Heteroatom-substituted secondary phosphine oxides for Suzuki-Miyaura cross-coupling reactions

Article abstract of DOI:10.1016/j.jorganchem.2016.02.007

Several di-substituted diimines (3a–3f) and heteroatom-substituted unsaturated secondary phosphine oxides (HASPO, 6a–6f) were prepared and characterized. Compounds 6a–6f are regarded as pre-ligands because of their ability of tautomerization to heteroatom-substituted phosphinous acid (HAPA, 7a–7f). An unexpected 3e-coordinated palladium dibromide 8e was observed from the reaction of compound 6e with PdBr₂. Molecular structures of pre-ligands 6a, 6c, and 6e, as well as palladium complexes 8e were determined by single crystal X-ray diffraction methods. When pre-ligand 6a was applied to palladium-catalyzed Suzuki-Miyaura cross-coupling reactions, satisfactory yields were obtained. Density functional theory were employed to examine the electronic properties of HASPO 6a–6f pre-ligands, their corresponding 1,3-di-N-substituted tautomers 7a–7f, and the saturated counterpart 7as of 7a. Compound 7a is the most effective and genuine ligand in Suzuki-Miyaura reaction that is confirmed by its higher-lying lone-pair (LP) molecular orbital (HOMO-1). The LP orbital of 7c–7f is lower-lying HOMO-5. For each 7c–7f, two conformational rotamers with minute energy difference were located. Hirshfeld charge and population analysis of 7c–7f were also calculated in order to comprehend the electronic properties for these two rotamers for each HAPAs. Besides, the steric effect of HAPAs was estimated in terms of the Percent Buried Volume (%V_bur). This model has shown that 7a has similar steric property to that of PCy₃, which is an effective ligand in Suzuki-coupling reactions.

Full text of DOI:10.1016/j.jorganchem.2016.02.007

Accepted Manuscript
Heteroatom-Substituted Secondary Phosphine Oxides for Suzuki-Miyaura Cross-
coupling Reactions
Yu-Chang Chang, Yi-Chang Lee, Meng-Fan Chang, Fung-E. Hong
PII:
S0022-328X(16)30040-7
10.1016/j.jorganchem.2016.02.007
JOM 19391
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 19 November 2015
Revised Date: 29 January 2016
Accepted Date: 2 February 2016
Please cite this article as: Y.-C. Chang, Y.-C. Lee, M.-F. Chang, F.-E Hong, Heteroatom-Substituted
Secondary Phosphine Oxides for Suzuki-Miyaura Cross-coupling Reactions, Journal of Organometallic
Chemistry (2016), doi: 10.1016/j.jorganchem.2016.02.007.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Heteroatom-Substituted Secondary Phosphine Oxides for Suzuki-Miyaura
Cross-coupling Reactions
Yu-Chang Chang, Yi-Chang Lee, Meng-Fan Chang, Fung-E Hong*
Department of Chemistry
National Chung Hsing University
250 Kuo-Kuang Road, Taichung 40227, Taiwan
E-mail: fehong@dragon.nchu.edu.tw
HAPA 7c
LP orbital
HAPA 7a
LP orbital
HOMO-1: -6.75 eV HOMO-5: -7.29 eV

