Rate and Computational Studies for Pd-NHC-Catalyzed Amination with Primary Alkylamines and Secondary Anilines: Rationalizing Selectivity for Monoarylation versus Diarylation with NHC Ligands

Article abstract of DOI:10.1002/chem.201903362

The relative rates of arylation of primary alkylamines with different Pd-NHC catalysts have been measured, as have the relative rates of arylation of the secondary aniline product in an attempt to understand the key ligand design features necessary to have high selectivity for the monoarylated amine product. As the substituents on the N-aryl ring of the NHC increase in size, selectivity for monoarylation increases and this is further enhanced by chlorinating the back of the NHC ring. Computations have been performed on the catalytic cycle of this transformation in order to understand the selectivity obtained with the different catalysts.

Full text of DOI:10.1002/chem.201903362

DOI: 10.1002/chem.201903362
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Catalysis |Hot Paper|
Rate and Computational Studies for Pd-NHC-Catalyzed Amination
with Primary Alkylamines and Secondary Anilines: Rationalizing
Selectivity for Monoarylation versus Diarylation with NHC Ligands
Christopher Lombardi,[a] Richard P. Rucker,[a] Robert D. J. Froese,[b] Sepideh Sharif,[a, d]
Pier Alexandre Champagne,[c, d] and Michael G. Organ*[a, d]
Abstract: The relative rates of arylation of primary alkyl-
amines with different Pd-NHC catalysts have been measured,
as have the relative rates of arylation of the secondary ani-
line product in an attempt to understand the key ligand
design features necessary to have high selectivity for the
monoarylated amine product. As the substituents on the N-
aryl ring of the NHC increase in size, selectivity for monoaryl-
ation increases and this is further enhanced by chlorinating
the back of the NHC ring. Computations have been per-
formed on the catalytic cycle of this transformation in order
to understand the selectivity obtained with the different cat-
alysts.
Introduction
Anilines can be found throughout many important industrial
applications making their preparation of great importance to
synthetic chemists.[1] As such, several methods have been de-
veloped for the stoichiometric[2–4] and catalytic[5–7] preparation
of primary, secondary, and tertiary anilines. In particular, the
palladium-catalyzed amination of aryl halides, commonly re-
ferred to as the Buchwald-Hartwig amination,[8–10] enjoys prom-
inence as one of the most robust and generally applicable pro-
tocols for the synthesis of anilines.[11,12]
The catalytic cycle for Pd-mediated amination has been pro-
posed to follow one of two paths (Figure 1).[13,14] Oxidative ad-
dition (OA) of an Ar-X to Pd0 (6) creates intermediate 1. Coordi-
nation of an amine to 1 in Pathway I creates amine complex 2,
which following intermolecular deprotonation leads to metal
amido complex 3. Conversely, ligand exchange of 1 with tert-
butoxide leads to 7 (Pathway II), which after amine coordina-
tion (8), can now undergo an intramolecular proton transfer to
Figure 1. Palladium-catalyzed amination catalytic cycle. Structures are meant
to show constitution only (hence squiggly lines); no geometry is to be infer-
red from structures.
[a] C. Lombardi, Dr. R. P. Rucker, Dr. S. Sharif, Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele St, Toronto, ON M3J 1P3 (Canada)
E-mail: organ@yorku.ca
deliver 3. Reductive elimination (RE) of the amide and aryl
partner via transition state 4 delivers the product (5), while re-
ducing PdII back to Pd0 (6), thus completing the cycle. As the
understanding of the role(s) played by ancillary ligands on
each step in this transformation has become clearer, significant
advances in the overall process have been realized.[15–18]
[b] Dr. R. D. J. Froese
Core R&D, The DOW Chemical Company, Midland, MI 48647 (USA)
[c] Prof. P. A. Champagne
Department of Chemistry and Environmental Science
New Jersey Institute of Technology, Newark, NJ 07102 (USA)
N-heterocyclic carbenes (NHC) have been pursued as ligands
for transition-metal catalysis due to their ease of synthesis, air
and moisture stability, and powerful s-donating capabili-
ties.[19–23] In contrast to monodentate phosphine ligands, which
project their steric bulk away from the metal center, NHC li-
gands project inward to the metal center.[24] This increased
steric bulk renders the metal less susceptible to oxidation and
[d] Dr. S. Sharif, Prof. P. A. Champagne, Prof. M. G. Organ
Centre for Catalysis Research and Innovation (CCRI)
Department of Chemistry and Biomolecular Sciences
University of Ottawa, 75 Laurier Ave East, Ottawa, ON, K1N 6N5 (Canada)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.201903362.
