Bulky alkylphosphines with neopentyl substituents as ligands in the amination of aryl bromides and chlorides

Article abstract of DOI:10.1021/jo060303x

Di(tert-butyl)neopentylphosphine (DTBNpP) in combination with palladium sources provided catalysts with comparable or better activity for the Hartwig-Buchwald amination of aryl bromides than tri(tert-butyl)phosphine (TTBP) under mild conditions. DTBNpP also provided effective catalysts for amination reactions of aryl chlorides at elevated temperatures. Further replacement of tert-butyl groups with neopentyl substituents resulted in less effective ligands for amination reactions. Computationally derived cone angles showed that replacement of a tert-butyl group with a neopentyl group significantly increased the cone angle of the phosphine. The larger cone angle of DTBNpP than TTBP appears to correlate with the higher activity of catalysts derived from DTBNpP in the amination of aryl bromides. TTBP is a stronger electron donor than DTBNpP, which may explain the higher activity for TTBP-derived catalysts toward aryl chlorides.

Full text of DOI:10.1021/jo060303x

Bulky Alkylphosphines with Neopentyl Substituents as Ligands in
the Amination of Aryl Bromides and Chlorides
Lensey L. Hill,† Lucas R. Moore,† Rongcai Huang,† Raluca Craciun,† Andrew J. Vincent,†
David A. Dixon,*,† Joe Chou,‡ Christopher J. Woltermann,‡ and Kevin H. Shaughnessy*,†
Department of Chemistry, The UniVersity of Alabama, Box 870336, Tuscaloosa, Alabama 35487-0336, and
FMC Corporation, Lithium DiVision, Highway 161, Box 795, Bessemer City, North Carolina 28016-0795
kshaughn@bama.ua.edu
ReceiVed February 14, 2006
Di(tert-butyl)neopentylphosphine (DTBNpP) in combination with palladium sources provided catalysts
with comparable or better activity for the Hartwig-Buchwald amination of aryl bromides than tri(tert-
butyl)phosphine (TTBP) under mild conditions. DTBNpP also provided effective catalysts for amination
reactions of aryl chlorides at elevated temperatures. Further replacement of tert-butyl groups with neopentyl
substituents resulted in less effective ligands for amination reactions. Computationally derived cone angles
showed that replacement of a tert-butyl group with a neopentyl group significantly increased the cone
angle of the phosphine. The larger cone angle of DTBNpP than TTBP appears to correlate with the
higher activity of catalysts derived from DTBNpP in the amination of aryl bromides. TTBP is a stronger
electron donor than DTBNpP, which may explain the higher activity for TTBP-derived catalysts toward
aryl chlorides.
Introduction
The palladium-catalyzed coupling of aryl halides with amines
and other nitrogen derivatives developed by Hartwig and
Buchwald (Hartwig-Buchwald (H-B) coupling) has become
widely used in organic synthesis as well as in fine chemical
manufacturing of pharmaceutical precursors, electronic materi-
als, and agricultural chemicals.1-5 While the initial catalyst
systems developed for aryl amination were based on mono- and
bidentate triarylphosphines, recent research has shown that
† University of Alabama.
‡ FMC Corporation.
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FIGURE 1. Commonly used ligands in H-B amination reactions.
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electron-rich, sterically demanding ligands, such as trialkyl-
phosphines (i.e., 1, 2, Figure 1),6-12 dialkylphosphinous acids,13
dialkylarylphosphines (i.e., 3, 4),8,14-21 bicyclic triaminophos-
phines (5),22-24 and imidazol-2-ylidenes and imidazolin-2-
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10.1021/jo060303x CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/03/2006
J. Org. Chem. 2006, 71, 5117-5125
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Hill et al.
ylidenes (6),8,25-29 provide optimal activity and generality for
the H-B coupling reaction. Sterically demanding ligands pro-
mote ligand dissociation, which is the rate-limiting step in the
oxidative addition of aryl bromides to L2Pd0 complexes (L )
sterically demanding alkylphosphine), while it is a reversible
step prior to rate-limiting oxidative addition of aryl chlorides.30
Electron-rich ligands promote oxidative addition, which is
particularly important with less reactive aryl bromides and
chlorides. Oxidative addition is the rate-limiting step in the
amination of aryl halides.31
While it is clear that a combination of steric demand and
strong electron-donating ability in the ligand provides highly
active catalysts for the H-B amination and other palladium-
catalyzed cross-coupling reactions, the relative importance of
these elements has not been carefully examined. We have
recently reported a study of the roles of steric and electronic
ligand parameters in determining catalyst activity in the aqueous-
phase Suzuki-Miyaura coupling of aryl bromides.32 Compu-
tationally determined cone angles were found to be a good
predictor of catalyst activity, while ligand electronic parameters
FIGURE 2. Bulky alkylphosphine ligands employed in this work.
determined from the CO stretching frequencies of LNi(CO)3
complexes gave a poor correlation with activity. We are thus
interested in how these findings might relate to other syntheti-
cally important cross-coupling reactions. In addition, we sought
to explore ligands with even larger cone angles than those
explored in our previous studies.
