Origins of unique gold-catalysed chemo- and site-selective C-H functionalization of phenols with diazo compounds

Article abstract of DOI:10.1039/c5sc04319k

In past decade, gold revealed more and more unique properties in carbene chemistry. It was disclosed in our recent communication (J. Am. Chem. Soc. 2014, 136, 6904) that gold carbenes have unprecedented chemo- and site-selectivity and ligand effect toward

Full text of DOI:10.1039/c5sc04319k

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Graphic abstract
The origin of unique gold-catalyzed C-H functionalization of phenols with diazo compounds was disclosed by
combined computational and experimental study.
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Origins of Unique Gold-Catalysed Chemo- and Site-Selective C-H
Functionalization of Phenols with Diazo Compounds
Received 00th January 20xx,
Accepted 00th January 20xx
Yuan Liu,ab‡ Zhunzhun Yu,a‡ John Zenghui Zhang,b Lu Liu,*a Fei Xia,*ab and Junliang Zhang*a
In past decade, gold revealed more and more unique properties in carbene chemistry. It was disclosed by our recent
communication (J. Am. Chem. Soc. 2014, 136, 6904.) that the gold carbenes have an unprecedented chemo- and site-
selectivity and ligand effect toward the functionalization of C-H bond of phenols. In this full article, we report a
comprehensively combined theoretical and experimental study on the mechanism of the insertion of gold carbenes into
the C-H and O-H bonds in phenol. It significantly revealed that the ligands have an important effect on the C-H insertion
and the reaction proceed through a pathway involving the formation of enolate-like intermediate. Moreover, two water
molecules serving as a proton shuttle is believed to be the key issue for achieving the chemoselective C-H functionalization,
which is strongly supported by the DFT calculations and control experiments. It is the first time to give a clear explanation
about the prominent catalysis of gold carbenes toward C-H functionalization based on the theoretical and experimental
study.
DOI: 10.1039/x0xx00000x
www.rsc.org/
overall pathways of aromatic C(sp2)-H insertion with carbene has
been provided so far. To further understand the origin of this
Introduction
unique behaviour of gold carbene8 in site selective C-H
functionalization of phenol, we decided to carry out DFT
calculations and experimental study to gain insights on the
mechanism. Herein, we present a combined computational and
experimental study to elucidate the origin of ligand effect on the
chemoselectivity. Furthermore, the trace amount of water in the
reaction mixture serving as a proton shuttle is proposed to be the
key to give rise to the product Pro-c8 of C-H insertion, which is
supported by our current DFT calculations and control experiments.
Phenols are not only frequently found in natural products and
pharmaceutics, but also powerful versatile platforms in organic
synthesis.1 Thus, the catalytic functionalization of phenols in a
chemo- and site-selective manner is the most encompassing issue
in organic chemistry.2 In this context, the transition-metal-
promoted decomposition of diazo compounds to generate metal
carbenes has broad applications3 in the direct site-selective
functionalizations of phenols. In most cases, the O-H insertion takes
place catalysed by a series of transition-metal catalysts such as
copper, palladium, iron, and rhodium complexes.4 In contrast, very
recently, we and Shi independently found an unprecedented C(sp2)-
H bond functionalization of phenols with α-diazoesters,5 furnishing
para-substituted phenols Pro-c8 via para C-H functionalization
rather than the O-H insertion product Pro-o8. Meanwhile, the
chemoselectivity is heavily dependent on the nature of ligand of
gold catalyst6 (Table 1). Although Nakamura and Pérez etc.7 have
theoretically studied the mechanism on the C(sp3)-H insertion with
carbene as well as Shi and co-workers5b analysed the electronic
structures of gold carbenes by using the Density Functional Theory
(DFT) calculations, no comprehensive mechanistic insight on the
Table 1. Various conditions.
entry Catalyst (5 mol%)
Time
5 min
5 min
12 h
Pro-c8a
Pro-o8a
1b
2b
3b
4
Cu(OTf)2
0
11
9
Cu(OTf)·toluene
[Pd(CH3CN)2Cl2]
Fe(OTf)2
0
0
33
12 h
NR
0
5c
6b
7
FeCl2
12 h
0
[Rh2(OAc)4]
Ph3PAuSbF6
(PhO)3PAuSbF6
5 min
5 min
5 min
0
36
45
0
33
82
8
a NMR yield. b Then conversion of 1 is 100% and the major product is dimer
of 1. c Trace amount of dimer from 1 was detected.
