Nickel-catalyzed arylation of heteroaryl-containing diarylmethanes: Exceptional reactivity of the Ni(NIXANTPHOS)-based catalyst

Article abstract of DOI:10.1039/c5sc03704b

Nickel(0)-catalyzed cross-coupling of heteroaryl-containing diarylmethanes with both aryl bromides and chlorides has been achieved. The success of this reaction relies on the introduction of a unique nickel/NIXANTPHOS-based catalyst system, which provides a direct route to triarylmethanes from heteroaryl-containing diarylmethanes. Reactivity studies indicate the Ni(NIXANTPHOS)-based catalyst exhibits enhanced reactivity over XANTPHOS derivatives and other Ni(phosphine)-based catalysts in the reactions examined.

Full text of DOI:10.1039/c5sc03704b

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Nickel-catalyzed arylation of heteroaryl-containing
diarylmethanes: exceptional reactivity of the
Ni(NIXANTPHOS)-based catalyst†
Cite this: DOI: 10.1039/c5sc03704b
Xinyu Cao,ab Sheng-Chun Sha,b Minyan Li,b Byeong-Seon Kim,b Catherine Morgan,b
a
c
b
*
Rudan Huang, Xiaodong Yang and Patrick J. Walsh
Nickel(0)-catalyzed cross-coupling of heteroaryl-containing diarylmethanes with both aryl bromides and
chlorides has been achieved. The success of this reaction relies on the introduction of a unique nickel/
NIXANTPHOS-based catalyst system, which provides a direct route to triarylmethanes from heteroaryl-
containing diarylmethanes. Reactivity studies indicate the Ni(NIXANTPHOS)-based catalyst exhibits
enhanced reactivity over XANTPHOS derivatives and other Ni(phosphine)-based catalysts in the reactions
examined.
Received 30th September 2015
Accepted 7th October 2015
DOI: 10.1039/c5sc03704b
www.rsc.org/chemicalscience
and Yang11 groups with enantioenriched benzylic pivalates and
aryl boronic acid derivatives. More recently, the Jarvo group
1 Introduction
reported Suzuki reaction as a complementary method to the
previously reported nickel-catalyzed Kumada coupling.8b
Our approach to triarylmethanes differs from these impor-
tant contributions in that it involves the catalytic
Triarylmethanes have attracted signicant attention due to
their diverse applications as leuco dye precursors,1 uorescent
probes,2 and photochromic agents.3 They also nd uses in
medicinal chemistry.4 Given the utility of triarylmethanes, it is
not surprising that considerable effort has been invested in
their synthesis.5,6 Recently, triarylmethanes have been prepared
using transition metal catalyzed cross-coupling reactions,
usually employing palladium-based catalysts.7 To decrease costs
and increase sustainability of these processes, much effort has
focused on employing earth abundant rst row transition
metals in reactions traditionally catalyzed by palladium.8–11
Given nickel's position directly above palladium, and its high
reactivity with aryl halides,12 nickel stands out as a clear starting
point for the development of rst-row transition metal catalyzed
processes. Indeed, it has been used successfully in many cross-
coupling reactions.12–14
The synthesis of triarylmethanes via nickel-catalyzed reac-
tions has been achieved through traditional Kumada and
Suzuki–Miyaura coupling approaches.8–11 In 2012 and 2013, the
Jarvo group demonstrated the synthesis of triarylmethanes with
high ee by coupling of enantioenriched benzylic ethers with aryl
Grignard reagents8a (Scheme 1A) and arylboronic esters
(Scheme 1B).9 Related strategies were reported by the Watson10
aKey Laboratory of Cluster Science of Ministry of Education, School of Chemistry,
Beijing Institute of Technology, Beijing 100081, PR China
bDepartment of Chemistry, University of Pennsylvania, 231 S. 34th St., Philadelphia,
PA 19104, USA. E-mail: pwalsh@sas.upenn.edu; Web: https://sites.google.com/site/
titaniumupenn/; Fax: +1-215-573-6743
cKey Laboratory of Medicinal Chemistry for Natural Resource, School of Chemical
Science and Technology, Yunnan University, Kunming, 650091, PR China
† Electronic supplementary information (ESI) available: Data for new compounds,
experimental procedures, 1H and 13C NMR spectra. See DOI: 10.1039/c5sc03704b
Scheme 1 Synthetic approaches to triarylmethanes.