We were motivated to explore neopentyl-substituted phos-
phines for several reasons. Di-tert-butylneopentylphosphine
(DTBNpP, Figure 2), which will soon be available in bulk
scale,33 can be easily handled as a 10% solution or as an air-
stable phosphonium salt and is economically competitive with
other ligands, since it is not encumbered by licensing issues.
Most importantly, the series of ligands in Figure 2 would allow
us to further address questions about the relative importance of
steric and electronic parameters in determining catalyst activity.
Finally, although neopentyl-substituted phosphines have been
used in coordination chemistry for over 30 years, they have
received little attention as ligands in catalysis.34-38 The lone
example of the use of a neopentylphosphine in a cross-coupling
reaction that we have found involved the unsuccessful applica-
tion of trineopentylphosphine to the coupling 3-bromothiophene
with a primary amine.39
The neopentyl substituent provides a different set of steric
and electronic factors than the tert-butyl group. Tolman40
initially estimated the cone angle of trineopentylphosphine
(TNpP) to be approximately 180°, comparable to the 182° cone
angle he determined for tri-tert-butylphosphine (TTBP), which
would suggest that neopentyl and tert-butyl substituents have
similar steric demands. Computationally determined cone angles
reported herein show that substitution of neopentyl groups for
tert-butyl substituents increases the cone angle of the ligand
significantly, however. Replacement of a tert-butyl group with
a neopentyl group decreases the electron-donating ability of the
phosphine.41 Thus, the neopentylphosphines would allow us to
explore trialkylphosphines with larger cone angles than TTBP,
although these ligands would have decreased electron-donating
abilities. We hypothesized that the increased cone angle would
give more effective catalysts for couplings of aryl bromides,
while the decreased electron-donating ability of the ligands
would not be a significant issue. We expected that the decreased
electron-donating ability of the neopentylphosphines might result
in less effective catalysts toward aryl chlorides.
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5118 J. Org. Chem., Vol. 71, No. 14, 2006

Amination of Aryl Bromides and Chlorides
TABLE 1. Pd/DTBNpP‚HBF4 Catalyzed Coupling of Aniline and
TABLE 2. Pd/DTBNpP‚HBF4-Catalyzed Coupling of Morpholine
4-Bromotoluenea
and 4-Bromotoluenea
Pd source
L/Pd ratio
T (°C)
time (h)
yield of 11ab (%)
Pd source
L/Pd ratio
yield of 9ab (%)
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
1:1
1:1
1:1
1:1
0.75:1
1:1
23
23
50
50
50
50
50
18
18
1
4
1
40
90
33
90
99
99
99
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
1:1
1:1
2:1
0
>99
>99
73
0.75:1
1
1
a 4-Bromotoluene (1 equiv), aniline (1.25 equiv), NaO-t-Bu (1.1 equiv),
Pd (1 mol %), DTBNpP‚HBF4 (0.75-2 mol %), toluene, rt, 1 h. b GC yield
determined using response factors obtained from authentic samples of the
product.
2:1
a 4-Bromotoluene (1 equiv), morpholine (1 equiv), NaO-t-Bu (1.5 equiv),
Pd (1 mol %), DTBNpP‚HBF4 (0.75-2 mol %), toluene. b GC yield
determined using response factors obtained from authentic samples of the
product.
Herein, we report an evaluation of the ability of mixed
neopentyl tert-butylphosphines (Figure 2) to give active catalysts
for the H-B coupling of aryl bromides and chlorides with
primary and secondary amines. DTBNpP was found to give
comparable or better levels of activity in the coupling of aryl
bromides. This ligand also gave effective catalysts toward the
coupling of aryl chlorides. We also report calculated cone angles
and electronic properties for these neopentyl ligands based on
DFT-optimized geometries using an approach recently devel-
oped by us.32 The role of steric and electronic parameters in
determining catalyst efficiency is discussed.
Results
DTBNpP as a Ligand in the H-B Coupling. Initial
optimization of the reaction was carried out with the HBF4 salt
of DTBNpP (DTBNpP‚HBF4) in combination with Pd(OAc)2
and Pd2(dba)3 as catalyst precursors in the model coupling of
4-bromotoluene with aniline in toluene using 1 mol % of
palladium at room temperature (eq 1). Pd(OAc)2 was ineffective
as a catalyst precursor in this reaction, presumably because there
is no mechanism to reduce the Pd2+ precursor to the Pd0 active
species (Table 1). Pd2(dba)3 was an effective precatalyst for this
reaction. Complete conversion to product was seen after 1 h
with DTBNpP/Pd ratios of 1:1 or 2:1, while at a 0.75:1
DTBNpP/Pd ratio, the reaction had not reached completion in
the same time frame. In contrast, the TTBP/Pd(dba)2 catalyst
system gave optimal activity with a 0.8:1 L/Pd ratio.6 Higher
L/Pd ratios required elevated temperatures to proceed with
TTBP.