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also can increase the rate of RE.[25] These desirable properties
have attracted interest from researchers wishing to improve
the overall scope and efficiency of palladium-catalyzed amina-
tion.
Table 1. Effect of reactant and catalyst concentration on the rate of reac-
tion with octylamine nucleophile.[a]
A wealth of information exists for the systematic variation of
phosphine ligand structure and its impact on catalytic activi-
ty,[26–28] but comparably little information is available for NHC li-
gands. To further complicate matters, the arylation of primary
amines can give either desired secondary (mono-coupled) or
undesired tertiary (di-coupled) aniline products, thus selectivity
is of paramount importance in these reactions. Although we[16]
and others[29–32] have presented kinetic data for amination
using secondary amines catalyzed by Pd-NHC complexes, there
are no reports on the kinetics and selectivity of amination of
primary aliphatic amines using the same or related catalysts.
Herein, we present kinetic data to examine the effect of ligand
structure on the overall rate and selectivity of palladium-cata-
lyzed amination of primary alkylamines using Pd-PEPPSI
(PEPPSI=pyridine-enhanced precatalyst preparation, stabiliza-
tion, and initiation) precatalysts (Figure 2).
Catalyst
[mol%]
4-Chloroanisole NaOtBu
Octylamine Initial Rate
[m]
[m]
[m]
[msÀ1
]
1
2
3
4
5
6
7
8
9
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
1.5
0.1
0.2
0.05
0.1
0.1
0.1
0.1
0.1
0.1
0.115
0.115
0.115
0.115
0.115
0.173
0.058
0.115
0.115
0.11
0.11
0.11
0.22
0.055
0.11
0.11
0.11
0.11
1.2ꢁ10À4
1.2ꢁ10À4
1.2ꢁ10À4
1.3ꢁ10À4
1.3ꢁ10À4
1.8ꢁ10À4
6.3ꢁ10À5
6.2ꢁ10À5
1.8ꢁ10À4
[a] Percent conversion was measured by 1H NMR spectroscopy of the reac-
tion mixture using an internal standard. Reactions and analyses were per-
formed in duplicate.
way I) or one of the steps of the ligand exchange route
(Figure 1, Pathway II) to be rate-determining. When the con-
centration of NaOtBu was changed, a proportional change (i.e.,
first order dependence) in the rate of reaction was observed
(entries 1, 6, and 7).
In a similar fashion, we examined dependencies in the
second coupling of the N-octyl-N-arylamine nucleophile
(Table 2). The reaction again showed a zeroth-order depend-
ence (entries 1, 2 and 3) in amine (now a secondary aniline)
whereas the NaOtBu (entries 1, 4 and 5) now showed a very re-
duced role in the observed rate (slightly above zeroth-order).
Of note, both reactions (Table 1, entries 1, 8 and 9 and Table 2,
entries 1 and 6) show first order kinetics in the catalyst (12).
The relative rates for the amination reaction between 4-
chloroanisole and octylamine (Reaction A, monoarylation vs.
Reaction B, diarylation) using different precatalysts are present-
ed in Table 3. Comparing entries 1, 3 and 5, one can see that
Figure 2. Pd-PEPPSI precatalysts used in this amination study.
