Amination with Pd-NHC complexes: Rate and computational studies on the effects of the oxidative addition partner

Article abstract of DOI:10.1002/chem.201002988

Pd-PEPPSI-IPent, a recently-developed N-heterocyclic carbene (NHC) complex, has been evaluated in amination reactions with secondary amines and it has shown superb reactivity under the most mildly basic reaction conditions. Rate and computational studies were conducted to provide insight into the mechanism of the transformation. The IPent catalyst coordinates to the amine much more strongly than the IPr variant, thus favouring deprotonation with comparatively weak bases. Indeed the reaction is first order in base and only slightly more than zeroth order in amine.

Full text of DOI:10.1002/chem.201002988

DOI: 10.1002/chem.201002988
Amination with Pd–NHC Complexes: Rate and Computational Studies on
the Effects of the Oxidative Addition Partner
Ka Hou Hoi,[a] SelÅuk C¸ alimsiz,[a] Robert D. J. Froese,[b] Alan C. Hopkinson,[a] and
Michael G. Organ*[a]
Pd-catalyzed amination has become an important and
widely employed method to introduce nitrogen into an or-
ganic molecule.[1] By far the most commonly used support-
ing ligands for this reaction are phosphane based;[2] consid-
erably fewer attempts have been made using N-heterocyclic
carbene (NHC)-based ligands.[3] A general mechanism for
this transformation,[4] which uses structures that are relevant
to this study, is presented in Scheme 1.
are very adept at undergoing oxidative addition even with
unactivated aryl chlorides in light of their comparatively
strong s-donating properties,[5] whereas phosphane-derived
catalysts are more sluggish in this respect. By contrast,
amine coordination is encouraged by a more electron-poor
Pd center, making phosphanes well suited for this step. Re-
cently, we illustrated that the electronic nature of the aryl
moiety of the oxidative addition partner impacts the Pd
center significantly following that step.[3d] Employing the
moderately bulky N,N-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene NHC ligand (17, Figure1, Pd-PEPPSI-IPr) in mildly
basic conditions (e.g., Cs2CO3), electron-withdrawing groups
(EWGs) led to good levels of conversion, whereas electron-
donating groups (EDGs) slowed product formation.[3d] With
NHC ligands, this would be consistent with amine-coordina-
tion (Scheme 1, 8!9) or deprotonation of the subsequent
complex (Scheme 1, 9!10) being rate limiting. Further,
KOtBu, a relatively strong base, promoted good levels of
amination seemingly irrespective of the electronic structure
of the aryl halide.[6] This illustrates that amine coordination
and deprotonation are not unrelated events. Under mildly
basic conditions, strong amine coordination to the metal is
necessary to lower the pKa of the metal ammonium salt
enough to allow deprotonation to take place. While these
reaction conditions are strongly preferred by those working
in the field, the procedure is only useful with electron-poor
aryl halides, such as aryl rings decorated with EWGs or het-
erocycles.[7]
The nature of the primary supporting ligand (depicted as
an NHC in Scheme 1) plays a crucial role in determining
which step in the cycle is rate limiting. NHC–Pd complexes
Here we have systematically evaluated the effects of
steric and electronic properties of NHC ligands on catalyst
performance and we believe that we have found a link be-
tween NHC bulk around the metal and the charge state of
the metal. With the aid of spectroscopy and calculation, we
have preliminary data to suggest that increasing the bulk
around the coordination sphere of Pd leads to an increase in
the positive charge on the metal.[8,9] Following this trend, we
have further enhanced NHC bulk with the creation of Pd-
PEPPSI-IPent (18, Figure1)[10] and investigated this effect
on amination reactions employing rate studies and computa-
tion; the results are detailed below.
Rate studies: To evaluate the above hypothesis, a rate
study was conducted (Figure1) on the amination of morpho-
line[3d,11,12] with a range of electron-poor to electron-rich aryl
chlorides using complexes 17 and 18. Clearly, the bulkier
IPent catalyst 18 significantly outperforms IPr catalyst 17.
Scheme 1. The proposed mechanism for the coupling of aryl chlorides
with morpholine (OA=oxidative addition, Dep=deprotonation, RE=
ꢀ
reductive elimination). Complex 6 (Ar Cl···Pd–NHC), which is lower in
binding energy than 5, has been omitted for clarity (see Table 1).
[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, MI, 48674 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002988.