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functionalization of weakly acidic sp3-hybridized C–H bonds via phosphine ligands, the Ni(NIXANTPHOS)-based catalyst out-
a deprotonative-cross-coupling process (DCCP).15,16 In our prior performed the other nickel catalysts in the arylation of 2-pyr-
studies, diarylmethanes were reversibly deprotonated in the idylmethyl amine under the conditions examined.
presence of a Pd(NIXANTPHOS) catalyst and the resulting
carbanions coupled with aryl bromides17a,c and chlorides17b in
2 Results and discussion
high yields. It is noteworthy that early work on the deprotona-
tion/cross coupling of both aromatic C(sp2)–H's and C(sp3)–H's 2.1 Catalyst identication
of uorinated hydrocarbons were reported by Daugulis
We evaluated nickel precursors in the presence of phosphine
ligands by screening 37 electronically diverse mono- and
bidentate phosphines using Ni(COD)2 as the nickel source.
Coupling of 2-benzylpyridine 1a (1.2 equiv.) with 1-bromo-4-tert-
employing base metal catalysts (Cu and Fe).17d–g
One of the most signicant ndings of our early investiga-
tions is that under the basic reaction conditions, van Leeuwen's
wide bite-angle ligand,18 NIXANTPHOS' N–H (pKa ꢀ 22)19 is
butylbenzene 2a (1 equiv.) in the presence of NaN(SiMe3)2 (3
deprotonated under the reaction conditions and the resulting
equiv.), catalytic Ni(COD)2 (10 mol%) and ligand (20 mol% for
heterobimetallic catalyst displays exceptional reactivity when
monodentate phosphine ligands and 10 mol% for bidentate
compared with other bidentate phosphine-based palladium
ligands) were performed in cyclopentyl methyl ether (CPME) on
microscale (0.01 mmol, 0.1 M) at 110 ꢁC. Aer heating for 16 h,
catalysts.17b The most striking comparison is between the
NIXANTPHOS- and XANTPHOS-based palladium catalysts.
the reactions were worked up and analyzed by HPLC (retention
Despite the outward similarity of these ligand scaffolds, the
times, UV/vis characteristics and integration against an internal
standard, see ESI† for details). Of the 37 different phosphine
ligands tested, NIXANTPHOS was the only promising hit. Inter-
estingly, as discussed below, the XANTPHOS-based catalyst was
NIXANTPHOS-based catalyst exhibited over 90% assay yield (AY,
determined by 1H NMR) in the coupling of 1-chloro-4-tert-
butylbenzene with diphenylmethane to afford the triaryl-
methane product, while the parent XANTPHOS-based catalyst,
much less active in this transformation. Translation of the
under identical conditions, exhibited only 1% conversion (eqn
microscale results with commercially available NIXANTPHOS to
(1)). Furthermore, other ligands known to participate in cross-
laboratory scale (0.1 mmol) under the same reaction conditions
coupling reactions with aryl chlorides, including the Buchwald
resulted in 78% assay yield (AY, as determined by 1H NMR in all
family of ligands, were examined in this reaction and found to
cases) (Table 1, entry 1). Examination of different nickel to
ligand ratios indicated that a 1 : 1 ratio at 10 mol% loading
provided the best yields (entries 2–3). Decreasing the equiva-
give less than 2% product. These results attest to the difficulty of
this reaction, particularly with aryl chlorides.
