Amination with Pd-NHC complexes: Rate and computational studies involving substituted aniline substrates

Article abstract of DOI:10.1002/chem.201102428

The amination of aryl chlorides with various aniline derivatives using the N-heterocyclic carbene-based Pd complexes Pd-PEPPSI-IPr and Pd-PEPPSI-IPent (PEPPSI=pyridine, enhanced precatalyst, preparation, stabilization, and initiation; IPr=diisopropylphenylimidazolium derivative; IPent= diisopentylphenylimidazolium derivative) has been studied. Rate studies have shown a reliance on the aryl chloride to be electron poor, although oxidative addition is not rate limiting. Anilines couple best when they are electron rich, which would seem to discount deprotonation of the intermediate metal ammonium complex as being rate limiting in favour of reductive elimination. In previous studies with secondary amines using PEPPSI complexes, deprotonation was proposed to be the slow step in the cycle. These experimental findings relating to mechanism were corroborated by computation. Pd-PEPPSI-IPr and the more hindered Pd-PEPPSI-IPent catalysts were used to couple deactivated aryl chlorides with electron poor anilines; while the IPr catalysis was sluggish, the IPent catalyst performed extremely well, again showing the high reactivity of this broadly useful catalyst. Copyright

Full text of DOI:10.1002/chem.201102428

FULL PAPER
DOI: 10.1002/chem.201102428
ꢀ
Amination with Pd NHC Complexes: Rate and Computational Studies
Involving Substituted Aniline Substrates
Ka Hou Hoi,[a] SelÅuk C¸ alimsiz,[a] Robert D. J. Froese,[b] Alan C. Hopkinson,[a] and
Michael G. Organ*[a]
Abstract: The amination of aryl chlor-
ides with various aniline derivatives
using the N-heterocyclic carbene-based
Pd complexes Pd-PEPPSI-IPr and Pd-
PEPPSI-IPent (PEPPSI=pyridine, en-
hanced precatalyst, preparation, stabili-
zation, and initiation; IPr=diisopropyl-
phenylimidazolium derivative; IPent=
diisopentylphenylimidazolium deriva-
tive) has been studied. Rate studies
have shown a reliance on the aryl chlo-
ride to be electron poor, although oxi-
dative addition is not rate limiting.
Anilines couple best when they are
electron rich, which would seem to dis-
count deprotonation of the intermedi-
ate metal ammonium complex as being
rate limiting in favour of reductive
elimination. In previous studies with
secondary amines using PEPPSI com-
plexes, deprotonation was proposed to
be the slow step in the cycle. These ex-
perimental findings relating to mecha-
nism were corroborated by computa-
tion. Pd-PEPPSI-IPr and the more hin-
dered Pd-PEPPSI-IPent catalysts were
used to couple deactivated aryl chlor-
ides with electron poor anilines; while
the IPr catalysis was sluggish, the IPent
catalyst performed extremely well,
again showing the high reactivity of
this broadly useful catalyst.
Keywords: amination · carbene li-
gands · catalysis · computational
chemistry · palladium
Introduction
um; see Table 1)[6,7] was suitably electron poor at Pd to still
be able to negotiate these steps, while the more electron-
rich (relatively) Pd-PEPPSI-IPr derivative (4; IPr=diisopro-
pylphenylimidazolium) could not.[1]
Recently we addressed the impact of the electronic proper-
ties of the oxidative-addition partner (e.g., Ar-X) on the ob-
served rate of Pd-catalysed amination using N-heterocyclic
carbene (NHC) ligands.[1–3] In the amination catalytic cycle,
the metal centre changes its electronic nature from being
nucleophilic during oxidative addition (OA), to being elec-
trophilic during amine coordination/deprotonation (Dep)
and reductive elimination (RE). As N-heterocyclic carbenes
are strong sigma donors,[4] oxidative addition is seldom a
problem and it is generally now believed to be amine coor-
dination and/or deprotonation that is/are rate limiting in
amination (or transmetallation in analogous organometallic
cross-coupling such as the Negishi reaction).[5] Consistent
with this, we demonstrated that electron-rich aryl halides,
once added to Pd, suppress the amination cycle by discour-
aging amine coordination to the metal and/or subsequent
deprotonation of the aryl palladium amide complex. Fur-
ther, we showed that the Pd-PEPPSI-IPent NHC catalyst (5;
PEPPSI=pyridine, enhanced precatalyst, preparation, stabi-
lization, and initiation; IPent= diisopentylphenylimidazoli-
Not unlike the catalystꢀs metal centre that must walk an
electronic tightrope to allow electronically divergent steps
to occur, so must the amine. To coordinate Pd, the amine
must be electron rich, and yet if it is too basic the pKa of
the aryl palladium amide complex intermediate rises, disfa-
vouring deprotonation; this is especially troublesome when
desirable mild bases such as carbonate are used. Herein we
investigate how the electronics of the amine interplay with
those of the metal centre of Pd–NHC complexes in the pur-
suit of one catalyst that will have very wide substrate toler-
ance and high reactivity.