A similar reaction optimization study was carried out with
morpholine as the amine (eq 2). At room temperature, the
coupling of 4-bromotoluene and morpholine required much
longer reaction times (18 h) to near completion (Table 2). In
contrast to the results with aniline, Pd(OAc)2 gave a more
effective catalyst than did Pd2(dba)3. The increased effectiveness
of Pd(OAc)2 as a catalyst precursor for coupling of morpholine
compared to aniline can be explained by the ability of morpho-
line to reduce the Pd2+ precursor by coordination followed by
â-hydride elimination. The reason for the low activity of the
catalyst derived from Pd2(dba)3 compared to Pd(OAc)2 is not
clear at this time, though. At 50 °C, the coupling was complete
after 1 h using the Pd(OAc)2/DTBNpP‚HBF4 catalyst system,
while using Pd2(dba)3 as the palladium source again gave a
FIGURE 3. Conversion profiles for L/Pd2(dba)3-catalyzed (0.5 mol
% of Pd, 1:1 L/Pd) coupling of 4-bromoanisole and N-methylaniline
at room temperature: TTBP (square), DTBNpP (triangle), TBDNpP
(open circle), TNpP (diamond). The curves for DTBNpP and TBDNpP
overlap, reaching 100% yield prior to the first observation at 60 min.
slower rate of conversion to product. At 50 °C, the Pd(OAc)2/
DTBNpP‚HBF4 catalyst system was insensitive to the L/Pd ratio
over the range of 0.75:1 to 2:1.
Ligand Comparison. With optimal conditions determined
for the Pd/DTBNpP‚HBF4 system, we wanted to compare the
activity of catalysts derived from the four ligands in Figure 2.
For these studies, the free phosphines were used, rather than
the phosphonium salts. Control reactions showed that compa-
rable activity was achieved with both ligand precursors, as was
originally shown by Fu.42 The rate of product formation in the
coupling of 4-bromoanisole, a deactivated aryl bromide, and
N-methylaniline at room temperature was determined for
catalysts derived from Pd2(dba)3 (0.5 mol % of Pd, 1:1 L/Pd)
and TTBP or the neopentylphosphines (DTBNpP, TBDNpP,
TNpP). The conversion profiles determined by GC analysis of
the reaction mixtures are shown in Figure 3. Complete conver-
sion was seen for the DTBNpP and TBDNpP catalyst systems
when the first measurement was made after 1 h. In the reactions
using TTBP and TNpP, only 40% conversion to product was
observed after 1 h at room temperature. Allowing the reaction
(42) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295-4298.
J. Org. Chem, Vol. 71, No. 14, 2006 5119

Hill et al.
secondary amine 10a did result in more sensitivity to the steric
demand of the aryl bromide than was seen with aniline.
2-Bromotoluene (7f) gave a similar yield to unhindered aryl
bromides, but no product was formed with 2-bromo-m-xylene
(7g) at 80 °C after 16 h (entries 7 and 8). Coupling of un-
hindered aryl bromides 7b and 7d with diphenylamine (10b)
gave yields comparable to those obtained with 10a (entries 9
and 10). Diphenylamine was more sensitive to steric bulk than
10a, however. Coupling of 10b with 7f gave only a 54%
yield after 6 h, despite using a higher catalyst loading (1 mol
%, entry 11).
Secondary aliphatic amines were also effective substrates with
the DTBNpP/Pd catalyst system. For these reactions, Pd(OAc)2
was used as the palladium source on the basis of our initial
studies. Coupling of morpholine (12a) with aryl bromides
ranging from electron rich to electron deficient gave excellent
yields of the corresponding N-aryl morpholine at 50 °C (eq 5,
Table 5). The sensitivity to the steric demand of the aryl halide
was similar to that seen with N-methylaniline. A good yield
was obtained with mono-ortho-substituted aryl bromides 7f and
7i (entries 5 and 6), but no product was formed with 2-bromo-
m-xylene. Acyclic dialkylamines (12b) gave yields comparable
to those seen with morpholine. In neither case was any evidence
of hydrodehalogenation seen in GC analyses of the reaction
mixtures. Attempts to arylate primary alkylamines were unsuc-
cessful.
FIGURE 4. Conversion profiles for L/Pd(OAc)2-catalyzed (1 mol %
of Pd, 1:1 L/Pd) coupling of 4-bromoanisole and morpholine at
50 °C: TTBP (square), DTBNpP (triangle), TBDNpP (circle), TNpP
(diamond).
to proceed for an additional 4 h resulted in a slight increase in
yield for the TTBP system to 50%, while the TNpP system gave
no further conversion after 1 h.
A similar comparison of the activity of the catalysts derived
from the ligands was carried out in the coupling of morpholine
and 4-bromoanisole at 50 °C with catalysts derived from the
ligands and Pd(OAc)2 (1 mol %, 1:1 L/Pd, Figure 4). Again,
the catalyst derived from DTBNpP gave the fastest rate of
conversion to product. This catalyst system gave nearly complete
conversion to product (90%) after 30 min and had converted
completely to product after 1 h. The TTBP system also gave
nearly complete conversion (87%) after 1 h but had given only
a 38% yield after 30 min. Unlike the N-methylaniline case,
TBDNpP gave a much less active catalyst than either DTBNpP
or TTBP reaching only 36% conversion to product after 1 h.