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Figure 1. The calculated free energy profiles G and the corresponding structures of intermediates and transition states along different
possible C-H insertion pathways catalyzed by (PhO)3PAuSbF6. The reasonable pathways are shown in red and other possible pathways are
in blue. All values of free energies are relative to the reactants of gold carbene and phenol and in the units of kcal/mol.
description of noncovalent interactions. The Lanl2dz basis set13
In the previous work on rhodium catalysed intramolecular aromatic
C(sp2)-H insertion reactions, Padwa and Doyle assumed that the
combined with the relativistic effective core potential for the inner
electrons and double zeta basis for covalent electrons was used to
describe the heavy elements Au and P, and the 6-31G* basis set14
was used to describe the nonmetallic elements C, N, O and H. The
frequency analyses were also performed based on the structures
obtained in the gas phase to confirm that the intermediates are
local minimum and the transition states have only one imaginary
frequency. The intrinsic reaction coordinate (IRC) calculations15
were performed to make sure that the crucial transition states
connect the correct reactants and products. The solvent effect of
CH2Cl2 was evaluated with the single point calculations using the
integral equation formalism model (IEFPCM)16 with the dielectric
constant ε = 8.93 based on the structures in gas phase. All discussed
energy values of intermediates and transition states throughout this
paper are the Gibbs free energies in the units of kcal/mol that were
calculated at the temperature 298 K, including the corrections of
solvation free energies from the IEFPCM model. The 3D images of
calculated structures were plotted using GaussView.17 More
structural details of intermediates and transition states can be
found in the Supporting Information.
reactions were triggered by the electrophilic addition of the
metallocarbene intermediate to the aromatic ring, then followed by
a [1,2]-H migration step.9 Nevertheless, the reaction mechanisms
for the prominent activity of gold carbenes toward C-H bonds still
remain elusive. On the other hand, despite Yu and coworkers10 have
performed the mechanistic study of copper- and rhodium-catalysed
O-H insertion of water with carbene using DFT calculations, the
mechanism of gold-catalyzed O-H insertion has not yet been
explored so far. In principle, there are three pivotal questions
unsolved in this transformation: (1) Is the mechanism on the C(sp2)-
H insertion with gold carbenes as same as that of other metals such
as rhodium? (2) What is the origin of ligand effect on the
chemoselectivity? (3) Besides on the ligand, any other factors affect
the chemoselectivity?
Computational Methods
All the DFT calculations were carried out in the Gaussian 09
software package.11 The geometric structure of intermediates and
transition states were optimized and located by using the M06
functional,12 since the M06 functional has been demonstrated to
generate accurate results for the organometallics especially in the
Results and discussion
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On the pathway of C-H functionalization catalysed by 23.6 kcal/mol. Such high activation barriers of TS*-c1 and TS**-c1
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DOI: 10.1039/C5SC04319K
(PhO)3PAuSbF6. It has been widely accepted that the metal catalysts prevent the carbenes from adding at the ortho- and meta-positions
could catalyse the diazo compounds to release N2 and form reactive of phenol. The current DFT results are consistent with our
Au-carbenes, which were regarded as the precursors responsible experimental observations that the addition at the para-sites of
for the C-H bonds insertions.5,8a-e To account for the generation of substituted phenols was the predominant even with bulky steric
crucial precursors preceding C-H insertion, we calculated the hindrance (i.e.3, 5-dimethyl phenol).5a According to the previous
reaction pathways of α-diazoesters and metal catalysts AuL calculations,10 the intermediate Int-c2 may be isomerize to the
(L=(PhO)3P and Ph3P) in solution (Figure S1 of Supporting enolate via the mechanism of [1,3]-metal migration and yield a
Information). The calculated free energy profiles indicate that the stable intermediate. However, it is found that such a stable
generation of Au-carbene species is quite facile and drastically
exothermic, with the low barriers of 6.5 and 11.4 kcal/mol
respectively. Therefore, the gold carbenes and phenol are regarded
as the reactants for the subsequent C-H bond insertion reactions
and the sum of their free energies is set as the benchmark, with the
value of 0.0 kcal/mol.
