZnBr2 may have a dual effect by
increasing the concentrated of dissolved cyanide ion13 and/
or forming some other active zinc species such as Zn(CN)-
(Br).9,21 Addition of water has a dramatic effect on the
apparent order of the reaction and has implications on the
catalytic cycle. This different reaction order may be explained
by a change of the rate-limiting step from a mass transfer
step (dissolution of Zn(CN)2 solid) to a step that could be
the oxidative addition (first order in bromobenzene and
palladium). This change of the rate-limiting step is likely a
consequence of an increase in the solubility of zinc cyanide22
in the presence of water and an inactivation of catalyst due
to the increased concentration of dissolved cyanide ions.3
Optimization of the water amount was considered a good
means to identify conditions with an optimum rate, which
struck a compromise between an increase in the mass transfer
rate while simultaneously minimizing catalyst deactivation.
Acknowledgment. The authors wish to thank Dr. Y. K.
Ye (BMS) for solubility measurements, Dr. D. Kronenthal
(BMS), Dr. J. Muslehiddinoglu (BMS), Dr. M. Hamedi
(Schering Plough), Dr. T. Rosner (BMS), Dr. M. Futran
(BMS), and Professor D. G. Blackmond (Imperial College)
for helpful discussions.
(20) (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046. (b)
Amatore, C.; Broeker, G.; Jutand, A.; Khalil, F. J. Am. Chem. Soc. 1997,
119, 5176–5185.
Supporting Information Available: Experimental pro-
cedures and kinetic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(21) Knochel, P.; Singer, R. D. Chem. ReV. 1993, 93, 2117.
(22) MacDiarmid, A. G.; Hall, N. F. J. Am. Chem. Soc, 1954, 76, 4222–
4228.
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