Over this time period, no product was seen in the reaction
catalyzed by TNpP/Pd(OAc)2.
Synthetic Scope for the Amination of Aryl Bromides with
DTBNpP. The catalyst derived from DTBNpP and Pd2(dba)3
was applied to the coupling of aryl bromides and aniline
derivatives at room temperature using 1 mol % of palladium
(eq 3, Table 3). The phosphonium tetrafluoroborate salt of
DTBNpP was used for most reactions in a 1:1 ratio with
palladium. The catalyst system gave similar yields for electron-
deficient and electron-rich substrates, although the yield was
somewhat lower for the very electron-rich 7e (entry 6).
2-Bromotoluene (7f) gave a similar yield to sterically unde-
manding aryl bromides (entry 7), but the more sterically
hindered 7g required higher catalyst loading (2 mol %) and
temperature (50 °C) to reach completion. Sterically hindered
anilines 8c and 8d could be coupled with 7c at room temper-
ature, although the yields were lower than were achieved with
aniline (entries 9 and 10). Coupling of 8c with 7g at 50 °C
using 2 mol % of palladium gave the tetra-ortho-substituted
diarylamine product in 75% yield (entry 12). An attempt to
couple 7g and 8d was unsuccessful, however.
Amination of Aryl Chlorides. Good to excellent yields of
coupled products were obtained in the amination of aryl
chlorides using DTBNpP as the ligand at elevated temperatures
(eq 6). High temperatures, higher catalyst loadings, or both were
required in the coupling reactions of aryl chlorides in compari-
son with those of aryl bromides. Coupling of aniline with non-
activated or deactivated aryl chlorides required temperatures
g120 °C (Table 6). Little activity was observed below this
temperature, even with higher catalyst loadings. Both 4-chlo-
rotoluene (14b) and 2-chlorotoluene (14d) gave good yields of
diarylamine at 120 °C using 1 mol % of Pd/DTBNpP (entries
1 and 3). In the case of 4-chloroanisole (14c), it was necessary
to raise the temperature to 140 °C to achieve complete
conversion using 1 mol % of Pd.
N-Methylaniline, morpholine, and dibutylamine could be
coupled with aryl chlorides at lower temperatures than aniline,
although higher catalyst loadings were required in some cases
(Table 6). 4-Chlorobenzonitrile (14a), an activated aryl chloride,
could be coupled with N-methylaniline (10a) or morpholine
(12a) at 50 and 80 °C, respectively (entries 4 and 7), using the
same catalyst loadings as were used for aryl bromides (0.5 and
1 mol %, respectively). In the coupling of 4-chlorotoluene (14b)
with N-methylaniline 10a, it was necessary to raise the reaction
temperature to 100 °C and increase the catalyst loading to 1
mol % (entry 5). 4-Chloroanisole (14c) required increasing the
catalyst loading to 5 mol %. Performing the coupling of 14c
and 10a at 120 °C using 1 mol % of Pd/DTBNpP gave only a
low conversion to product. Morpholine and dibutylamine could
be coupled with 14b and 14c at 80 °C using 2 and 5 mol % of
Pd, respectively (entries 8-11). Again, attempts to carry out
these reactions at higher temperature with lower catalyst loading
were not successful.
The DTBNpP catalyst system was also effective for the
coupling of aryl bromides with N-methylaniline (10a) and
diphenylamine (10b). The scope of aryl halides tolerated with
10a was similar to that found with aniline (Table 4). Changing
from electron-deficient aryl halides, such as 7a, to the very
electron-rich aryl halide (7e) had no significant effect on product
yield, although reactions with the more electron-rich substrates
took longer (6 h vs 1 h). Coupling with the more hindered
Ligand Steric and Electronic Properties. In an effort to
understand how the structure of the neopentyl ligands affects
their ability to give active catalysts for the H-B reaction,
electronic and steric parameters of the ligands were determined.
5120 J. Org. Chem., Vol. 71, No. 14, 2006

Amination of Aryl Bromides and Chlorides
TABLE 3. DTBNpP/Pd2(dba)3-Catalyzed Coupling of Aryl Bromides and Aniline Derivativesa
a Aryl bromide (0.8 mmol), aniline (1.0 mmol), NaO-t-Bu (0.85 mmol), Pd (1 mol %), DTBNpP‚HBF4 (1 mol %), toluene (2 mL), rt, 3-4 h. b Average
isolated yield of two runs. 1H and 13C NMR spectral data were consistent with previously reported data. c Reaction ran at 50 °C with 2 mol % of Pd/
DTBNpP.
The electron-donating ability of the ligands was estimated from
the carbonyl stretching frequencies of the corresponding trans-
L2Rh(CO)Cl complexes.43 The rhodium complexes were pre-
pared from [Rh(CO)2(µ-Cl)]2 by trimethylamine N-oxide pro-
moted ligand substitution (eq 7). The crude reaction mixtures
were analyzed by FT-IR spectroscopy to determine the carbonyl
stretching frequency (Table 7).
frequency for the TNpP complex was slightly lower than that
of (n-Bu)3P, showing that the electron-donating ability of the
neopentyl group is only slightly stronger than that of a simple
n-alkyl group, based on these measurements.