Figure 1 displays the calculated free energy profiles for the
C(sp2)-H functionalization of phenol with gold carbene with the
(PhO)3P as the ligand, where the structural details of intermediates
and transition states are provided in Supporting Information. The
previous theoretical investigations on the C(sp3)-H insertions of
rhodium, copper or silver carbenes, performed by Nakamura and
Pérez, indicate that the first step of reactions involve the formation
of σ-bond complexes of carbenes and the C(sp3)-H bond.7 Recently,
Pérez and coworkers suggested that the mechanism of aromatic
C(sp2)-H bond insertion might be entirely different from that of
aliphatic C(sp3)-H bond insertion.8c In our DFT calculations, a
transition state TS-c1 with a barrier 15.6 kcal/mol is located for the
addition of gold carbene at para-position of phenol. The TS-c1
represents the transition state of direct C(sp2)-C(sp2) coupling of
phenol and gold carbene, leading to the final para-C-H insertion
product Int-c2. Accordingly, the addition of carbene at the ortho
site of phenols gives rise to an intermediate Int*-c2 with higher
energy (8.2 kcal/mol vs Int-c2’s 3.1 kcal/mol) via the transition state Figure 2. Optimized structures of transition states TS-c3 and TS*-c3
TS*-c1 with 19.3 kcal/mol. It is not surprising to find that the meta- corresponding to Figure 1. The distances are in the units of
position of phenol is the most unfavourable site for the addition angstroms and the values of free energies G are in kcal/mol.
with gold carbene, which needs an activation energy barrier up to
Figure 3. The structures of TS-c6-1w, TS-c6-2w, TS-c7-1w and TS-c7-2w in the pathways of C-H functionalization of phenol catalysed by
(PhO)3PAuSbF6. The values of free energy barriers G are in kcal/mol.
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intermediate hardly exists after the [1,3]-Au migration in Int-c2, The calculated distance between the oxygen and hydrogen atom in
since a kind of cyclopropanation product of Büchner reaction is TS-c6-2w of Figure 3 are 1.87 Å and its energy is 2.2 kcal/mol lower
obtained, as shown by Int*-c4.18 Meanwhile, this process of [1,3]- than that of TS*-c6-2w, indicating a possible stabilization effect of
Au migration seems to be unfavorable in energetics, with the the metal complex (PhO)3PAu+ for the water chain in TS-c6-2w.
endothermicity of 9.1 kcal/mol to give Int*-c4. Additionally, in order
to examine whether the commonly accepted mechanism of direct
[1,2]-H shift is feasible, we located the transition state TS*-c3 with
the corresponding structure displayed in Figure 2. Our calculated
results imply that TS*-c3 has a considerable barrier of 30.1 kcal/mol,
which could definitely rule out the mechanism of direct [1,2]-H shift
in Int-c2. During the course of optimization, we happened to
hypothesize that the carbonyl oxygen atom may intend to directly
abstract the proton at the original para-site of phenol via a five-
membered transition state TS-c3 in Figure 2, to generate Int-c4.
This process is quite facile according to the current calculations,
merely with a small barrier 8.6 kcal/mol. Also, the Int-c4 is more
stable than Int*-c4 by 17.6 kcal/mol. Subsequently, the
intermediate Int-c4 undergoes an unexpected isomerization to the
enol Int-c5 through
a [1,3]-migration of the metal complex
(PhO)3PAu+ to the phenyl ring rather than Int*-c5.
Scheme 1. Control experiments.