Results and Discussion
The model reaction chosen for this study was the amination of
electron-rich 4-chloroanisole with octylamine (Table 1). This
particular transformation has been reported to be catalyzed by
a number of mono- and bidentate phosphines[33À36] with mod-
erate to high selectivity for monoarylation. Using Pd-PEPPSI-
IPentCl (12), the coupling was found to be zeroth-order in 4-
chloroanisole (entries 1–3), meaning that OA is not rate-deter-
mining. NHC ligands are strong s-donors, which facilitates OA
with substrates that are electronically deactivated (i.e., elec-
tron-rich), such as 4-chloroanisole.[15] We recently reported the
first successful Pd-mediated cross-coupling at À788C, further il-
lustrating this point.[37,38]
Table 2. Effect of amine and base concentration on the initial rate of reac-
tion with N-octyl-N-arylamine nucleophile.[a]
Catalyst [mol%] N-Octyl-N-arylamine [m] NaOtBu [m] Initial rate [msÀ1
]
1
2
3
4
5
6
1.0
1.0
1.0
1.0
1.0
0.5
0.1
0.1
0.1
0.1
0.15
0.05
0.1
8.9ꢁ10À5
9.7ꢁ10À5
8.9ꢁ10À5
9.2ꢁ10À4
7.8ꢁ10À5
4.2ꢁ10À5
0.15
0.05
0.1
0.1
0.1
When we looked at the concentration of the amine partner
the reaction was found to be zeroth-order in octylamine sug-
gesting coordination of N-alkylamines to aryl palladium com-
plex 2 is not a significant factor in the overall reaction rate (en-
tries 1, 4 and 5). In light of the above rate data, this leaves RE
(3 to 5) or either deprotonation leading to 3 (Figure 1, Path-
[a] Percent conversion was measured by 1H NMR spectroscopy of the reac-
tion mixture using an internal standard. Reactions and analyses were per-
formed in duplicate.
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with the relatively fast first arylation, there was no formation of
the diarylated product detected in the product mixture with
15 under these reaction conditions.
Table 3. Rate of reaction for different Pd-NHC catalysts.[a]
Computational Study
In order to gain further insight into the catalytic process, we
conducted DFT calculations for Pathways I and II (see Figure 1)
using the computational models ethylamine, N-ethyl-N-phenyl-
amine, and chlorobenzene with catalyst 12, as this catalyst
demonstrated high selectivity (Scheme 1) and can be more
readily modeled computationally than 13, 14, or 15.
Cat. Rate [msÀ1] for Reaction Rate [msÀ1] for reaction Selectivity
A (t = A in min.)
B (t = B in min)
(mono:di)[b]
1
1
2
2
1
2
3
4
5
6
7
9
1.7ꢁ10À5 (65)[b]
1.0ꢁ10À4 (8.6)
4.8ꢁ10À4 (1.6)
2.2ꢁ10À4 (3.8)
8.1ꢁ10À5 (12)
1.8ꢁ10À4 (2.9)
4.5ꢁ10À5 (25)[c]
8.6ꢁ10À6 (165)
0.8:1
1.0:1
4.4:1
20:1
8.0:1
16:1
10 2.9ꢁ10À5 (36)
11 2.4ꢁ10À5 (40)
12 1.1ꢁ10À4 (8.0)
13 1.4ꢁ10À5 (58)[b]
14 4.8ꢁ10À5 (19)
15 8.9ꢁ10À5 (10)
>99:1
[a] Percent conversion and selectivity were measured by 1H-NMR spectros-
copy of the reaction mixture using an internal standard. Reactions and anal-
yses were performed in duplicate. [b] This selectivity is derived from Reac-
tion A. [c] The initial rate measured did not intersect the origin owing to a
slight induction period (see Supporting Information), thus the maximum
rate is reported.
increasing the length of the alkyl chains of the N-aryl moiety
on the NHC has an initial positive effect on rate, but then
slows the reaction for Pd-PEPPSI-IHept (13). Selectivity for
monoarylation of these same catalysts increases significantly as
the catalyst gains steric bulk from lengthening the N-aryl alkyl
chains.