Results and Discussion
Rate studies: Perhaps the most suitable compound family to
study the effect of varying amine basicity is aniline.[9] If we
compare the pKa of a typical secondary amine such as mor-
pholine (~35) with aniline (~25), we would expect aniline to
retard coordination to Pd. However, once coordinated, the
intrinsic electron-poor nature of aniline, relative to alkyl
amines, should dramatically improve deprotonation. Thus,
the use of substituted anilines provides a possibility to dif-
ferentiate amine coordination from deprotonation. Further,
this should provide further information on the electronic
properties of the Pd centre in the IPr derivative 4 versus the
IPent derivative 5, where one would predict the latter to
[a] K. H. Hoi, Dr. S. C¸ alimsiz, Prof. A. C. Hopkinson, Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele Street, Toronto, ON, M3J 1P3 (Canada)
Fax : (+1)416-736-5936
E-mail: organ@yorku.ca
[b] Dr. R. D. J. Froese
The Dow Chemical Company, Midland, Michigan, 48674 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102428.
Chem. Eur. J. 2012, 18, 145 – 151
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
145

demonstrate higher reactivity on the basis of the extent of
positive charge on the metal centre following oxidative addi-
tion.
To begin, we varied the electronic properties of the oxida-
tive addition partner to see how the reactivity of unsubsti-
tuted aniline compares with that of a typical secondary
amine (Table 1, entries 6–10). As for morpholine, Pd-
Table 1. Yield of amination reactions varying both the aryl chloride (1)
and aniline (2) for both Pd-PEPPSI-IPr (4) and Pd-PEPPSI-IPent (5).
Entry
R
R1
Product
Yield[a]
Yield[a]
using 4
using 5
1
2
3
4
5
6
7
8
NO2
CN
H
CH3
OCH3
NO2
CN
OCH3
OCH3
OCH3
OCH3
OCH3
H
H
H
H
H
CN
CN
CN
CN
CN
CN
CO2Me
CO2Me
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3c
3j
3k
3g
3l
90
87
61
17
0
97
79
29
26
0
2
0
0
0
0
0
0
0
96
91
99
95
96
90
89
93
H
9
CH3
OCH3
NO2
CN
92
92
10
11
12
13
14
15
16
17
18
96[b]
75[b]
93
H
CH3
OCH3
OCH3
CH3
OCH3
86
3b
3b
3m
3n
49
70[c]
86
79
[a] Yields are determined on isolated product following silica gel flash
chromatography; reactions were performed in duplicate. [b] Significant
problems in product isolation were encountered due to the high insolubili-
ty of compounds 3j and 3k. [c] 3.0 Equivalents of KtOBu were used in-
stead of Cs2CO3.
PEPPSI-IPr displayed a strong reliance that 1 be decorated
with electron-withdrawing substituents, while Pd-PEPPSI-
IPent possessed sufficient intrinsic reactivity to provide ex-
cellent conversion of all aryl chlorides after 24 h. When the
rates of these same five transformations were monitored for
the IPr derivative 4 (Figure 1a), it was found that a similar
set of curves were produced with aniline as were obtained
for morpholine.[1] Analysis of the kinetic data was compli-
cated by the presence of induction periods that varied with
differently substituted aryl chlorides; nevertheless, we en-
deavoured to obtain initial rates (see Table 2) and these
were used to construct the Hammett 1 plot (Figure 1c). The
positive 1 value (2.1) established that groups that withdraw
Figure 1. Comparative rates of amination of various chloroarenes with
aniline using a) Pd-PEPPSI-IPr (4) and b) Pd-PEPPSI-IPent (5). c) Ham-
mett plot for amination of various substituted chlorobenzenes with ani-
line using catalysts 4 and 5.