Two possible pathways might exist between the enol Int-c5 and
the final product Pro-c8. One is the gold-associated pathway, where
the proton transfers through TS-c6-1w or TS-c6-2w to yield the
intermediate Int-c7. Then, the metal complex (PhO)3PAu+
dissociates from Int-c7 to yield Pro-c8. The other is the gold-free
pathway, where the catalyst (PhO)3PAu+ firstly dissociates from Int-
c5 to yield the gold-free Int-c6 and then proton transfer occurs via
TS-c7-1w or TS-c7-2w to yield Pro-c8. As far as the two pathways
are concerned, the key question is how the proton transfers from
the hydroxyl to the final carbon in enol? In this work, we propose
that the water in solvent plays a crucial role in undertaking the
remote proton shuttle. Based on this proposal, we located the one-
water assisted transition states TS-c6-1w and TS-c7-1w, as well as
the two-water assisted transition states TS-c6-2w and TS-c7-2w
along the reaction pathways, with the corresponding activation
energy barriers of elementary steps displayed in Figure 3. The DFT
results indicate that TS-c6-1w and TS-c7-1w involving one water
molecule has higher energy barriers than that two-water assisted
TS-c6-2w and TS-c7-2w. Figure 3 shows that the carboxyl group in
TS-c6-1w and TS-c7-1w has to distort from the planar structures to
form the hydrogen bonds with H2O, but they still remain planar in
TS-c6-2w and TS-c7-2w. The structural distortion in TS-c6-1w and
TS-c7-1w might be the reason why they are in the high energy
states. Interestingly, it is found that the oxygen atoms in the metal
ligand (PhO)3P form hydrogen bonding interactions with the shuttle
waters in TS-c6-2w, whereas it doesn’t exist in another located
transition state TS*-c6-2w (Figure S2 in Supporting Information).
Control experiments were carried out in our lab (Scheme 1) to
demonstrate the proposed mechanisms of gold carbene insertion
into the C-H bond of phenol. When 1 equivalent of D2O was added
into the reaction system, and product Pro-o8 was deuterated with
the percentage of 22% (eq. 1). The relative low deuterium ratio
might be attributed to the existence of trace amount of H2O19 that
could also undertake the function of proton transfer. Additionally, it
is well known that the hydrogen in the OH group of phenol could
readily exchange with the deuterium in D2O, which leads to the
increased H2O or DOH in solution. If a great number of H2O
participate in the process of proton shuttle, the ratio of deuterated
product Pro-o8 will definitely decrease. We also considered the
possibility whether the phenols can serve as the proton shuttle.
However, the calculated energy barrier between the transition state
structure TS-c6-2p (Supporting Information) and Int-c5 for the [1,3]-
H shift is highly up to 36.1 kcal/mol, which implies it hardly occurs.
The eq. 2 manifests that the direct proton exchange of Pro-o8 with
D2O is impossible under the reaction conditions. More importantly,
the eq.3 demonstrates that the reaction of 1 and deuterated phenol
2-5d gives rise to the product Pro-o8 without deuterium, which
support the direct [1,2]-H shift9 (TS*-c3) indeed does not occur in
this case. The control experiments demonstrate that this kind of C-
H bond insertion reactions governed by gold-carbene follows a
novel mechanism involving water assisting process, rather than the
previous commonly proposed direct [1,2]-H shift.5,8a,8c, 9
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Figure 4. The calculated free energy profiles G and corresponding structures of intermediates and transtion states along different possible
O-H insertion pathways catalyzed by (PhO)3PAuSbF6. The reasonable pathway is shown in red and other possible pathways are in blue. All
values of free energies are relative to the reactants of gold carbene and phenol and in the units of kcal/mol
Proposed pathway of O-H insertion catalysed by (PhO)3PAuSbF6. the DFT calculations reveal that the thermal stability of
We next turn to address the question why the O-H insertion of intermediate of C-H insertion remarkably differs from that of O-H
phenol does not occur with the (PhO)3PAuSbF6 as the catalyst. In
Figure 4, the calculated results show that an oxonium ylide20 Int-o2
formed through the TS-o1 with a modest barrier. In the case of O-H
bond insertion, a possible migration of complex LAu+ to the
carbonyl group in Int-o2 is also taken into account, but the resulted
structure Int*-o4 is quite high in energy. The oxonium ylide Int-o2
tends to isomerize to the more stable Int-o4 via the TS-o3. The
migration of gold catalyst to the phenyl group in Int-o4 leads to the
isomer Int-o5. It should note that Int*-o5 is quite unstable in
energetics, where the gold complex attaches to the oxygen atom in
the hydroxyl group. Similar to the mechanism of C-H insertion in
Figure 1, the rearrangements of Int-o5 to Pro-o8 pass through the
gold-associated or gold-free pathways via the specific water-
assisted transition states. We also locate the two-water assisted
transition states TS-o6-2w for the gold-associated pathway and TS-
o7-2w for the gold-free pathway, respectively (Figure 5). The
activation barrier of TS-o6-2w (15.8 kcal/mol) is relatively lower
that of TS-o7-2w (18.4 kcal/mol), indicate that the transformation
of Int-o5 to Pro-o8 favours the gold-associated pathway via the TS-
o6-2w rather than TS-o7-2w.