Comparing chlorinated versus non-chlorinated NHC cores
(e.g., entry 3 vs. 4 and 5 vs. 6), there is a dramatic increase in
rate and selectivity for monoarylation. Again, increasing alkyl
chain length to 4-heptyl (i.e., Pd-PEPPSI-IHeptCl, 14) causes
both reactions (A and B) to slow relative to Pd-PEPPSI-IPentCl
(12) (entry 4 vs. entry 6). Counterintuitively, the selectivity for
monoarylation is slightly lower for Pd-PEPPSI-IHeptCl (14) than
Pd-PEPPSI-IPentCl (12). One might have anticipated that since
14 is the bulkier catalyst, and presumably better able to dis-
criminate coordination/deprotonation of octylamine over the
larger, less basic aniline product, that the two steps would
have been more different in rate than with 12 leading to
better mono selectivity, but there appear to be more factors at
work here.
Scheme 1. Calculated Pathways I and II for the reaction of ethylamine and
chlorobenzene (computational models) with Pd-PEPPSI-IPentCl (12). a) First
arylation of ethylamine; b) Second arylation of N-ethylaniline. Free energies
(in kcalmolÀ1) were obtained at the B3LYP-D3/6-31G(d)/LANL2TZ(F)(Pd)/
CPCM(PhMe)// B3LYP-D3/6–311+G(d,p)/ LANL2TZ(F)(Pd)/SMD(PhMe) level of
theory.
Entry 7 shows the results for highly branched complex 15,
which was recently used for the selective monoarylation of
ammonia.[39] This catalyst was able to catalyze the monoaryla-
tion reaction (Reaction A) faster than Pd-PEPPSI-IHeptCl (14),
which is unexpected. It appeared the smaller Pd-PEPPSI-IPentCl
(12) had the ideal steric/electronic properties for this reaction
based on the discussion above regarding Pd-PEPPSI-IHeptCl
(14) and anything larger would make it slower. This is indeed
the case for the second arylation with 15 where the rate was
much slower than all of the other catalysts (entry 7). Combined
Assuming direct insertion of Pd into the PhCl bond during
OA, square-planar intermediate 16 or its isomer with the Cl
and phenyl groups switched would be formed initially. The
latter structure is unlikely as it is 13.1 kcalmolÀ1 less stable (see
Supporting Information). Further, the structure with the Cl and
phenyl groups cis to the NHC (and an empty coordination site
trans from the NHC) spontaneously rearranges to 16. This
leaves the monoalkylamine (Scheme 1a) to bind to the remain-
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ing coordination site cis to the NHC ligand of 16 leading to
17a (Pathway I), which is mildly exergonic (À0.6 kcalmolÀ1).
Being that the amine and aryl ring must be cis to ultimately
undergo RE, isomerization must occur. If we presume that iso-
merization occurs prior to deprotonation, then isomer 18a re-
sults, which is 6.7 kcalmolÀ1 more stable. Deprotonation to
provide 19a is endergonic (10.4 kcalmolÀ1) and under the
warm reaction conditions, would quickly undergo RE. Collec-
tively, this potential energy surface (PES) is in line with the fact
that the reaction is first-order in base as it has a role to play in
between the resting state (18a) and rate-limiting RE TS 20a.
If instead ligand exchange from 16 to 21 occurs, that is,
swapping tert-butoxide for chloride this leads to Pathway II
(also see Figure 1). Intramolecular deprotonation from 22a
yields 19a, which now renders deprotonation mildly exergonic
compared to Pathway I, but RE occurs just the same. In this
case the maximum single barrier to overcome is only 17.4 kcal
ity is essentially a fork in the road of the reaction mechanism,
as is the case, for example, in enantioselective transformations
where a reaction either takes place on one face of a complex
or the other.
If stoichiometry of the OA partner and the alkylamine are
close to 1:1, which would be the operationally desired situa-
tion, there will only be monoarylation at the beginning, while
closer to the end of the reaction there is primarily monoaryl-
amine (i.e., aniline) present and little alkylamine. To achieve
20:1 overall selectivity, the alkylamine must be equally compet-
itive with the arylamine at ꢀ90% conversion, presuming that
only monoarylation has occurred up to that point in the trans-
formation. At this point there would be 9 times as much ani-
line present relative to alkylamine. Something very profound
must be favoring monoarylation for the reaction to even pro-
vide 50/50 selectivity during the final 10% conversion, that is,
through to complete consumption of the OA partner.
molÀ1
.