ACCEPTED MANUSCRIPT
Heteroatom-Substituted Secondary Phosphine Oxides for Suzuki-Miyaura
Cross-coupling Reactions
Yu-Chang Chang, Yi-Chang Lee, Meng-Fan Chang, Fung-E Hong*
Department of Chemistry, National Chung Hsing University,
250 Kuo-Kuang Road, Taichung 40227, Taiwan
E-mail: fehong@dragon.nchu.edu.tw
* Author to whom correspondence should be addressed
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Abstract
Several di-substituted diimines (3a-3f) and heteroatom-substituted unsaturated
secondary phosphine oxides (HASPO, 6a-6f) were prepared and characterized.
Compounds 6a-6f are regarded as pre-ligands because of their ability of
tautomerization to heteroatom-substituted phosphinous acid (HAPA, 7a-7f). An
unexpected 3e-coordinated palladium dibromide 8e was observed from the reaction of
compound 6e with PdBr2. Molecular structures of pre-ligands 6a, 6c, and 6e, as well
as palladium complexes 8e were determined by single crystal X-ray diffraction
methods. When pre-ligand 6a was applied to palladium-catalyzed Suzuki-Miyaura
cross-coupling reactions, satisfactory yields were obtained. Density functional theory
were employed to examine the electronic properties of HASPO 6a-6f pre-ligands,
their corresponding 1,3-di-N-substituted tautomers 7a-7f, and the saturated
counterpart 7as of 7a. Compound 7a is the most effective and genuine ligand in
Suzuki-Miyaura reaction that is confirmed by its higher-lying lone-pair (LP)
molecular orbital (HOMO-1). The LP orbital of 7c-7f is lower- lying HOMO-5. For
each 7c-7f, two conformational rotamers with minute energy difference were located.
Hirshfeld charge and population analysis of 7c-7f were also calculated in order to
comprehend the electronic properties for these two rotamers for each HAPAs.
Besides, the steric effect of HAPAs was estimated in terms of the Percent Buried
Volume (%Vbur). This model has shown that 7a has similar steric property to that of
PCy3, which is an effective ligand in Suzuki-coupling reactions.
Keywords: C-C coupling; Heteroatom Substituted Secondary Phosphine Oxide
(HASPO); Palladium; Density Functional Theory (DFT); Steric Effect.
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Introduction
Modern synthetic chemistry has cherished the grand triumphs concerning the
utilization of transition-metal complexes in catalyzing cross-coupling reactions for
making new C-X (X = C, N, O, S, etc.) bonds.[1-5] In particular, Suzuki-Miyaura
cross-coupling reaction is one of the most useful means for making C(sp2)-C(sp2)
bond.[6] Since its first report in 1979,[7-8] the scope of this reaction has been
extensively investigated by both experimental and computational approaches.[9-19]
Typically, the reaction is carried out with arylboronic acid and arylhalide, aryltriflate
or alkylhalide as substrates which is combined with a ligand-assisted palladium
complex and well-chosen base.[20-24]
Various types and shapes of ligands play crucial roles in the success of these
kinds of transition-metal catalyzed reactions.[25-26] Accordingly, searching for
efficient and accessible ligands has been one of the foremost missions for synthetic
chemists.[5, 27-30] Up to the present, numerous types and shapes of trialkyl- or
triaryl-phosphines have long been favorite choices due to their tunable steric and
electronic properties through delicate adjustment of the substituents on the
phosphorus atom.[31-34] Nevertheless, these electron-rich organophosphines are
vulnerable to oxidation and thereafter lose their coordinating abilities toward soft
metals, leading to great reduction on catalytic performances. Hence, it is an
undesirable property for soft phosphine ligands in terms of long-term storage.
Recently, several promising alternatives such as N-heterocyclic carbenes, oximes,
diazabutadienes, amines and imines are claimed to have advantages of low
environmental impact and less sensitivity towards air.[35-48] In spite of the successes
of these auxiliary ligands in catalysis, phosphines remain the most favorable choice
for ligand-assisted transition-metal-catalyzed reactions, providing its inclination
towards oxidation can be avoided.[49]
The pentavalent secondary phosphine oxides (R’R”PH(=O), SPO) could be a
solution to achieve stability desperately needed.[50] SPO is stable towards oxidation
and can be converted to phosphinous acid (R’R”POH, PA) through tautomerization
(Scheme1).[51-74] With the existence of metal fragment [MLn], the equilibrium of
SPO-to-PA is shifted to PA for ligand association. The formation of PA-coordinated
palladium complexes thereafter could work for various cross-coupling reactions.[75-
79]
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HO
O
R
[MLn]
H
HO
P
P
[MLnꢀ1
]
P
R'
R'
R'
R
R
Secondary Phosphine
Oxide (SPO)
Phosphinous Acid
(PA)
PAꢀcoordinated
metal complex
Scheme 1. The tautomerization of phosphinous acid (PA) and PA-coordinated metal
complex.
In the past few years, various kinds of SPOs were prepared and their ability as