Rationale of the Chemoselectivity. Compared these two
competitive reaction pathways in Figure 1 and Figure 4, it reveals
that both two rearrangements from Int-c5 or Int-o5 to the final
products are the rate-determining steps in the overall pathways,
with the almost same total barriers of 21.8 kcal/mol. Nevertheless,
Figure 5. The structures of TS-o6-2w and TS-o7-2w in the proposed
O-H functionalization of phenols catalysed by (PhO)3PAuSbF6. The
distances are in the units of angstroms and the values of free
energy barriers G are in kcal/mol.
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insertion. For example, the intermediate Int-c4 is more stable than
Int-o4 by 9.1 kcal/mol, with the exothermic energy 8.5 kcal/mol. As
for the final products, the energy of Pro-c8 is 10.8 kcal/mol lower
than the O-H insertion product Pro-o8. Besides, the endothermicity
of TS-c6-2w is 13.3 kcal/mol, whereas the corresponding energy of
TS-o6-2w is up to 22.4 kcal/mol relative to the sum of reactants.
Such a large endothermicity of TS-o6-2w means that it is more
difficult to pass through it to reach the product though the collision
in solution. The calculated reaction pathways in Figure 1 and Figure
4 reveal that the stability of intermediates plays an important role
in chemoselectivity and account for the unique chemoselectivity
toward the C(sp2)-H insertion.
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In order to further understand the chemoselectivity, the
reactions of phenol with α-phenyldiazoester catalysed by
(PhO)3PAuSbF6 at different temperatures were also carried out. The
ratios of Pro-c8 : Pro-o8 decreased from >20:1 to 2.5:1 along with
Figure 6. The reaction temperature on the chemoselectivity and the
competitive pathways for the formation of two key intermediates.
All values of free energies are relative to the reactants of gold
carbene and phenol and in the units of kcal/mol.
o
lowering the reaction temperature from rt to -40 C (Figure 6; For
details, see Supporting Information). These results indicated that
the C-H functionalization process was more favored at high
temperature than low temperature. According to the free energy
showed in Figure 1 and Figure 4, Int-c4 and Int-o4 should be the key
intermediates for C-H functionalization and O-H insertion. As shown
in Figure 6, Int-c4 was more stable via higher barrier whilst Int-o4
was more unstable via lower barrier. That is, the formation of Int-c4
was the process of thermodynamic control, leading to the C-H
functionalization. In contrast, the generation of Int-o4 underwent
kinetic control, leading to the O-H insertion. The control
experiments at different temperatures and DFT calculations are in
excellent consistency.
corresponding pathways in Figure 1 and Figure 4, we found that the
ligand Ph3P has a remarkable electronic effect on the change of
dynamics barriers of electrophilic addition to intermediates Int-o12
and Int-c12. For the C-H insertion, the addition barrier via TS-c9 was
enhanced to be 18.2 kcal/mol, with 2.6 kcal/mol higher than that of
TS-c1. In contrast, the barrier of O-H insertion via TS-o9 lowers from
13.0 to 11.8 kcal/mol. It is no doubt that the change of the barriers
of addition is disadvantageous to the C-H insertion but
advantageous to O-H insertion. On the other hand, the calculated
barrier of hydrogen transfer via TS-o15-2w in O-H insertion is 18.0
kcal/mol, relatively lower than the barrier of 22.0 kcal/mol C-H
insertion. Therefore, the reaction of C-H insertion shown in Figure 6
is significantly slowed down in comparison to the case catalysed by
Two competitive pathways catalyzed by Ph3PAuSbF6.
Additionally, the mechanisms of C-H and O-H insertions of phenol
catalyzed by Ph3PAuSbF6 are also shown in Figure 6, with the
corresponding barriers listed in Table 2. One hand, compared to the
Figure 7. The competitive pathways of C-H and O-H insertion catalyzed by Ph3PAuSbF6. The two reasonable pathways are shown in red and
other possible pathways in blue. All values of free energies are relative to the reactants of gold carbenes and phenol and in the units of
kcal/mol.
6 | J. Name., 2012, 00, 1-3
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(PhO)3PAuSbF6 in Figure 1. Products of C-H insertions are still
more stable than the counterparts of O-H insertion in
thermodynamics according to the current DFT calculations.