A closer look at the computational data may yield a clue as
to why Pd-PEPPSI-IPentCl (12) is so strongly selective for mono-
arylation, despite the kinetics above. If one views the PES’s as
being fully separate and assumes complete reversibility, the
PES diagrams actually are close to being in line with the kinetic
data, that is, little to no selectivity. If one looks at the maxi-
mum barrier in Pathway I, the lower energy Pathway for
PES (a) and (b), it is RE in both cases and the values are almost
identical (17.4 vs. 17.1 kcalmolÀ1). This would imply no selectiv-
ity, however we know that the base is first order in the aryla-
tion with the alkylamine, so the real barrier in PES (a) would be
deprotonation plus RE (18a to 20a), or 24.7 kcalmolÀ1. This
would suggest that diarylation would actually be favored
almost exclusively, yet we know the opposite is the case. So,
this analysis cannot be used to explain the observed selectivi-
ty.
The second arylation of N-ethyl-N-phenylaniline (over aryla-
tion) was also studied (Scheme 1b) and now the amine, an ani-
line, is much bulkier while at the same time much less basic/
nucleophilic. Whereas binding of ethylamine in PES a) was
mildly exergonic (À0.6 kcalmolÀ1), coordination of the N-ethyl-
N-phenylamine to produce 17b is strongly endergonic
(ꢀ14.6 kcalmolÀ1). Isomerization to 18b is favored as is depro-
tonation, which would be expected as the proton is now close
to ten orders of magnitude more acidic than its alkylamine
counterpart in PES (a). The barrier to RE (18.6 kcalmolÀ1) is no-
tably larger than for the first arylation in PES (a) (14.3 kcal
molÀ1). It might have been reasonable to anticipate RE in
PES (b) to be smaller than in PES (a) from the perspective of re-
lieving strain. However, as this is a reductive step, the dimin-
ished reducing potential of an aniline, relative to an alkyl
amine, may be the feature that governs this relative ranking.
To undergo Pathway II in PES b) (also see Figure 1) the bulky
amine would have to bind cis to the large NHC ligand in 21,
which now has the already bulky tert-butoxide moiety on it
leading to a very high energy intermediate (22b). This com-
pound can then rearrange to the more stable isomer 23. As
22b and 23 are required structures on the way to 19b from
Pathway II, the minimum barrier is significantly higher than for
Pathway I. This means that the reaction of N-ethyl-N-phenylani-
line with Pd-PEPPSI-IPentCl (12) therefore also goes through
Pathway I.
Of course, the reaction follows steady-state kinetics of the
two amination processes, that is, the reactions are not happen-
ing in the absence of one another. It is reasonable therefore to
assume that 18a is not only the resting state of PES (a), it is
the global resting state for the entire transformation. When 16
forms in the presence of even a small amount of ethylamine,
18a should form instantaneously as the global resting state.
From there, there are two ways for the molecule to go for-
ward. Either it gets deprotonated to form 19a (10 kcalmolÀ1
“barrier” that is easy under the reaction conditions in this
study) or it goes back to 16 and then forward to 17b (a collec-
tive 22 kcalmolÀ1 “barrier”) where it finally ends up at 19b. If
there is a complete and free equilibrium, the highest barrier
for monoarylation should be 24.7 kcalmolÀ1 (À7.3 to 17.4 kcal
molÀ1), and the highest barrier for diarylation 24.4 kcalmolÀ1
(À7.3 to 17.1 kcalmolÀ1). Thus, interleafing PES (a) and (b)
would predict a 1:1 mixture over the course of the reaction;
more monoarylation at the start of the reaction, more diaryla-
tion at the end. Again, in practice, this is nothing close to what
is observed in the actual transformation.
Explaining the origin of monoarylation selectivity with Pd-
PEPPSI-IPentCl (12)
It is intriguing that amine arylation with catalyst 12 is so pro-
foundly selective, yet neither rate studies nor computations, at
first glance, would predict anything even close to the selectivi-
ty observed. In Table 3 the initial rate of the first arylation (of
octylamine) is only 1.35 times that of N-ocytyl-N-(4-methoxy-
phenyl)amine, yet the observed selectivity is 20:1 (>95%
monoarylated product). Of course, one is dealing here with
steady-state kinetics, that is, the product of the first reaction is
necessary for the second one. This is not a case where selectiv-
In order to explain the observed selectivity, one has to make
the argument that deprotonation is, in fact, not reversible.