electron density from the Pd centre strongly increase the
rate, whereas electron donors slow the reaction. While the
maximum rates for the same five aryl halides were similar
with morpholine, with aniline the rates showed a substantial
dependence on the substituents, as illustrated by the linear 1
plot (Figure 1c). The substituent effect for the Pd-PEPPSI-
146
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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 145 – 151

ꢀ
Amination with Pd NHC Complexes
FULL PAPER
Table 2. Initial rates, d[P]/dt, for product formation in percent conversion
per hour for Pd-PEPPSI-IPr (4) and Pd-PEPPSI-IPent (5).
p-Substituent on
aryl chloride or aniline
Varying substituents
in aryl chloride[a]
Varying substituents
in aniline[b]
IPr (4)
IPent (5)
IPent (5)
p-OCH3
p-CH3
p-H
p-CN
p-NO2
–
2.18
3.93
5.11
80.8
150.0
–
148.0
83.2
35.5
–
–
35.5
27.5
0.27
1.17
29.3
81.1
–
p-COOMe
p-COMe
–
–
[a] Aryl chlorides (varied) 1m; aniline (p-H) 1.5m. [b] Aryl chloride
(chlorobenzene) 0.1m; anilines (varied) 0.15m.
IPent catalyzed reaction was smaller but still appreciable (1
value 1.8) showing that for both catalysts there is a buildup
in electron density at the reaction centre in the rate-deter-
mining transition state.
To gain additional mechanistic insight, the electronic char-
acter of the aniline (Table 1, entries 1–5 and 11–16 and
Figure 2) was also varied by using a variety of p-substituents
and this provided important information concerning the
rate-limiting step of the amination cycle employing NHC-
based Pd catalysts. With the strongly electron-donating p-
OCH3 substituent (Table 1, entries 1–5), Pd-PEPPSI-IPent
showed a slight improvement to near quantitative conver-
sion over all aryl chlorides, whereas Pd-PEPPSI-IPr saw no
significant change in yield (Table 1, entries 6–10 vs. 1–5)
except when R=H. However, when the electron-withdraw-
ing p-CN substituent was used, significant differences were
seen, in particular for the IPr derivative (Table 1, entries 11–
15); regardless of the oxidative addition partner, no amina-
tion occurred at all with the IPr catalyst. However, with the
IPent catalyst the reaction still proceeded quite well al-
though the effects of an electron-poor aniline became ex-
posed when the chloroarene (1) was electron rich (Table 1
entries 11–15). For example, if the oxidative addition partner
is fixed as chloroanisole and one looks at entries 5 and 10 in
Table 1 for which the aniline is relatively electron rich, the
yields are excellent; a noticeable reduction in yield is ob-
served for the electron-poor aniline in Table 1, entry 15. Of
course, this is still quite a remarkable result, as this is one of
the worst possible electronic pairings for this transformation
and speaks well for the high reactivity of Pd-PEPPSI-IPent
for amination.
A study of the rates of reactions of substituted anilines
with chlorobenzene provided the Hammett plot in Fig-
ure 2c. Despite some scatter in the data points, it is clear
that the 1-value is negative (ca. ꢀ0.8), indicating that elec-
tron density flows away from the aniline in the rate-deter-
mining step. If the deprotonation step is rate determining
then electron-withdrawing substituents in both the aryl chlo-
ride and in the aniline should lead to faster reactions, that is,
both 1-values should be positive with the value associated
with the anilines being larger. This is not consistent with the
experimental data. The substituent effects are more consis-
tent with reductive elimination being rate determining, as
Figure 2. Comparative rates of amination of chlorobenzene with various
substituted anilines using a) Pd-PEPPSI-IPr (4) and b) Pd-PEPPSI-IPent
(5). c) Hammett plot for amination of chlorobenzene with various para-
substituted anilines using Pd-PEPPSI-IPent (5).
previously reported in the formation of diarylamines by re-
ductive elimination from 1,1-bis(diphenylphosphino)ferro-
cene-ligated aryl palladium amido complexes.[8]
A study to determine the order of the reactants provided
further mechanistic insight into NHC-Pd-cataysed amination
involving substituted anilines. The reaction was zero order
in aryl chloride, confirming that oxidative addition is fast
and not rate-determining for these reactive Pd-NHC cata-
Chem. Eur. J. 2012, 18, 145 – 151
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
147

M. G. Organ et al.
lysts with their relatively electron-rich metal centres. The re-
action rate showed a first-order dependence on the concen-
tration of aniline, implicating it in the rate-determining step.