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Chem. Eur. J. 2011, 17, 3086 – 3090

COMMUNICATION
Figure 1. Substituent effects on the reaction of morpholine with para-sub-
stituted aryl chlorides as catalysed by Pd-PEPPSI-IPr (17) and Pd-
PEPPSI-IPent (18). a) Rate study of test reaction using 17. b) Rate study
Figure 2. Effect of concentration of pNC-Ar-Cl, morpholine, and base on
amination using catalyst 17. a) Varying [pNC-Ar-Cl] ([14b]=1.0, 2.0, and
4.0 mmolmLꢀ1, respectively); 3.0 equiv of Cs2CO3. b) Varying [morpho-
line]; 3.0 equiv of Cs2CO3. c) Varying [Cs2CO3]; 1.0 equiv of 14b,
of test reaction using 18. The final [14] is 1.0 mmolmLꢀ1
.
1.5 equiv of 15. The final [14b] in runs b) and c) is 1.0 mmolmLꢀ1
.
We knew that 17 readily oxidatively adds all five aryl chlor-
ides used in this study from analogous Suzuki–Miyaura reac-
tions that we had performed, supporting the notion that oxi-
dative addition is not rate limiting (or at least not problem-
atic).[3d]
To learn something about the order of the reactants and
base, we conducted three additional studies keeping the cat-
alyst fixed (17) while varying separately the concentrations
of 14, 15, and Cs2CO3 (Figure 2).[12] Analysis was difficult as
all reactions involving morpholine (and other alkyl amines)
and the PEPPSI catalysts produced sigmoidal curves indi-
cating that catalyst activation has an induction period. As a
consequence, we looked at maximum rates, rather than ini-
tial rates, in a qualitative sense to spot trends. Surprisingly,
the rate of the reaction decreases slightly with an increase in
the concentration of the aryl chloride (Figure 2a), which fur-
ther supports the idea that oxidative addition (i.e.,
Scheme 1, 5!8) is not rate limiting. When the concentration
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3087

M. G. Organ et al.
of morpholine was increased
(Figure 2b), the maximum rate
increased slightly (doubling
morpholine concentration in-
creased the maximum rate
approx. 20%), but not suffi-
ciently to claim that amine co-
ordination (i.e., Scheme 1, 8!
9) by itself is rate limiting.
However,
increasing
the
amount of Cs2CO3 (Figure 2c),
had a much more significant
impact on the rate as we did
see an approximate doubling of
the rate when we doubled the
amount of base present. This
would support the notion that
deprotonation (i.e., Scheme 1,
9!10) is involved in the critical
step. We have conducted solu-
bility studies and found that es-
sentially no Cs2CO3 dissolves in
DME at 808C; thus we believe
Figure 3. The potential energy surface for the coupling of chlorobenzene with morpholine using the Pd-
PEPPSI-IPr (17) catalyst. Two sets of energies (kcalmolꢀ1) relative to NHC–Pd (3) are provided: bold face
numbers are free energies at 808C (solid line) and the lower set of numbers are enthalpies (dashed line).
that the deprotonation occurs at the surface of the heteroge-
neous base. This is consistent with results reported by Maes
and co-workers who saw significant differences in yield
when even different sources of the same reported quality
Cs2CO3 were used in amination studies;[7a] presumably this
points to differences in particle size and surface area. None-
theless, the result suggests that the rate is heavily influenced
by the amount of the base (i.e., deprotonation). To assess
this, the reaction in Figure 2 using 17 was repeated with two
variations: 1.5 equiv of KOtBu were used (instead of
3.0 equiv Cs2CO3) and the reaction was performed at room
temperature (instead of at 808C); the reaction completed
after just 15 s!
line is comparable to that of 3-Cl-pyridine, and given its
much greater concentration, one would expect this complex
(4) to be the resting state of the catalytic cycle, once activa-
tion is achieved. The activation process is complicated as
there are other steps than those shown here, but the mini-
mal 19.4 kcalmolꢀ1 barrier (free energy from 1!TS-7) could
slow down activation. For the bare Pd0 Ln species (3) pres-
ent during catalysis, morpholine binds by 14.4 kcalmolꢀ1 and
the pre-equilibrium relating the dissociation of morpholine
and binding of chlorobenzene is endoergonic by
4.5 kcalmolꢀ1 (4!5). This leads to an overall free energy
barrier for oxidative addition (4!7) of 17.4 kcalmolꢀ1. Due
to the strong binding of morpholine, we examined whether
oxidative addition could occur with a bound amine. Transi-
tion states were located for this process (4!TS-7’!9) and
the relative enthalpies are collected in Table 1. The enthalpy
of TS-7 is always lower than TS-7’ and these values do not
include the additional entropy associated with the binding
of morpholine that will raise the free energy of TS-7’ signifi-
cantly. We conclude that the morpholine complex (4) is the
likely resting state, but it must dissociate before oxidative
addition can occur. Similarly, the reductive elimination step
(10!TS-11!12!3+13 via) has a barrier of 12.6 kcalmolꢀ1.