We have previously shown that the geometries and frequen-
cies of transition-metal complexes32,44 can be predicted reliably
at the local density functional theory (LDFT) level.45 Geometries
were optimized at the LDFT level with the polarized double-ú
DZVP2 basis set on all atoms except Pd.46 We used the Stuttgart
relativistic pseudopotential and the associated basis set for Pd.47
There are 28 electrons in the core of the ECP and the basis set
for Pd is contracted to [6s5p3d]. The LDFT calculations were
done with the potential fit of Vosko, Wilk, and Nusair for the
correlation functional48 and the exchange functional of Slater.49
Replacing a tert-butyl group with a neopentyl substituent
decreased the electron-donating ability of the phosphine. The
DTBNpP complex gave a CO stretching frequency that was 18
cm-1 higher than that of the TTBP complex, indicating that
DTBNpP is less electron donating than TTBP. Each subsequent
replacement resulted in a smaller increase in the stretching
frequency (7 and 4 cm-1, respectively). The TBDNpP complex
gave a stretching frequency that was identical to the reported
value for the (i-Pr)3P complex (1946 cm-1).43 The stretching
(44) Sosa, C.; Andzelm, J.; Elkin, B. C.; Wimmer, E.; Dobbs, K. D.;
Dixon, D. A. J. Phys. Chem. 1992, 96, 6630-6636.
(45) Parr, R. G.; Yang, W. Density-Functional Theory of Atoms and
Molecules; Oxford University Press: New York, 1989.
(46) Godbout, N.; Salahub, D. R.; Andzelm, J.; Wimmer, E. Can. J.
Chem. 1992, 70, 560-571.
(47) Ku¨chle, W.; Dolg, M.; Stoll, H.; Preuss, H. J. Chem. Phys. 1994,
100, 7535-7542 and references therein; http://www.theochem.uni-
stuttgart.de/pseudopotentials/.
(43) Vastag, S.; Heil, B.; Marko´, L. J. Mol. Catal. 1979, 5, 189-195.
(48) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, 1200.
J. Org. Chem, Vol. 71, No. 14, 2006 5121

Hill et al.
TABLE 4. DTBNpP/Pd2(dba)3-Catalyzed Coupling of Aryl Bromides and Secondary Aniline Derivativesa
a Aryl bromide (0.8 mmol), amine (1 mmol), NaO-t-Bu (1 mmol), Pd2(dba)3 (5 µmol), DTBNpP‚HBF4 (10 µmol), toluene (2 mL), rt, 1-6 h. Reaction
times were not optimized. b Average isolated yield of two runs. 1H and 13C NMR spectral data were consistent with previously reported data. c 80 °C, 1 mol
% of Pd, 1 mol % of DTBNpP‚HBF4, 16 h. d rt, 1 mol % of Pd, 1 mol % of DTBNpP‚HBF4, 4 h.
TABLE 5. DTBNpP/Pd2(dba)3-Catalyzed Coupling of Aryl Bromides and Secondary Alkyl Aminesa
a Aryl bromide (0.8 mmol), amine (1 mmol), Na-t-OBu (1 mmol), Pd(OAc)2 (1 mol %), DTBNpP‚HBF4 (1 mol %), toluene (2 mL), 50 °C, 2 h. Reaction
1
times were not optimized. b Average isolated yield of two runs. H and 13C NMR spectral data were consistent with previously reported data.
The bond energies were calculated at the gradient-corrected level
at the LDA-optimized geometries with the B3LYP exchange-
correlation functional with the above basis sets.50,51 The cone
angles were calculated from the LDA-optimized geometries for
the (phosphine)Pd0 complex by using the STERIC program, and
the volumetric parameters for the atoms therein with the Pd
atom set at the origin.52,53
The LDFT-optimized structures of the monosphosphine com-
plexes are shown in Figure 5. For the structures with a neopentyl
group, the CH2 group bonded to P is rotated in the optimized
structures so as to maximize the distance of the H atoms from
the Pd. This orientation leads to the tert-butyl fragment being
oriented toward the Pd center. Other orientations were studied
and shown to be of significantly higher energy. This orientation
(49) Slater, J. C. Phys. ReV. 1951, 81, 385.
(50) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.
(51) Lee, C.; Yang, W.; Parry, R. G. Phys. ReV. B 1988, 37, 785-789.
(52) Taverner, B. C. J. Comput. Chem. 1996, 17, 1612-1623.
(53) Taverner, B. C. STERIC, 1.11, 1995; http://www.ccl.net/cca/
software/SOURCES/C/steric/index.shtml.
5122 J. Org. Chem., Vol. 71, No. 14, 2006

Amination of Aryl Bromides and Chlorides
TABLE 6. DTBNpP/Pd-Catalyzed Amination of Aryl Chloridesa
with neopentyl substituents resulted in a continued increase in
the cone angle. As can be seen in the space filling structures in
Figure 5, the three neopentyl groups of TNpP shield a significant
amount of the Pd atom.