lents of NaN(SiMe3)2 from 3 to 2 resulted in an increase in the
yield of coupling product 3aa to 83% (entry 4). Reducing the
Table 1 Optimization of Ni-NIXANTPHOS catalyzed DCCP of 1a with
2aa
t
Entry 1a : 2a : base Ni/L (mol%) T (ꢁC) (h) Concn Yieldb (%)
(1)
1
2
3
4
5
6
7
8
1.2 : 1 : 3
1.2 : 1 : 3
1.2 : 1 : 3
1.2 : 1 : 2
1.2 : 1 : 2
1 : 1.5 : 2
1 : 1.5 : 2
1 : 1.5 : 2
1 : 1.5 : 2
1 : 1.5 : 2
1 : 1.5 : 2
1 : 1.5 : 2
10/10
10/15
10/20
10/10
10/10
10/10
10/10
10/10
10/10
10/10
2.5/2.5
1/1
110
110
110
110
110
110
110
110
50
16 0.1
16 0.1
16 0.1
16 0.1
16 0.05
16 0.05
78
71
62
83
85
93
77
81
99
99
99(99)
72
In the present study, our goals were to (1) develop a nickel
catalyst to promote the DCCP of heteroaryl-containing diaryl-
methane derivatives and (2) determine if the high reactivity
imparted to palladium when chelated by a deprotonated
NIXANTPHOS ligand translates to nickel catalysts. Herein, we
describe the synthesis of triarylmethanes by DCCP of hetero-
aryl-containing diarylmethanes and aryl bromides and chlo-
8
0.05
24 0.05
16 0.05
16 0.05
16 0.05
16 0.05
9
10
11c
12
rt
rt
rt
rides catalyzed by
a Ni(NIXANTPHOS)-based system. To
determine if the exceptional reactivity of the Ni(NIXANTPHOS)-
based catalyst translates to additional reactions, we also report
preliminary results on the previously unknown arylation of a 2-
pyridylmethyl amine. Compared with 37 mono- and bidentate
a
Reactions conducted on a 0.10 mmol scale. b Yield determined by 1H
NMR spectroscopy of the crude reaction mixtures. c Isolated yield aer
chromatographic purication.
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concentration to 0.05 M resulted in generation of product 3aa in pyridines, because it is the most difficult to deprotonate.
85% (entry 5). Nonetheless, the more acidic dipyridin-3-ylmethane (1d)
Optimization was continued by adjusting other reaction underwent coupling with aryl bromide 2a and 2 equiv. of
parameters. Changing the ratio of 2-benzylpyridine to aryl LiN(SiMe3)2 in 75% isolated yield. Unlike analogous palladium-
bromide and base to 1.0 : 1.5 : 2.0 rendered product 3aa in 93% catalyzed reactions with less acidic diarylmethanes,7 such as
AY (entry 6). Changing the reaction times from 16 to 8 or 24 h diphenylmethane (pKa ¼ 32 in DMSO)20 the Ni(NIXANTPHOS)-
led to lower yields (entries 7 and 8). Lowering the temperature based catalyst failed to give product with substrates with
from 110 ꢁC to 50 ꢁC and room temperature increased the AY to benzylic C–H pKa's values greater than about 30. This result is
99% at both the lower temperatures (entries 9 and 10). not totally surprising. Based on the assumption that the reac-
Decreasing the catalyst loading to 2.5 mol% at room tempera- tion pathways are similar,21 we hypothesize that the decreased
ture also resulted in 99% AY (entry 11). Further decreasing the electronegativity of nickel (1.91) relative to palladium (2.20,
catalyst loading to 1 mol% at rt led to 72% AY (entry 12). Under Pauling scale) renders the Ni catalyst less electrophilic.22 This,
the optimized conditions of entry 11, the triarylmethane combined with the smaller size of Ni compared to Pd23 and the
product was isolated in 99% yield. Substitution of XANTPHOS small value of the equilibrium for deprotonation (pKa of
for NIXANTPHOS at twice the catalyst loading (5 mol%), under HN(SiMe3)2 in THF ¼ 26),24 likely results in very little or no
otherwise identical conditions afforded only 30% AY. This transmetallation
result prompted a series of experiments probing the difference diphenylmethane.
with
the
anion
derived
from
in reactivity between these two structurally similar ligands (see
later sections).
In addition to benzylpyridines, other diphenylmethane
derivatives underwent nickel-catalyzed coupling reactions.
These include uorene (1e) and xanthene (1f, pKa in DMSO ¼
30.0).19 The triarylmethane derivatives 3ea and 3fa were isolated
in 99 and 81% yield, respectively. Notably, reactions with the
more acidic uorene required only 1 mol% catalyst loading.