Considering both the dynamic and thermodynamic effects, the
calculated pathways could account for the low chemoselectivity
for Pro-c8 and Pro-o8 catalysed by Ph3PAuSbF6 that has been
observed in our experiments.
Notes and references
1
Synthetic and Natural Phenols, ed. J. H. P. Tyman, Elsevier,
1996.
For recent highlights, see: (a) D.-G. Yu, F. de Azambuja and F.
Glorius, Angew. Chem. Int. Ed., 2014, 53, 7710; (b) P.
MacLellan, Nat. Chem., 2014, 6, 375; For selected examples,
2
see: (c) R. B. Bedford, S. J. Coles, M. B. Hursthouse and M. E.
Limmert, Angew. Chem. Int. Ed., 2003, 42, 112; (d) R. B.
Bedford and M. E. Limmert, J. Org. Chem., 2003, 68, 8669; (e)
J. Luo, S. Preciado and I. Larrosa, J. Am. Chem. Soc., 2014,
Table 2. The calculated free energetic spans G of hydrogen
transfer through transition states (TSs) assisted by one water and
two water molecules in Figure 6. The values of G are in the
units of kcal/mol.
136, 4109; (f) R. Zhu, J. Wei and Z.-J. Shi, Chem. Sci., 2013, 4,
3706; (g) Z. Huang, L. Jin, Y. Feng, P. Peng, H. Yi and A. Lei,
Angew. Chem. Int. Ed., 2013, 52, 7151; (h) Z. Wu, F. Luo, S.
Chen, Z. Li, H. Xiang and X. Zhou, Chem. Commun., 2013, 49
,
7653; (i) H.-X. Dai, G. Li, X.-G. Zhang, A. F. Stepan and J.-Q. Yu,
J. Am. Chem. Soc., 2013, 135, 7567; ( eoane,
asano a, i ones, ascare as and M. Gulías, J. Am.
Chem. Soc., 2014, 136, 834; (k) Y. E. Lee, T. Cao, C. Torruellas
and M. C. Kozlowski, J. Am. Chem. Soc., 2014, 136, 6782; (l) C.
S. Sevov and J. F. Hartwig, J. Am. Chem. Soc., 2013, 135, 9303;
(m) K. V. N. Esguerra, Y. Fall, L. Petitjean and J.-P. Lumb, J.
Am. Chem. Soc., 2014, 136, 7662; (n) Y. Kuninobu, T. Matsuki
and K. Takai, J. Am. Chem. Soc., 2009, 131, 9914; (o) C.-L.
Ciana, R. J. Phipps, J. R. Brandt, F.-M. Meyer and M. J. Gaunt,
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TSs
TS-c14-2w
TS-c15-2w
TS-o14-2w
TS-o15-2w
G
24.1
22.0
20.5
18.0
Conclusions
In summary, the origin of unique chemoselectivity of C-H bond
functionalization of phenol with diazo compounds catalyzed by
(PhO)3PAuSbF6 is due to its high thermodynamic stability of
intermediates and products, as well as the modest energy barrier of
the rate-determining step. It is the first time to propose that the
reactions of gold carbenes with phenol pass through the specific
pathways involving the formation of stable enol. The hydrogen
transfers in the rearrangements from enol to final products follow a
novel reaction pathway with the two water molecules serving as a
proton shuttle rather than the previous commonly proposed direct
[1,2]-H shift. The DFT calculations also reveal that the oxygen atoms
in the ligand (PhO)3P play an important role in stabilizing the
transition states of hydrogen transfer. The observed ligand effects
of metal complexes on the reaction pathways are well rationalized
based on the results of present DFT calculations. The novel
mechanistic insights delineated above will refine the model of gold
catalyst in carbene chemistry and contribute to the future
development of this field as well as the rational designing in chemo-
and site-selective organic transformation.
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Acknowledgements
Financial support by the 973 Program (2011CB808600),
Shanghai Pujiang Program (14PJ1403100), National Natural
Science Foundation of China (21572065, 21433004, 21473056,
21425205), Changjiang Scholars and Innovative Research Team
in University (PCSIRT) are greatly appreciated. We
acknowledge the support of the NYU-ECNU Center for
Computational Chemistry at NYU Shanghai.
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8 | J. Name., 2012, 00, 1-3
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