The DFT-optimized geometries resulted in a significantly
larger calculated cone angle for TNpP than was estimated by
Tolman. We have found a general trend for the cone angles
obtained from LDFT-optimized structures to be larger than those
estimated by Tolman. In some cases, these differences can be
significant and result in different trends than were predicted by
Tolman, such as TTBP compared with DTBNpP. Tolman, in
determining his cone angle values, chose ligand conformations
that minimize the cone angle. In contrast, the computed
geometries are allowed to adopt the lowest energy conformation,
which in many cases is not the one with the smallest cone angle.
The nature of these conformational effects on cone angles will
be discussed in more detail in a forthcoming paper detailing
our computational approach to obtaining cone angle values.
The projection of the tert-butyl groups of the neopentyl
substituents toward the metal center leads to the potential for
agostic interactions. There are two such interactions in the
DTBNpP and TBDNpP complexes and three in the TNpP
complex (Table 7). These agostic interactions have smaller bond
distances and hence increased interactions for the more sterically
demanding TBDNpP and TNpP ligands than for smaller ligands
such as DTBNpP or TTBP. The Pd-P bond strengths decrease
with increasing cone angle as would be expected from the steric
repulsion effects, with the exception of PPh3. The bond strengths
all are lower than we previously reported for Ph3P and TTBP32
due to the use of a different exchange-correlation functional.
The highest bond strength is found for the least sterically
hindered ligand, P(n-Bu)3.
a Aryl chloride (0.8 mmol), amine (0.82-1 mmol), Na-t-OBu (1 mmol),
Pd2(dba)3 (0.5-5 mol % of Pd), DTBNpP‚HBF4 (1 equiv/Pd), toluene (2
mL), 50 °C, 2 h. Reaction times were not optimized. b Average isolated
yield of two runs. 1H and 13C NMR spectral data were consistent with
previously reported data. c Xylene used as solvent. d Pd(OAc)2.
Discussion
DTBNpP in combination with palladium sources gave a
highly effective catalyst for the Hartwig-Buchwald amination
of aryl bromides at room temperature. The activity was superior
to that of catalysts derived from TTBP in direct comparisons
of reaction profiles. In contrast, TNpP was a less effective ligand
for these coupling reactions than either TTBP or DTBNpP.
TBDNpP gave catalysts with activities comparable to DTBNpP
or TTBP depending on the amine substrate. Although a direct
comparison was not performed, the DTBNpP catalyst system
gave comparable yields in the amination of aryl bromides to
those reported for catalysts derived from biphenylphosphine 3
using similar catalyst loadings and shorter reaction times.15
In the case of aryl chlorides, DTBNpP again gave effective
catalysts for the amination reactions at elevated temperatures.
Similar palladium loadings were required with DTBNpP and
TTBP, but the DTBNpP catalyst system required higher
temperatures than TTBP to achieve similar yields.6 The tem-
peratures required for amination of aryl chlorides using DTBNpP
are comparable or lower than those required with adamantyl-
phosphine 2,11,12 although higher catalyst loadings are required
in most cases for the DTBNpP system. The DTBNpP catalyst
system generally required higher temperatures than catalysts
derived from biphenylphoshphine 3 for aminations of aryl
chlorides.15,17
TABLE 7. Steric and Electronic Properties of
Neopentylphosphines
P-Pd
LPd(0)
bond
c
d
νRh-CO θDFT θT
energye R(Pd-H)f HOMOg GAPh
a
ligand (cm-1
)
(deg) (deg) (kcal/mol)
(Å)
(eV)
(eV)
TTBP
1921
DTBNpP 1939
TBDNpP 1946
194 182
198
210
37.3
35.8
35.2
33.7
38.7
39.2
37.1
2.69
2.41
2.32
2.38
2.93
3.06
3.07
4.51
4.50
4.52
4.46
4.64
4.66
4.91
3.33
3.27
3.24
3.16
3.47
3.48
3.42
TNpP
1950
227 180
(i-Pr)3P
1946b 182 160
(n-Bu3)P 1953b 177 132
Ph3P
1978b 173 145
a Carbonyl stretching frequency measured in solution of in situ prepared
trans-(L)2Rh(CO)Cl complex. b Literature values.43 c Cone angle values
determined from LDFT-optimized LPd(0) structures using the STERIC
program. d Cone angle values determined by Tolman.40 e Calculated at the
DFT level with the B3LYP exchange-correlation functional at the LDA-
optimized geometries. f Closest nonbonded Pd-H distances. For the neo-
pently-substituted compounds this is for the methyl groups showing agostic
interactions. g HOMO energy at the B3LYP level. h GAP ) |E(HOMO) -
E(LUMO)|.
results in the neopentyl substituent having a large steric demand.