Similarly, the reaction clearly showed a first dependence on
the amount of the cesium carbonate base (present as a
finely divided solid).
provides a thermodynamic assessment of the deprotonation
step for different combinations of aryl chlorides, anilines
and catalysts. Our goal was to see if the calculations could
predict the experimental trends in varying the aryl chloride,
varying the aniline, and varying the catalyst from the IPr de-
rivative to the IPent derivative.
Details of the potential energy surfaces are provided in
Table 3 and Table 4. The lower parts of these tables are of
particular interest as the experimental data indicate that ani-
line binding and deprotonation may both be kinetically im-
portant. As shown in these calculations and also in the ex-
periments, oxidative addition is not rate limiting. Starting
with oxidative addition product 11 (see Scheme 1 for struc-
tures), formation of the aniline adduct 12 is exothermic and
Computational studies: The catalytic cycle for amination
was modeled by using density functional theory at the
B3LYP level[9] with the LANL2TZ(f) basis set on Pd[10] and
6-31G*[11] on the remaining atoms.[12] Computationally it is
difficult to study the deprotonation step using cesium car-
bonate and we have examined it qualitatively by addition of
KOtBu leading to the elimination of KCl and HOtBu. This
Table 3. DFT enthalpies (kcalmolꢀ1) relative to compound 8, Pd0 Ln, using Pd-PEPPSI-IPr.[a]
Ar-NO2
Ar-CN
Ar-H
Ar-Me
Ar-OMe
9
10
11
ꢀ21.5
ꢀ10.3
ꢀ34.8
ꢀ20.4
ꢀ9.6
ꢀ18.4
ꢀ6.7
ꢀ18.0
ꢀ6.4
ꢀ18.6
ꢀ6.2
ꢀ34.3
ꢀ31.4
ꢀ31.1
ꢀ30.8
Ar-An
12
13
14
15
NO2/OMe
ꢀ53.5
ꢀ45.8
ꢀ32.7
ꢀ58.2
ꢀ41.6
11.2
CN/CN CN/H CN/OMe
ꢀ49.4 ꢀ51.5 ꢀ52.8
ꢀ46.1 ꢀ43.9 ꢀ44.4
ꢀ30.9 ꢀ30.7 ꢀ31.1
ꢀ51.8 ꢀ53.3 ꢀ56.2
ꢀ37.1 ꢀ39.3 ꢀ40.5
H/CN H/CO2Me H/COMe H/H H/Me H/OMe
Me/OMe
ꢀ48.7
ꢀ40.9
ꢀ25.3
ꢀ54.2
ꢀ36.7
11.6
OMe/CN OMe/H OMe/OMe
ꢀ46.6 ꢀ46.6
ꢀ43.3 ꢀ41.9
ꢀ26.7 ꢀ25.9
ꢀ51.5 ꢀ52.0
ꢀ35.9 ꢀ36.1
11.7 11.7
ꢀ46.3
ꢀ42.4
ꢀ26.1
ꢀ51.5
ꢀ36.1
11.7
ꢀ48.0 ꢀ48.9 ꢀ49.0
ꢀ39.9 ꢀ40.5 ꢀ40.0
ꢀ25.4 ꢀ25.4 ꢀ25.8
ꢀ53.4 ꢀ53.3 ꢀ53.0
ꢀ36.5 ꢀ36.7 ꢀ37.1
11.7 11.7 11.7
ꢀ8.5 ꢀ9.1 ꢀ8.6
14.5 15.1 14.2
ꢀ16.6 ꢀ17.5 ꢀ17.6
ꢀ46.2
ꢀ43.2
ꢀ25.5
ꢀ51.9
ꢀ35.6
12.4
ꢀ47.5 ꢀ48.7
ꢀ39.3 ꢀ40.1
ꢀ24.1 ꢀ24.6
ꢀ52.4 ꢀ53.1
ꢀ35.6 ꢀ35.9
16
9!10
11!13
13!14
11!12
11!14
12!13
12!14
10.8
ꢀ11.8 ꢀ9.6 ꢀ10.1
15.2 13.2 13.3
10.8 10.8
12.4
ꢀ8.5
15.2
12.4
ꢀ9.3
15.5
ꢀ11.0
ꢀ11.9 ꢀ10.5
ꢀ11.0
ꢀ9.8
ꢀ12.4
13.1
16.6 16.0
16.3
15.6