Both these free energy barriers are low enough to be fast re-
actions and not reflective of a rate-limiting step that takes
on the order of hours.
Computational study: Density functional (B3LYP/
LANL2TZ(f),6-31G*) calculations were used to examine
important segments of the potential energy surface for the
aminations reported above.[13] Computationally, it is difficult
to study the deprotonation step and we have chosen to ex-
amine it qualitatively by the addition of KOtBu and the cor-
responding elimination of KCl + HOtBu. This provides a
relative measure of the susceptibility to deprotonation for
different catalyst/aryl chloride combinations.
Figure 3 depicts the potential energy surface (enthalpy
and free energy at 808C) for the Pd-PEPPSI-IPr (17)-cata-
lyzed coupling of chlorobenzene and morpholine (the same
was done for 18, not shown, see Table 1 for values). One
can consider the reaction in five steps: activation (not con-
sidered here), oxidative addition, amine adduct formation,
deprotonation, and reductive elimination with the latter
four repeated for catalysis. Introduction of the reduced pre-
catalyst (1) into the catalytic cycle requires the dissociation
of 3-Cl-pyridine, which binds more strongly to Pd than
DME or the aryl chloride. However, the binding of morpho-
Everything taken together, deprotonation would seem to
be the key step in the catalytic cycle and this was anticipated
based on Figure 2 where the [Cs2CO3] was shown to be im-
portant in the rate-limiting step. Thus with poor deprotonat-
ing agents (due to pKa or solubility), deprotonation becomes
the rate-limiting step, while with stronger deprotonating
agents, the rate-limiting step is calculated to be oxidative ad-
dition, which has a higher barrier than reductive elimina-
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Chem. Eur. J. 2011, 17, 3086 – 3090

Amination with Pd–NHC Complexes
COMMUNICATION
Table 1. DFT enthalpies (kcalmolꢀ1) relative to compound 3, Pd0 Ln. See
Scheme 1 and Figure 1 for the structures.
PEPPSI-IPr catalysts based on experiments, the reactivities
of aryl chlorides are NO2 > CN> H> CH3 > OCH3 (Fig-
ure 1a), whereas the computed deprotonation energies are
ꢀ5.6, ꢀ5.3, ꢀ4.2, ꢀ3.9, ꢀ4.1 kcalmolꢀ1, respectively, in good
agreement. Only the Pd-PEPPSI-IPr catalyzed NO2-Ph-Cl
has a reaction rate comparable to the slowest Pd-PEPPSI-
IPent reaction suggesting that the deprotonation for Pd-
PEPPSI-IPent for all substrates is at least as exothermic as
this ꢀ5.6 kcalmolꢀ1 value. Indeed, the deprotonation enthal-
pies with Pd-PEPPSI-IPent are between ꢀ7.2 kcalmolꢀ1 and
ꢀ6.1 kcalmolꢀ1.
Pd-PEPPSI-IPr (17)
ꢀ
Ar X
NO2
CN
H
CH3
OCH3
1
2
3
ꢀ24.4
ꢀ11.2
0.0
4
ꢀ24.6
ꢀ18.4
ꢀ11.9
ꢀ6.7
5[1]
6[1]
TS-7
TS-7’
8
ꢀ21.5
ꢀ12.5
ꢀ10.3
ꢀ9.0
ꢀ20.4
ꢀ12.4
ꢀ9.6
ꢀ18.0
ꢀ12.4
ꢀ6.4
ꢀ18.6
ꢀ11.9
ꢀ6.2
ꢀ7.5
ꢀ2.7
ꢀ2.4
ꢀ2.0
ꢀ34.8
ꢀ53.9
ꢀ40.4
ꢀ30.0
ꢀ57.8
ꢀ41.2
14.3
ꢀ34.3
ꢀ53.4
ꢀ39.6
ꢀ28.6
ꢀ57.0
ꢀ40.4
15.0
ꢀ31.4
ꢀ50.0
ꢀ35.6
ꢀ23.4
ꢀ55.3
ꢀ37.7
17.9
ꢀ31.1
ꢀ49.7
ꢀ35.0
ꢀ22.7
ꢀ54.6
ꢀ37.4
18.2
ꢀ30.8
ꢀ50.2
ꢀ34.9
ꢀ21.8
ꢀ54.4
ꢀ36.8
18.4
While oxidative addition and reductive elimination
appear not to be slow steps in these couplings, one can still
look at the trends associated with para substitution of the
aryl chloride as well as differences between the two cata-
lysts. For oxidative addition, strongly electron-withdrawing
groups on the aryl chloride lead to reduced barriers. In all
cases, the Pd-PEPPSI-IPent has lower barriers for oxidative