Thus, the cone angle for DTBNpP of 198° is larger than the
value for TTBP of 194° showing a larger steric demand for the
former ligand (Table 7). Further replacement of tert-butyl groups
We have previously shown that calculated cone angles were
a good predictor of catalyst activity for a family of water-soluble
alkylphoshines in the Suzuki coupling of aryl bromides.32 In
this work, we find that with cone angles greater than 200°,
J. Org. Chem, Vol. 71, No. 14, 2006 5123

Hill et al.
FIGURE 5. Space-filling models of LDFT:optimized geometries for LPd0 complexes (H ) light gray, C ) dark gray, P ) gold, Pd ) green).
catalyst efficiency appeared to decrease with increasing cone
angle. In our prior work, we found that catalyst activity increased
upon increasing the cone angle over the range of 185 to 194°.
Although our prior work dealt with the Suzuki coupling, Hartwig
has shown that ligands with smaller cone angles than TTBP,
such as tricyclohexylphosphine or (n-Bu)3P, gave less active
catalysts in the H-B coupling.8 The sum of these results
suggests that the optimal cone angle for these reactions falls
between 190° and 200°, whereas ligands with larger or smaller
cone angles give less effective catalyst systems.
If the cone angle is less than 180°, then the two ligands in a
linear L2Pd complex will not have a significant steric repulsion
and can reach their optimal Pd-L bond distances. Ligand
dissociation to give coordinatively unsaturated will not be
promoted by ligands of this size. For ligands with cone angles
greater than 180°, steric interactions between the ligands will
lead to a lower bond energy, assuming equal electronic
contribution, resulting in more facile ligand dissociation. For
ligands with substantially larger cone angles than 180°, ligand
dissociation should be even more facile. The steric demand of
the ligand may block incoming substrates from approaching the
metal center, however. In addition, the weaker metal-phosphine
bond energies may result in catalysts with poor stability. Thus,
TBDNpP and TNpP, with cone angles larger than 200°, may
be too large to serve as effective ligands in cross-coupling
reactions.
The activity of catalysts derived from the neopentylphos-
phines also decreases with increasing CO stretching frequency
of trans-L2Rh(CO)Cl complexes. The significance of this
correlation is unclear, since steric and electronic properties of
these phosphines are directly coupled. Replacement of a tert-
butyl group with a neopentyl group increases the cone angle of
the phosphine, while decreasing its electron donating ability.
TTBP is more electron donating than DTBNpP, but has a
smaller cone angle. DTBNpP gave more active catalysts for
H-B amination of aryl bromides than TTBP. This result
suggests that the cone angle could be more important in
determining catalyst activity toward aryl bromides than the
electronic properties of the ligands. Of course, it must be noted
that the differences in cone angle and especially the CO
stretching frequencies are relatively small. In the case of aryl
chlorides, we see a reversal in the relative activity of catalysts
derived from TTBP and DTBNpP from that seen with aryl
bromides. The increased activity of the catalyst derived from
TTBP seems to correlate to the increased electron-donating
ability of this ligand compared to DTBNpP.
defined as |E(HOMO) - E(LUMO)|, does decrease with
substitution of a tert-butyl substituent by a neopentyl group
tracking the change in frequencies and thus may serve as another
means to estimate the electronic parameter. The GAP at the
DFT level correlates reasonably well with the first excitation
energy.54,55 A smaller GAP is consistent with it being easier to
excite an electron from the HOMO to the LUMO. This value
is lower than the ionization process as the LUMO has a negative
eigen value. This correlation is consistent with a single electron
excitation process correlating with increased reactivity. The
HOMO values show little variation among the ligands, but the
LUMO values do vary with substituent. We note that the
reactivity changes occur over less than an order of magnitude.
Assuming the same preexponential factor, at room tempera-
ture, the differences in activation energy must be less than 1.4
kcal/mol, which is consistent with the small differences in the
electronic parameters of the various phosphines.
The different contributions of steric and electronic properties
suggest a different rate-limiting step in the catalytic cycle for
aryl bromides and chlorides. In the coupling of aryl chlorides,
oxidative addition is likely to be the rate-limiting step.31 More
electron-donating ligands would be expected to promote oxida-
tive addition. Oxidative addition is likely not to be the rate-
limiting step in the case of aryl bromides. The key step in the
case of aryl bromides may well be the initial ligand dissociation
to give the highly reactive LPd(0) species. Hartwig30 has shown
that ligand dissociation is the rate-limiting step in the oxidative
addition of aryl bromides to palladium(0) complexes of bulky
alkylphosphines, while the mechanism for aryl chlorides
involved reversible ligand dissociation followed by rate limiting
oxidative addition. Increased steric demand would be expected
to favor ligand dissociation, although the low activity of catalysts
derived from TBDNpP and TNpP may indicate that they are
either too large or not strongly electron-donating enough, or
possibly a combination of both factors, to provide effective
catalysts.