Related triarylmethanes with these core structures have been
found to have various applications.25,26
2.2 Scope of the diphenylmethane derivatives
Under the optimized conditions of entry 12 in Table 1, the scope
of heteroaryl-containing diarylmethanes with 4-tert-butyl bro-
mobenzene (2a) was examined (Scheme 2). The isomeric 2-, 3-
and 4-benzylpyridine substrates have pKa values of 28.2, 30.1,
and 26.7 in DMSO, respectively.19 It is not entirely surprising
that their reactions required different conditions to achieve
high yields (Scheme 2, see ESI† for details). Nonetheless,
coupling of 2-, 3- and 4-benzylpyridine furnished products 3aa,
3ba and 3ca in 99, 67 and 96% isolated yields, respectively. 3-
Benzylpyridine was the most challenging of the benzyl
2.3 Scope of the aryl halide
To probe the ability of the Ni(NIXANTPHOS)-based catalyst to
promote reactions with different electrophiles, 2-benzylpyridine
was coupled with various aryl bromides (Scheme 3). Bromo-
benzene (2b) gave coupling product 3ab in 93% yield with 5
mol% catalyst loading at room temperature. Under the same
conditions, electron rich 4-bromoanisole (2c) and 4-bromo-N,N-
Scheme 2 Scope of heteroaryl-containing diarylmethanes in Ni-
a
NIXANTPHOS catalyzed DCCPa,b
.
Reactions conducted on a 0.1
b
mmol scale at 0.05 M. Isolated yields after chromatographic purifi-
c
d
cation.
2.5 mol% Ni(COD)2/2.5 mol% NIXANTPHOS.
10 mol% Scheme 3 Scope of aryl bromides in Ni-NIXANTPHOS catalyzed
e
Ni(COD)2/10 mol% NIXANTPHOS. 1 mol% Ni(COD)2/1 mol% NIX- DCCP with 1aa,b
.
a Reactions conducted on a 0.1 mmol scale at 0.05 M.
f
g
h
b
c
ANTPHOS. 2 equiv. of NaN(SiMe3)2. 4 equiv. of NaN(SiMe3)2. 2.5
Isolated yields after chromatographic purification.
5 mol%
10 mol% Ni(COD)2/10 mol%
i
j
d
equiv. of LiN(SiMe3)2.
2
equiv. of LiN(SiMe3)2.
1.5 equiv. of Ni(COD)2/5 mol% NIXANTPHOS.
k
l
m
f
NaN(SiMe3)2. Room temperature. 50 ꢁC. 110 ꢁC.
NIXANTPHOS. e Room temperature. 50 ꢁC.
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dimethylaniline (2d) furnished products 3ac and 3ad in 91 and
83% yields, respectively. Aryl bromide with a 4-uoro- group
afforded triarylmethane 3ae in 83% isolated yield, (5 mol%
catalyst loading at 50 ꢁC). Keto-containing 4-bromobenzophe-
none delivered 3af in 74% yield with 10 mol% catalyst at room
temperature. Aryl bromide bearing a 3-CF3 substituent fur-
nisꢁhed the product 3ag in 86% yield with 5 mol% catalyst at
50 C.
Scheme 5 Gram scale reaction via nickel-catalyzed DCCP reaction.
We next examined our Ni(NIXANTPHOS)-based catalyst with
more challenging aryl chlorides (Scheme 4). We were pleased to reaction in 73% yield with 5 mol% catalyst loading at room
nd that the Ni(NIXANTPHOS)-based catalyst gave good to temperature. Overall, good scope of the nickel-catalyzed DCCP
excellent yields in the coupling of aryl chlorides with was demonstrated in Schemes 2–4, and aryl chlorides were
found to be better substrates than aryl bromides (based on
yields).
To demonstrate the potential utility of our method, we
conducted a gram scale reaction of chlorobenzophenone (4f, 5
mmol, 1.08 g) and the 2-benzylpyridine (1a, 10 mmol, 1.61 mL)
2-benzylpyridine using catalyst loadings as low as 2.5 mol%.
Coupling chlorobenzene, 1-tert-butyl-4-chlorobenzene, and
4-chloroanisole furnished products in 99 (3aa), 92 (3ab) and
99% (3ac) yields with 2.5–5 mol% catalyst loadings at room
temperature. 4-Chloro-1-uorobenzene (4e) led to triaryl-
methane products 3ae in 90% yield with 10 mol% catalyst in 85% yield (Scheme 5), suggesting the reaction is scalable.