Under the actual reaction conditions of the transformation this
can be rationalized. The relatively non-polar reaction solvents
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that this reaction is performed in (e.g., benzene, toluene)
would cause the salt byproducts that are formed during de-
protonation (e.g., NaCl) to precipitate out of solution. Certainly,
the reactions take on a slurry appearance as they proceed that
would be consistent with this hypothesis. In this case, going to
19a from 18a only takes 10.4 kcalmolÀ1, while going to 18b
from 18a takes 22.0 kcalmolÀ1, a much more significant
hurdle. This barrier is easily crossed at the reaction’s tempera-
ture (i.e., ꢀ608C), but 18b is 7.5 kcalmolÀ1 less stable than
18a. Thus, only when there is a large excess of aniline can we
expect 18b to form in any significant amount.
Our calculations also indicate that the complexes 9–11 in
the catalyst family have notably lower steric bulk. This makes
the amine exchange reaction (going from 18a to 18b) faster,
meaning the aniline can compete with the alkylamine for bind-
ing much earlier in the transformation, resulting in more diaryl-
ation relative to 12 (see Supporting Information). Interestingly,
catalyst 12 is the only catalyst in the series for which formation
of 18b in endergonic from 16, meaning dissociation of the ani-
line is favorable even after the barrier for the formation of 17b
is crossed. This can further explain why monoarylation is so
much preferred with 12.
amine is acting to “inhibit” the second arylation, which normal-
ly completes in hours. We believe that these results are consis-
tent with intermediate 18a (Scheme 1) acting as the global
resting state for the entire catalytic process and that this com-
plex can only poison the second coupling if its deprotonation
is irreversible.
The final element of selectivity to explain is why the chlori-
nated NHC cores are so much more selective than their non-
chlorinated counterparts. Pd-PEPPSI-IHeptCl (14) is twice as se-
lective as Pd-PEPPSI-IHept (13) for monoarylation and Pd-
PEPPSI-IPentCl (12) is four times as selective as Pd-PEPPSI-IPent
(11) (Table 3, entries 3–6). While the presence of the chlorines
does render the metal center more electron deficient,[40] which
would hasten all steps in the catalytic cycle, we believe that
the principal effect is steric in origin. We have previously dem-
onstrated that selectivity between RE and beta-hydride elimi-
nation in the coupling of secondary alkyl nucleophiles is under
strong steric influence.[25,41,42] We found that both the bis
chlorinated (10) and bis methylated versions of Pd-PEPPSI-IPr
gave exactly the same level of selectivity for RE, which was 15
times greater than the parent bis hydrogen structure (i.e., 9).
In that case, we attributed the more sterically demanding 4-
membered-ring transition state for beta-hydride elimination
(vs. the 3-membered ring of RE) to be the key feature. Similarly,
here we believe that the chlorines push the N-aryl rings for-
ward toward Pd, and this adds an additional discrimination ele-
ment to discourage the aniline product from coordinating to
the oxidative addition intermediate, which leads to increased
monoarylation selectivity.
To see if we could obtain additional support for the above
hypothesis we performed a competition experiment between
octylamine and N-octyl-N-phenyl amine (1:1) with a limiting
amount (10%) of OA partner (Scheme 2). This will give an ac-
Conclusions
In summary, we have developed a family of bulky NHC ligands
featuring chlorinated NHC cores with N-aryl-substituted
branched alkyl chains of increasing length. Progressing from
smaller to larger in this ligand family increases the proportion
of the desired monoarylation of alkylamines. Taken independ-
ently, the measured initial rates of mono- versus di- (over) aryl-
ation predict that arylation of alkylamines using Pd-PEPPSI-
IPentCl (12) would be moderate at best; in actuality it is pro-
foundly selective (e.g., >20:1 mono:diarylation). Similarly, cal-
culations of the PES for both mono and diarylation, from an
alkyl- and aryl-amine, respectively, also predict low selectivity if
one assumes a Curtin–Hammett regime of complete reversibili-
ty.