addition than Pd-PEPPSI-IPr by 0.7–0.8 kcalmolꢀ1. Rela-
tive to 3, the corresponding sets of transition states (TS-7)
for the two catalysts are almost eqi-energetic, thus the lower
barriers for Pd-PEPPSI-IPent result from a 0.7 kcalmolꢀ1
weaker binding of morpholine to this catalyst. That is, the
IPr catalyst, which coordinates morpholine more tightly
than does IPent, has a higher barrier from 4. However, the
overall oxidative energies are not in-line with the experi-
mental data, which is consistent with this step not being
rate-limiting in the overall coupling. The reductive elimina-
tion barriers are also reduced when strongly electron-with-
drawing groups reside in the para-position of the aryl part-
ner. For example for Pd-PEPPSI-IPr, these barriers are
NO2 (10.4) <CN (11.0) <H (12.2) <CH3 (12.3) <OCH3
(13.1). These results are consistent with previous work,
where faster reductive elimination rates were observed
when the aryl chloride partner had electron-withdrawing
groups (note that the opposite trend was observed for para
substitution of the amine partner, in aniline).[14] Once again,
the reductive elimination step is slightly favored (0.4–
1.2 kcalmolꢀ1) with the Pd-PEPPSI-IPent catalyst, possibly
due to a reduction in the steric interactions of the more
bulky IPent ligands.
Interestingly, while morpholine binds more tightly to IPr
3 than to IPent 3 (ca. 0.7 kcalmolꢀ1), which are both Pd0
leading to resting state 4, IPent 8 binds morpholine consider-
ably more tightly (ca. 2 kcalmolꢀ1) than does IPr 8 (both
now PdII). This much stronger binding occurs despite greatly
increased hindrance; increased positive charge on the Pd of
IPent, relative to IPr, could account for this as we have sug-
gested (vide supra). This supports our contention that de-
protonation is indeed rate limiting; this heightened coordi-
nation to PdII will assist in lowering the pKa of the resultant
metal ammonium salt to allow the weak base carbonate to
deprotonate it. Thus, if we treat amine coordination and de-
protonation as a single step, as we have needed to for the
computational treatment, we can say that the transition
state is quite late implying that coordination of alkyl amines
to Pd must be tight and therefore significantly advanced
9
10
TS-11
12
13
OA[2]
Dep[2]
RE[2]
ꢀ5.6
ꢀ5.3
ꢀ4.1
ꢀ3.9
ꢀ4.1
10.4
11.0
12.2
12.4
13.0
Pd-PEPPSI-IPent (18)
ꢀ
Ar X
NO2
CN
H
CH3
OCH3
1
2
3
ꢀ24.4
ꢀ16.0
0.0
4
ꢀ23.9
ꢀ18.9
ꢀ11.9
ꢀ6.7
5[a]
6[a]
TS-7
TS-7’
8
ꢀ22.0
ꢀ10.9
ꢀ10.4
ꢀ8.4
ꢀ20.9
ꢀ10.7
ꢀ9.7
ꢀ17.5
ꢀ11.7
ꢀ6.4
ꢀ18.6
ꢀ11.2
ꢀ6.2
ꢀ7.0
ꢀ2.2
ꢀ1.9
ꢀ1.5
ꢀ32.2
ꢀ53.1
ꢀ39.4
ꢀ30.1
ꢀ58.0
ꢀ41.2
13.5
ꢀ31.7
ꢀ52.4
ꢀ38.7
ꢀ28.7
ꢀ57.2
ꢀ40.4
14.2
ꢀ28.4
ꢀ49.2
ꢀ34.6
ꢀ23.4
ꢀ55.1
ꢀ37.7
17.2
ꢀ28.0
ꢀ48.8
ꢀ34.7
ꢀ22.6
ꢀ55.0
ꢀ37.4
17.5
ꢀ27.8
ꢀ48.9
ꢀ33.9
ꢀ22.1
ꢀ54.8
ꢀ36.8
17.7
9
10
TS-11
12
13
OA[b]
Dep[b]
RE[b]
ꢀ7.2
ꢀ7.0
ꢀ6.2
ꢀ6.7
ꢀ6.1
9.3
10.0
11.2
12.0
11.8
[a] Two different binding modes of the aryl chloride were found through
the aromatic ring (5) and the chloride (6) with the former being lower in
energy and only discussed in the figures and text. [b] OA : oxidative addi-
tion barrier from 4!7. Dep: morpholine binding and deprotonation step
from 8!10; RE: reductive elimination barrier from 10!11.
tion. However, both oxidative addition and reductive elimi-
nation have barriers that reflect reactions that should be
complete very quickly; this is exactly what was seen with
KOtBu (vide supra) where the reaction completes within a
matter of seconds.