17.7
ꢀ18.7
2.1
7.7
ꢀ15.1 ꢀ17.2 ꢀ18.5
ꢀ15.2 ꢀ15.2
ꢀ14.9
5.3
3.9
ꢀ17.6
5.8
7.8
23.4
ꢀ2.0
ꢀ15.4
5.3
ꢀ16.7 ꢀ17.9
3.4
3.3
3.6
7.6
3.2
8.4
4.7
3.3
5.5
4.7
6.0
8.1
6.0
8.4
5.6
9.0
6.7
6.2
3.0
8.2
8.6
20.8
18.5
0.1
20.8 21.7
ꢀ4.0 0.1
19.9 20.7
1.4 0.8
20.2
1.4
22.6 23.5 23.2
ꢀ2.1 ꢀ2.4 ꢀ3.4
20.7
2.3
23.4
ꢀ1.5
24.1
ꢀ2.4
11!12 + ꢀ5.6
13!14
[a] Enthalpies of common species on the potential energy surface include 6 (ꢀ24.4 kcalmolꢀ1), 7 (ꢀ11.2 kcalmolꢀ1) and 8 (0.0 kcalmolꢀ1). See Table 1
and Scheme 1 for the structures.
Table 4. DFT enthalpies (kcalmolꢀ1) relative to compound 8, Pd0 Ln, using Pd-PEPPSI-IPent.[a]
Ar-NO2
Ar-CN
Ar-H
Ar-Me
Ar-OMe
9
10
11
ꢀ22.0
ꢀ10.4
ꢀ32.2
ꢀ20.9
ꢀ9.7
ꢀ18.9
ꢀ6.7
ꢀ17.5
ꢀ6.4
ꢀ18.6
ꢀ6.2
ꢀ31.7
ꢀ28.4
ꢀ28.0
ꢀ27.8
Ar-An
12
13
14
15
NO2/OMe
ꢀ52.9
ꢀ45.5
ꢀ33.3
ꢀ57.8
ꢀ41.6
11.6
CN/CN CN/H CN/OMe
ꢀ48.9 ꢀ51.1 ꢀ52.4
ꢀ46.6 ꢀ44.3 ꢀ44.7
ꢀ31.3 ꢀ30.9 ꢀ31.4
ꢀ52.0 ꢀ55.6 ꢀ57.7
ꢀ37.1 ꢀ39.3 ꢀ40.5
H/CN H/CO2Me H/COMe H/H H/Me H/OMe
Me/OMe
ꢀ48.3
ꢀ40.7
ꢀ25.5
ꢀ53.7
ꢀ36.7
11.1
OMe/CN OMe/H OMe/OMe
ꢀ46.2 ꢀ46.2
ꢀ43.7 ꢀ42.2
ꢀ27.1 ꢀ26.0
ꢀ50.1 ꢀ51.6
ꢀ35.9 ꢀ36.1
12.2 12.2
ꢀ46.3
ꢀ42.3
ꢀ26.1
ꢀ52.1
ꢀ36.1
12.2
ꢀ47.6 ꢀ48.0 ꢀ48.6
ꢀ40.5 ꢀ40.3 ꢀ41.2
ꢀ25.4 ꢀ25.6 ꢀ26.1
ꢀ52.9 ꢀ53.9 ꢀ54.0
ꢀ36.5 ꢀ36.7 ꢀ37.1
12.2 12.2 12.2
ꢀ12.1 ꢀ11.9 ꢀ12.8
15.1 14.7 15.1
ꢀ19.2 ꢀ19.6 ꢀ20.2
ꢀ45.9
ꢀ43.4
ꢀ25.9
ꢀ51.3
ꢀ35.6
12.4
ꢀ47.2 ꢀ48.2
ꢀ39.9 ꢀ40.5
ꢀ24.2 ꢀ24.8
ꢀ51.4 ꢀ54.0
ꢀ35.6 ꢀ35.9
16
9 ! 10
11 ! 13
13 ! 14
11 ! 12
11 ! 14
12 ! 13
12 ! 14
11.2
ꢀ14.9 ꢀ12.6 ꢀ13.0
15.3 13.4 13.3
11.2 11.2
12.4
12.4
ꢀ13.3
ꢀ15.3 ꢀ13.8
ꢀ13.9
ꢀ12.7
ꢀ15.5
ꢀ12.1 ꢀ12.6
12.2
16.6 16.2
16.2
15.2
17.5
15.7 15.7
ꢀ20.7
ꢀ1.1
ꢀ17.2 ꢀ19.4 ꢀ20.7
ꢀ17.8 ꢀ17.8
ꢀ17.9
2.3
4.0
ꢀ20.3
2.5
7.6
22.8
ꢀ5.1
ꢀ18.1
1.9
ꢀ19.4 ꢀ20.4
0.4
2.3
0.8
6.8
0.3
7.7
1.3
2.5
2.4
4.0
3.0
7.1
2.8
7.7
2.3
7.4
3.6
3.0
7.4
2.5
7.3
7.7
19.6
17.6
ꢀ1.9
20.2 21.0
ꢀ6.0 ꢀ7.4
19.1 20.2
20.2
22.2 22.4 22.5
20.0
ꢀ0.6
23.0
ꢀ3.7
23.4
ꢀ4.7
11 ! 12 + ꢀ8.5
ꢀ1.2 ꢀ1.6
ꢀ1.7
ꢀ4.1 ꢀ4.9 ꢀ5.1
13 ! 14
[a] Enthalpies of common species on the potential energy surface include 6 (ꢀ24.4 kcalmolꢀ1), 7 (ꢀ16.0 kcalmolꢀ1) and 8 (0.0 kcalmolꢀ1). See Table 1
and Scheme 1 for the structures.
148
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Chem. Eur. J. 2012, 18, 145 – 151

ꢀ
Amination with Pd NHC Complexes
FULL PAPER
ed for the aryl chlorides. For the reaction of the parent aryl
chloride (i.e., chlorobenzene) catalyzed by the IPr deriva-
tive, the calculated barriers for 11 ! 14 are CN 4.7, CO2Me