Scheme 2. Competition experiment between octylamine and N-octyl-N-(4-
methoxyphenyl)amine for a limiting amount (10%) of p-chloroanisole using
Pd-PEPPSI-IPentCl (12).
curate view of selectivity for monoarylation at the beginning
of the transformation (i.e., the first 10% of conversion) because
we know that both mono- and diarylation are zeroth-order in
aryl halide, so reducing its concentration should have minimal
bearing on kinetics or selectivity. This would put the relative ki-
netics of the mono- and diarylation in the same flask on full
display. When performed independently the rate of monoaryla-
tion is only 1.35 times faster than diarylation (Table 3). Even
under steady-state conditions in the competition experiment a
notable amount of diarylation, conceivably as much as 40%
based on independent rates, would be expected assuming
complete microscopic reversibility. In practice (Scheme 2), no
diarylated product forms.
For the above reasons, we propose that the amine arylation
under our reaction conditions is, overall, not a reversible pro-
cess. More specifically, we believe that under non-polar reac-
tion conditions salt byproducts crystallize out of solution
making deprotonation irreversible. While deprotonation to
19a is not favored (ꢀ10 kcalmolÀ1) relative to returning to OA
intermediate 16 (ꢀ7 kcalmolÀ1), it is much more favored than
accessing 19b from global resting state 18a (ꢀ22 kcalmolÀ1).
Thus, we propose that it is a combination of the bulk of the
NHC ligand, which makes aniline coordination especially unfav-
orable, and irreversible deprotonation of 18a that make the re-
action highly selective for monoarylation using catalyst 12.
By itself, arylation of N-octyl-N-phenyl amine is not a slow
process, yet none occurs in the presence of octyl amine when
limited aryl halide is employed. Clearly, the presence the alkyl
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J=7.2 Hz, 2H), 1.31–1.42 (m, 10H), 0.92 (t, J=6.8, 3H); 13C-NMR
(100 MHz, CDCl3) d 152.0, 142.9, 114.9, 114.0, 55.8, 45.1, 31.9, 29.7,
29.5, 29.3, 27.3, 22.7, 14.1. The spectral data of the major monoal-
kylated product are in accordance with those reported in the litera-
ture.[43]
Consistent with this hypothesis, when the NHC bulk is even
further exacerbated leading to catalyst 15 we no longer see
any diarylated products. Finally, while it has been proposed
that ligand exchange of tert-butoxide for the halogen on the
metal (Figure 1, Pathway II, 1–7; or Scheme 1, Pathway II on
PES (a) or (b), 16–21) can occur in amine arylation, we do not
believe this Pathway is operative, at least under the reaction
conditions reported in this manuscript using bulky NHC li-
gands.
Representative rate study procedure: In a glove box, an oven-
dried argon filled vial (8 mL) containing a Teflon coated magnetic
stir bar was charged with 44.2 mg of NaOtBu (0.46 mmol,
1.15 equiv.). The flask was sealed with a Telfon coated screw cap
and removed from the glove box. Then, in air, 3.4 mg of Pd-
PEPPSI-IPentCl (0.004 mmol, 1.0 mol%) and 33.4 mg of hexamethyl-
benzene (0.2 mmol) were added to the vial. The vial was then
sealed with a Teflon coated screw cap and backfilled with argon
three times. Then, benzene-d6 (4.0 mL), 49.0 mL of 4-chloroanisole
(0.4 mmol, 1.0 equiv.) and 72.7 mL of octylamine (0.44 mmol,
1.1 equiv.) were added via syringe. The vial was then placed in a
pre-heated oil bath at 608C and stirred. 50 mL samples were taken
via an argon purged syringe and quenched in 08C deuterated
chloroform. The samples were kept at 08C until the end of the rate
Experimental Section
General
All experiments were conducted under an atmosphere of dry
argon in oven-dried glassware using standard Schlenk techniques.