Conclusion
DTBNpP is a commercially available, sterically demanding,
electron-rich alkylphosphine that provides effective catalysts for
the Hartwig-Buchwald amination of aryl bromides and chlo-
rides. DTBNpP provides catalysts with higher activity in the
amination of aryl bromides than TTBP. DTBNpP is effective
toward aryl chlorides but requires higher temperatures than
TTBP. Studies of the steric and electronic properties of the
ligands show that the cone angle likely dominates the activity
in coupling of aryl bromide, whereas the electron-donating
ability of the phosphines becomes more important with aryl
There is very little change in the calculated ionization
potential from Koopmanns’ theorem (the negative of the HOMO
energy) for the substitution of a tert-butyl group by a neopentyl
substituent so the ionization potential for these systems is not
a good measure of the change in the electron-donating ability
of the ligand. This observation is consistent with prior compu-
tational studies on nickel phosphine complexes. The GAP,
(54) Garza, J.; Vargas, R.; Nichols, J. A.; Dixon, D. A. J. Chem. Phys.
2001, 114, 639-651.
(55) Zhan, C.-G.; Nichols, J. A.; Dixon, D. A. J. Phys. Chem. A 2003,
107, 4184-4195.
5124 J. Org. Chem., Vol. 71, No. 14, 2006

Amination of Aryl Bromides and Chlorides
solution in toluene) or DTBNpP‚HBF4 (10 µmol, 1 eq/Pd), sodium
tert-butoxide (1.5 mmol), and toluene (2.5 mL) were added to a
round-bottom flask in a glovebox. Upon removal of the septum-
sealed flask from the drybox, the aryl bromide (1.0 mmol) and
amine 12a or 12b (1.0 mmol) were added by syringe and the
reaction was allowed to stir for 2 h at 50 °C. The reaction mixture
was then adsorbed on silica gel and purified by flash chromatog-
raphy eluting with a mixture of hexane and ethyl acetate.
Typical Procedure for the Coupling of Aryl Chlorides and
Secondary Alkylamines. Pd(OAc)2 (10-50 µmol), DTBNpP (10%
solution in toluene) or DTBNpP‚HBF4 (10-50 µmol, 1 equiv/Pd),
sodium tert-butoxide (1.5 mmol), and toluene (2.5 mL) were added
to a round-bottom flask in a glovebox. Upon removal of the septum-
sealed flask from the drybox, the aryl chloride (1.0 mmol) and
amine 12a or 12b (1.0 mmol) were added by syringe. The flask
was placed in a preheated oil bath at 80 °C and stirred until judged
complete by GC. The reaction mixture was then adsorbed on silica
gel and purified by flash chromatography eluting with a mixture
of hexane and ethyl acetate.
chlorides. In couplings of aryl bromides, the ligand steric
demand appears to be a key parameter with the optimal cone
angle being between 190° and 200°. While steric bulk remains
important in the coupling of aryl chlorides, electronic factors
likely play a much more important role in determining catalyst
activity.
Experimental Section
Typical Procedure for the Coupling of Aryl Bromides and
Aniline Derivatives. Pd2(dba)3 (2-4 µmol), DTBNpP (10%
solution in toluene) or DTBNpP‚HBF4 (4-8 µmol, 1 equiv/Pd),
sodium tert-butoxide (0.85 mmol), and toluene (2 mL) were added
to a round-bottom flask in a glovebox. Upon removal of the septum-
sealed flask from the drybox, the aryl bromide (0.80 mmol) and
aniline derivative (8 or 10, 0.82-1.0 mmol) were added by syringe
and the reaction was allowed to stir for 1-6 h at room temperature
until judged complete by GC. The reaction mixture was then
adsorbed on silica gel and purified by flash chromatography eluting
with a mixture of hexane and ethyl acetate.
Acknowledgment. Financial support for this work by FMC
Corp., Lithium Division (and donations of alkylphosphines), the
Chemical Sciences, Geosciences and Biosciences Division,
Office of Basic Energy Sciences, U.S. Department of Energy
(DOE) (catalysis center program), and the Robert Ramsay Chair
Foundation is gratefully acknowledged.
Typical Procedure for the Coupling of Aryl Chlorides and
Aniline Derivatives. Pd2(dba)3 (2-20 µmol), DTBNpP (10%
solution in toluene) or DTBNpP‚HBF4 (4-40 µmol, 1 equiv/Pd),
sodium tert-butoxide (0.85 mmol), and solvent (toluene or xylene,
2 mL) were added to a round-bottom flask in a glovebox. Xylene
was used in place of toluene for reactions carried out at temperatures
above 100 °C. Upon removal of the septum-sealed flask from the
drybox, the aryl chloride (0.80 mmol) and aniline derivative (8 or
10, 0.82-1.0 mmol) were added by syringe. The flask was placed
in a preheated oil bath at the indicated temperature and stirred for
2-24 h until judged complete by GC. The reaction mixture was
then adsorbed on silica gel and purified by flash chromatography
eluting with a mixture of hexane and ethyl acetate.
Supporting Information Available: Detailed experimental data,
product characterization data, calculated optimized molecular
geometries in Å as well as total and zero point energies in au,
1
and H and 13C NMR spectra of the compounds in Tables 3-6.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Typical Procedure for the Coupling of Aryl Bromides and
Secondary Alkylamines. Pd(OAc)2 (10 µmol), DTBNpP (10%
JO060303X
J. Org. Chem, Vol. 71, No. 14, 2006 5125