5.5, COMe 5.3, H 6.0, Me 6.0 and OMe 5.6, a range of only
1.3 kcalmolꢀ1. If these barriers determine the relative rates,
then the reactivities would all be similar (as indicated in
Table 4).
Experimentally, the reaction is first order in aniline and
base; thus, the rate-limiting step is most likely the process of
aniline binding (11 ! 12), deprotonation (12 ! 13), and re-
ductive elimination (13 ! 14). This process, 11 ! 14, accu-
rately predicts that the IPent catalyst is more reactive than
the IPr catalyst and correctly predicts the order of reactivity
of the aryl chloride as CN > H > OMe. However, 11 ! 14
does not discern the small differences in the aniline substitu-
ents. One can accurately estimate the reactivity of the ani-
line by disregarding the deprotonation term and using the
(11 ! 12) + (13 ! 14) term (final entry in Tables 3 and 4).
It may be that the simple deprotonation model used is not
sufficient. It should be pointed out that this energetic pa-
rameter also predicts that the IPent catalyst is faster than
the IPr catalyst and predicts the correct order of reactivity
of the aryl chlorides.
Scheme 1. The proposed mechanism for the coupling of aryl chlorides
with aniline (OA=oxidative addition, Dep=deprotonation, RE=reduc-
tive elimination).
Reaction scope studies: The scope of aniline-based amina-
tion was investigated by using the IPent catalyst 5 and these
runs were compared directly with those with the IPr catalyst
4 to see how much ꢂvalue addedꢀ there is using this bulky,
and presumed-to-be more reactive catalyst. Table 5 also in-
cludes some of the reactions outlined in Table 1 for compar-
ison sake and completeness. Our rate studies have clearly
shown a negative effect on catalyst performance when the
oxidative addition partner is electron rich; electron-deficient
aniline derivatives also slow the rate. Thus, to show maxi-
mally the differences in catalytic ability, we focused largely
on examples that have electron-rich aryl chlorides and elec-
tron-poor anilines. In every single case, the IPent catalyst
out-performed the IPr catalyst and in most situations the
IPr catalyst either had no turnovers or very few. Additional-
ly, substrates possessing various levels of steric hindrance
(e.g. 18, 19, 20 and 21) were also investigated and again
there was a significant improvement in yield using the IPent
catalyst.