If deprotonation is rate-limiting, one can evaluate depro-
tonation based on the thermodynamics of the process lead-
ing from 8!10. Since this step is slow, we assume the amine
binding is reversible and the energy of this binding plays a
role in its ability to be deprotonated. For this reason, we
chose to consider 8!10 rather than 9!10. The values for
different aryl chlorides and the two catalysts are collected in
Table 1. An interesting trend emerges: the reactions have
higher exothermicities for Pd-PEPPSI-IPent compared with
Pd-PEPPSI-IPr, which is consistent with the former having
a faster rate of deprotonation, thus being a more active cata-
lyst. In fact, if one assesses the relative rates of the Pd-
Chem. Eur. J. 2011, 17, 3086 – 3090
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M. G. Organ et al.
along the reaction coordinate in order for deprotonation to
become possible.
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Substrate study using Pd-PEPPSI-IPr and Pd-PEPPSI-
IPent: By using the optimized conditions in the rate studies,
a variety of especially challenging couplings of aryl halides
to secondary amines was examined. For demonstration pur-
poses, both 17 and 18 were used and the bulkier IPent-based
catalyst consistently outperformed the less hindered (and
believed to be more electron-rich) IPr system (Scheme 2).
[4] S. Shekhar, P. Ryberg, J. F. Hartwig, J. S. Mathev, D. G. Blackmond,
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Scheme 2. Sample challenging animation reactions using Pd-PEPPSI-
IPent (18). All reactions were performed in duplicate using the reaction
conditions outlined in Figure 2 and compared with Pd-PEPPSI-IPr (17).
Reactions performed using PdCl2 as a control showed no conversion to
product.
In summary, Pd-PEPPSI-IPent (18)[15] is an incredibly re-
active catalyst for the coupling of electronically-deactivated
(i.e., electron-rich) and sterically hindered aryl chlorides to
a wide array of secondary, hindered amines under very mild
conditions. Rate studies have shown that Pd-PEPPSI-IPr
(17) has a very strong dependence on the electron-with-
drawing ability of the aryl chloride while 18 is more insensi-
tive. Computational studies have shown that the difference
in catalyst performance is closely associated with amine-co-
ordination/deprotonation; thus, we conclude it to be the
rate-limiting step. While the electron-rich Pd0 complex 3
binds the amine more tightly as the IPr derivative, the IPent
complex 8, now electron-poor (i.e., PdII), binds the amine
much more strongly than the IPr analogue of 8. Both of
these factors work in concert to make the IPent catalyst
more reactive; IPent is less stable in resting state 4, thus
pushing it into the catalytic cycle, while stronger amine coor-
dination in structure IPent 9 during deprotonation decreases
the pKa of the metal ammonium salt complex and lowers
the barrier to this rate-limiting step.
[9] H. N. Hunter, N. Hadei, P. Patschinski, G. T. Achonduh, S. Avola,
M. G. Organ, unpublished NMR studies.
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[11] To ensure that there is no unique effect coming from morpholine in
these studies, the reaction rates were studied by using piperidine as
the amine with 4-chlorotoluene and the rates were essentially super-
imposable in the otherwise identical reaction with morpholine.
[12] All details of the amination reactions and rate studies are provided
in the Supporting Information.
[13] All energies discussed in the text are free energies at 808C. Details
of the computations and further energetic and structural information
are provided in the Supporting Information.
[14] a) M. Yamashita, J. V. Cuevas Vicario, J. F. Hartwig, J. Am. Chem.
Soc. 2003, 125, 16347–16360; b) J. F. Hartwig, Inorg. Chem. 2007,
46, 1936–1947.
[15] Pd-PEPPSI-IPent is now commercially available through Sigma–Al-
drich (Catalogue Number 732117).
Acknowledgements
This work was supported by NSERC (Canada) and the ORDCF (On-
tario) .
Keywords: amination
·
carbene ligands
·
catalysis
·
Received: October 17, 2010
computational chemistry · kinetics · palladium
Published online: February 14, 2011
3090
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Chem. Eur. J. 2011, 17, 3086 – 3090