Experiments performed in an oil bath were done using Fisher Sci-
entific silicone oil in a Pyrex crystallizing dish on top of an IKA RCT
basic model magnetic hotplate stirrer with an ETS-D5 electronic
contact thermometer. Glovebox manipulations were performed in
an MBraun Unilab glove-box under an atmosphere of dry argon.
All reagents were purchased from Sigma–Aldrich or Alfa Aesar and
were used without further purification unless noted otherwise. Pre-
catalysts were acquired from Total Synthesis Ltd., Toronto, Canada.
All reaction vials (screw-cap threaded, caps attached, 15ꢁ45 mm)
were purchased from Fisher Scientific. Analytical thin layer chroma-
tography (TLC) was performed on EMD 60 F254 pre-coated glass
plates and spots were visualized with UV light (254 nm). Column
chromatography purifications were carried out using the flash
technique on ZEOprep 60 silica gel (40–63 mm). Toluene was dis-
tilled under argon over CaH2 prior to use. Benzene-d6 was dried
over 4 ꢂ molecular sieves and freeze-pump-thawed three times
prior to use. NMR spectra were recorded on a Bruker 400 AVANCE
spectrometer using hexamethylbenzene as internal standard to de-
1
reaction and promptly analyzed by H-NMR spectroscopy.
Acknowledgements
This work was supported by NSERC Canada in the form of a
CRD grant and by the Eli Lilly Research Award Program (LRAP).
Conflict of interest
Authors in this publication receive royalty payments from
some of the catalysts used in this manuscript.
Keywords: amination · catalysis · cross-coupling · PEPPSI · rate
study · selective
1
1
termine H-NMR conversions. The chemical shifts for H-NMR spec-
tra are given in parts per million (ppm) referenced to the residual
proton signal of the deuterated solvent; coupling constants are ex-
pressed in Hertz (Hz). 13C-NMR spectra were referenced to the
carbon signal(s) of the deuterated solvent. The following abbrevia-
tions are used to describe peak multiplicities: s=singlet, br s=
broad singlet, d=doublet, t=triplet, q=quartet, quint=quintet,
dd=doublet of doublets, tt=triplet of triplets, qt=quartet of trip-
lets, qd=quartet of doublets, and m=multiplet.
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Procedure for the synthesis of 4-methoxy-N-octylaniline: An
oven-dried argon filled round bottom flask (100 mL) containing a
Teflon coated magnetic stir bar was charged with 21.5 mg of Pd-
PEPPSI-IPentCl (0.025 mmol, 0.5 mol%), 529 mg of NaOtBu
(5.5 mmol, 1.1 equiv.). The flask was sealed with a rubber septum
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4-chloroanisole (5 mmol, 1.0 equiv.) and 0.99 mL of octylamine
(6 mmol, 1.2 equiv.) were then added via syringe. The flask was
then placed in a pre-heated oil bath at 608C and stirred for 1 hour.
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1
Rf =0.3) to yield 1.04 g of the desired product as a yellow oil. H-
NMR (400 MHz, CDCl3) d 6.80 (d, J=9.2 Hz, 2H), 6.59 (d, J=9.0 Hz,
2H), 3.76 (s, 3H), 3.30 (bs, 1H), 3.07 (t, J=7.2 Hz, 2H), 1.62 (quint,
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Manuscript received: July 23, 2019
Revised manuscript received: September 1, 2019
Version of record online: && &&, 0000
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FULL PAPER
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Catalysis
C. Lombardi, R. P. Rucker, R. D. J. Froese,
S. Sharif, P. A. Champagne, M. G. Organ*
&& – &&
Rate and Computational Studies for
Pd-NHC-Catalyzed Amination with
Primary Alkylamines and Secondary
Anilines: Rationalizing Selectivity for
Monoarylation versus Diarylation with
NHC Ligands
Bulky Pd-PEPPSI precatalysts perform
arylation of alkyl amines with high fidel-
ity for the mono coupled product and
staunchly avoids (over) arylating the
product aniline. This observation is a
consequence of two key features: for-
mation of global resting state A, and ir-
reversible deprotonation of A pushing
the mechanism through to reductive
elimination.
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