loading at room temperature. 4-Chlorobenzonitrile (4h) deliv-
ꢁ
ered 3ah in 79% yield with 10 mol% catalyst loading at 50 C,
2.4 Comparison of NIXANTPHOS and XANTPHOS
derivatives
despite the known reaction of nitriles with silyl amide bases.27
Chlorobenzophenone afforded 3af in 92% yield (5 mol% cata-
lyst loading at 50 ꢁC) while 3-chlorobenzotriuoride (4g) fur- We previously demonstrated that oxidative addition of aryl
nished 3ag in 90% yield with 5 mol% catalyst loading at 50 ꢁC. chlorides to a Pd0(NIXANTPHOS) catalyst took place at room
Heteroaromatic 6-chloroquinoline 4i successfully underwent temperature in the presence of base.17b This result was
surprising because the low energy pathway to oxidative addition
of unactivated aryl chlorides to Pd(0) has been shown to proceed
through a Pd–L intermediate, where L is a monodentate phos-
phine.28 Palladium complexes of bulky trialkyl phosphines and
certain Buchwald ligands will oxidatively add aryl chlorides at
room temperature or below.29 In contrast, Pd(0) complexes of
bidentate phosphines can oxidatively add aryl chlorides via
a higher energy ꢁPdL2 pathway.30 Such reactions usually take
place around 90 C, rather than at room temperature with our
Pd0(NIXANTPHOS)-based catalyst.31 We also demonstrated that
the NIXANTPHOS N–H must be deprotonated to perform the
oxidative addition of aryl chlorides at room temperature, and
that the actual catalyst is a heterobimetallic Pd/main group
metal complex (main group ¼ K, Na, Li). Although the precise
mechanism of the oxidative addition in this system is currently
unknown, we speculate that cooperativity between the metals
plays an important role. As a point of reference, the structurally
related Pd0(XANTPHOS) exhibited no reactivity with aryl chlo-
rides under the same reaction conditions.17b
With this backdrop, we were interested to determine if the
exceptional reactivity imparted to palladium when bound to
NIXANTPHOS would translate to an increase in reactivity of
analogous nickel complexes. Nickel-based phosphine catalysts
are more reactive toward oxidative addition than most palla-
dium complexes.12,32 Unfortunately, the nickel-based catalysts
proved more challenging to study than their palladium coun-
terparts, due to precipitate formation. Nonetheless, some
experiments are presented that highlight the signicant differ-
ences in reactivity between the nickel NIXANTPHOS and
XANTPHOS systems.
Scheme 4 Scope of aryl chlorides in Ni-NIXANTPHOS catalyzed
DCCP with 1aa,b
.
a Reactions conducted on a 0.1 mmol scale at 0.05 M.
b
c
Isolated yield after chromatographic purification.
Ni(COD)2/2.5 mol% NIXANTPHOS. 5 mol% Ni(COD)2/5 mol% NIX-
2.5 mol%
d
e
f
As discussed earlier, our initial ligand screen indicated that
the NIXANTPHOS-based nickel catalyst outperformed the
ANTPHOS.
10 mol% Ni(COD)2/10 mol% NIXANTPHOS.
room
g
temperature. 50 ꢁC.
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XANTPHOS-based nickel catalyst by a signicant margin. hindered Ni(t-Bu-XANTPHOS)-based catalyst undergoes slower
Additionally, the NIXANTPHOS ligand will be deprotonated transmetallation.
under the nickel-catalyzed reaction conditions outlined in these
arylation reactions.
When the reaction was conducted with the Ni(NIXANTPHOS)-
based catalyst, 2-benzylpyridine and chlorobenzene, the conver-
To probe this difference in reactivity, we compared conver- sion was 48% aer 4 h. The similarity of conversion in the
sions of NIXANTPHOS- and XANTPHOS-based nickel catalysts reactions with chloro and bromobenzene under otherwise iden-
in the arylation of 2-benzylpyridine with bromobenzene. As tical conditions suggests that oxidative addition is not turnover
shown in Scheme 6, the Ni(NIXANTPHOS)-based catalyst limiting (Scheme 6).
exhibited higher conversion (64%) aer 4 h at room tempera-
At this point, we can conclude that the Ni(NIXANTPHOS)-
ture than the XANTPHOS analogue (7% conversion by 1H NMR). based catalyst indeed exhibits much higher activity than the
The presence of a signicant quantity of precipitate in the structurally related XANTPHOS derived catalysts. Recall also
reaction with XANTPHOS was cause for concern, however. We that, as noted in the discussion of the initial screening, the
isolated the precipitate by ltration, but attempts to redissolve Ni(NIXANTPHOS) catalyst outperformed the other 36 mono-
it in common organic solvents for the purpose of characteriza- and bidentate phosphines of the initial reactivity screen.