probably without barrier. The deprotonation step (12 ! 13,
as shown in Scheme 1[13]) is endothermic, with electron-with-
drawing groups in both rings facilitating the reaction. Effects
are calculated to be much more pronounced for substituents
in the aniline (e.g., for the IPr derivative: CN 3.3, H 8.1,
OMe 9.0 kcalmolꢀ1) than in the aryl chloride (e.g., for the
IPr derivative: CN 7.6, H 8.1, OMe 8.2 kcalmolꢀ1), as antici-
pated due to the different proximities of the substituents to
the NH2 group undergoing deprotonation. On all surfaces,
structures 12 and 13 lie below 11, while 14, the transition
state to reductive elimination, is consistently higher than 11.
Furthermore, for any combination of aniline and aryl chlo-
ride the enthalpy differences 11 ! 14 are always smaller for
the Pd-PEPPSI-IPent-catalysed reactions than for the corre-
sponding Pd-PEPPSI-IPr-catalysed ones, suggesting faster
reactions for the former.
The energy barriers for 11 ! 14 (in kcalmolꢀ1) as a func-
tion of the substituent in the aryl chloride for any fixed ani-
line are always in the order CN < H < OMe; for example,
for the parent aniline the barriers are 3.6 for CN, 6.0 for H,
and 6.7 for OMe. The most extensive set of data is for the
p-OMe-substituted anilines for which the barriers for the
IPr catalyst are 2.1 for NO2, 3.2 for CN, 5.6 for H, 5.8 for
Me, and 6.2 for OMe. Using these barriers (11 ! 14) as a
predictor of relative rates for the aryl chlorides gives the
order of reactivity to be NO2 > CN > H > Me > OMe, the
same order as observed experimentally.
Conclusion
In this study, the NHC-based catalyst Pd-PEPPSI-IPent was
examined in the coupling of aniline derivatives with aryl
chlorides and compared head-to-head with Pd-PEPPSI-IPr.
In rate studies, electron-withdrawing groups on the aryl
chloride accelerated the rate, whereas electron-withdrawing
groups on the aniline made the reaction slower. While the
former result is consistent with deprotonation being rate-de-
termining, the latter one is not. Because the groups on ani-
line are directly conjugated with the aniline proton, and can
therefore play a more direct role in deprotonation than the
The data in Tables 3 and 4 also allow us to study the
effect of varying the substituent in the aniline with one par-
ticular aryl chloride. The barriers show a much smaller de-
pendence on the substituent in the aniline than was calculat-
Chem. Eur. J. 2012, 18, 145 – 151
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149

M. G. Organ et al.
Table 5. Scope study of amination reaction with challenging substrates
using Pd-PEPPSI-IPr (4) and Pd-PEPPSI-IPent (5).
aryl chloride substituents can, this suggests that deprotona-
tion is not problematic for aniline-based substrates. That
electron-donating groups on the aniline increase the rate,
while electron-withdrawing groups on the aryl chloride also
increase the rate is more consistent with reductive elimina-
tion being rate limiting. This was not the case for the cou-
pling of secondary alkyl amines using NHC catalysts where
deprotonation was clearly the slow step.[1]
The IPent ligand is clearly far more reactive in the cou-
pling of aniline derivatives than the IPr ligand, as it was for
secondary alkyl amines, despite the appearance that the
rate-determining step is different for the two transforma-
tions. The IPent catalyst effectively couples electron-rich
aryl chlorides with electron-poor anilines, while the IPr cata-
lyst is essentially inactive. Further, sterically challenging sub-
strates appear to pose no concern for IPent.
DFT calculations were performed and supported the
lower barrier for oxidative addition compared to the latter
steps. While experiments predicted a reaction dependent on
aniline and base, the computed energy differences predicted
more facile reactions only if the reductive elimination was
also included. Computed energy differences were found that
correctly predicted the order of reactivity of the aryl chlo-
ride substituents, the aniline substituents, and the IPr versus
IPent catalysts.
Acknowledgements
This work was supported by NSERC (Canada) and the Ontario Research
Fund (ORF, Ontario).
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ꢀ
Amination with Pd NHC Complexes
FULL PAPER
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Received: August 4, 2011
Published online: December 2, 2011
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