tion were thwarted by the insolubility. It has been reported that Determination of the origin of the difference in reactivity
Pd(XANTPHOS)2 also exhibits very low solubility.33
between Ni(NIXANTPHOS)- and Ni(NIXANTPHOS)-based cata-
We were worried that precipitate formation would decrease lysts has proven challenging in the arylation of 2-benzylpyridine
the amount of active catalyst in the solution. We therefore under our reaction conditions.
synthesized the structurally similar 4,7-di-tert-butyl-XANTPHOS
(t-Bu-XANTPHOS, Scheme 6, see ESI† for details). Palladium
2.5 Determination of the reactivity of the Ni(NIXANTPHOS)-
based catalyst in the arylation of 2-pyridylmethyl amines
complexes of t-Bu-XANTPHOS exhibit greater solubility than
analogous XANTPHOS complexes in palladium catalyzed reac-
tions.28 When t-Bu-XANTPHOS was used in the nickel-catalyzed
reactions, no solubility problems were encountered. However,
we were surprised to nd that under the same conditions the
reaction with t-Bu-XANTPHOS exhibited lower conversions than
both NIXANTPHOS- and XANTPHOS-based catalysts. It is
possible that transmetallation is turnover limiting and the more
As outlined in eqn (1), we previously demonstrated that the
reactivity of the Pd(NIXANTPHOS)-based catalyst is remarkable
compared to other palladium phosphine-based catalyst. Our
hypothesis is this is due to the deprotonation of the palladium-
Scheme 7 Reactivity comparisons with Ni-based catalysts and 2-
pyridylmethyl amine 5a with bromobenzene.
Scheme 6 Reactivity comparisons with Ni-based catalysts.
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Acknowledgements
We thank the National Science Foundation [CHE–1464744] and
National Institutes of Health (NIGMS 104349) for nancial
support. This work is funded by International Graduate
Exchange Program of Beijing Institute of Technology.
Notes and references
Scheme 8 Reactivity comparisons with Ni(NIXANTPHOS) and Ni(X-
ANTPHOS)-based catalysts in the arylation of 2-pyridylmethyl amine
5a with bromobenzene.
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a novel deprotonative cross-coupling process of a 2-pyr-
idylmethyl amine with bromobenzene and LiN(SiMe3)2 as base
(see ESI† for a list of all ligands and details). This reaction and
the results are illustrated in Scheme 7. The Ni(NIXANTPHOS)-
based catalyst exhibited the highest product/internal standard
ratio (2.29), outperforming the other 37 ligands. The other
ligands with the highest product/internal standard ratio were
tBu-MePhos (1.22), di-tBuXPhos (1.20), cataCXium PIntB (1.17),
JohnPhos (1.13), Kwong's indole ligand (1.12)34 and CataXCium
PtB (1.12).35
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NIXANTPHOS. The isolated yield was 93% (Scheme 8). The
XANTPHOS based catalyst, however, exhibited only 24%
conversion under the same reaction conditions.
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3 Conclusions
In summary, we have presented an efficient method to form
triarylmethane derivatives from diarylmethanes and aryl
bromides and chlorides employing a Ni(NIXANTPHOS)-based
catalyst. The method enables functionalization of C(sp3)–H's
and does not require prefunctionalized organometallic
reagents. A reactivity comparison between NIXANTPHOS- and
XANTPHOS-based catalysts points to enhanced reactivity of
NIXANTPHOS-based nickel catalyst. To test the generality of the
Ni(NIXANTPHOS)-based catalyst, a novel arylation of a 2-pyr-
idylmethyl amine was examined. Out of the 37 mono- and
bidentate cross-coupling ligands examined with Ni(COD)2,
NIXANTPHOS again showed the highest reactivity. These results
are the rst hint that the exceptional reactivity of NIXANTPHOS-
based palladium catalysts may be translatable to other transi-
tion metal catalysts. This topic is currently under investigation
in our research group.
6 (a) Shi reported
coupling via
a
Fe-catalyzed cross dehydrogenative
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Friedel–Cras-type mechanism with
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Z. J. Shi, Angew. Chem., Int. Ed., 2009, 48, 3817; (b) Han
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