effective ligands in cross-coupling reactions have been reported.[51-73, 80-83]
Recently, Ackermann had demonstrated the potential application of saturated
heteroatom-substituted secondary phosphine oxides (HASPO Ia, II-IV in Diagram 1),
which are inexpensive and ambient-stable with high steric hindrance via substitutions
on phosphorus atom, in various palladium-catalyzed cross-coupling reactions.[63, 84-
91] Most of these ligands are effective even in the cases of using arylchlorides as
substrates. When nickel-based pre-catalyst is loaded with saturated HASPO ligands,
cross-coupling reactions with unreactive electron-deficient or steric-crowded aryl-
halides can be accomplished at ambient temperature.[92-93] Particularly, in the broad
field of cross-coupling reactions, many researchers show interests towards
diaminophosphine oxide, which has structural resemblance to N-heterocyclic
carbene.[94]
Diagram 1. Selected heteroatom-substituted secondary phosphine oxides (HASPO).
Herein we report the preparation and characterization of several unsaturated
diaminophosphine oxides (Ib-type). Their capacities as efficient auxiliary ligands in
palladium-catalyzed Suzuki-Miyaura cross-coupling reactions were investigated.
Preliminary catalytic screening revealed that with 1,3-di-tert-butyl substituted
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HASPO 6a a satisfactory catalytic performance was obtained. Hereby, density
functional theory (DFT) and the Percent Buried Volume (%Vbur) methods were
employed to examine the electronic and steric properties of saturated heteroatom-
substituted phosphinous acid (saturated HAPA 7as) and unsaturated
diaminophosphine oxides (unsaturated HAPA 7a-7f), respectively. The effectiveness
of phosphinous acid HAPA 7a (the genuine ligand, a tautomer of pre-ligand HASPO
6a) in the Suzuki-Miyaura cross-coupling reactions is examined by DFT calculations
in conjugation with its adequate steric property (%Vbur).
Results and Discussion
Preparation of diimines (3a-3f) and heteroatom-substituted secondary phosphine
oxides (HASPO) (6a-6f)
Six diimines (3a-3f) were prepared in fair to good yields from the reactions of
anilines with oxalaldehyde or biacetyl (Scheme 2). Intermediates 4a-4f could be
obtained in further reactions of 3a-3f with PBr3 in the presence of excess cyclohexene
in dichloromethane at 25 °C for 12 hours. Subsequently, reactions of 4a-4f with
diethylamine at 25 °C for 2 hours presumably yielded intermediates 5a-5f. The
targeted HASOPs 6a-6f (Scheme 2) were obtained after the hydrolysis of 5a-5f and
thereafter workup.
Scheme 2. Preparation of diimines (3a-3f) and heteroatom-substituted secondary
phosphine oxides (6a-6f).
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All six HASPOs, 6a-6f, were characterized by spectroscopic methods.[95] A
distinctively large coupling constant (JP-H) around 650 Hz for all compounds strongly
substantiates the existence of a P-H bond. Molecular structures of compounds 6a, 6c
and 6e were revealed by single-crystal X-ray diffraction methods and their ORTEP
diagrams are depicted in Figure 1. The existence of double bonds between
P=O/alkenyl C=C on the five-membered ring of 6a, 6c and 6e are reflected on their
bond lengths of 1.4735(10)/1.3270(18) Å, 1.4555(18)/1.323(2) Å and 1.4746(13)/
1.338(2), respectively. The five atoms on the five-membered ring of 6a, 6c or 6e are
roughly coplanar, a characteristic for the delocalization of π-electron density on the
ring.
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Figure 1. ORTEP plots of 6a, 6c and 6e. Some hydrogen atoms are omitted for clarity.
Unexpected results from reactions of 6c or 6e with palladium salts
As HAPA tautomer is the genuine auxiliary ligand in a catalytic reaction,
molecular structures of 7a-7f are illustrated in Diagram 2. Attempts to prepare
HAPA-coordinated palladium complexes followed by structural determination were
carried out. Monitored by 31P NMR, HASPO 6e was reacted with PdBr2 in THF at 25
°C for 2 hours. The disappearance of the large coupling constant of JP-H might
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indicate the conversion of 6e to its phosphinous acid 7e and presumably the formation
of a 7e-coordinated palladium complex, trans-PdBr2(7e) or cis-PdBr2(7e) (Scheme 3).
Nevertheless, an unexpected 3e-coordinated palladium complex 8e (PdBr2(3e)), was
obtained while attempting to grow crystals in a THF solution. The crystal structure of
8e was determined by single-crystal X-ray diffraction methods and the ORTEP
drawing is depicted in Figure 2. A closely related PdCl2(3e) complex was reported
previously.[96] The conversion of 7e to 8e implies that the P-N bond in 6e is weak in
the presence of trace amount of water in the duration of crystal growing process. The
formation of 8e also indicates that diimine itself having the capacity as a bi-dentate
ligand towards palladium metal.
Diagram 2. Selected HAPA 7a-7f (tautomers of pre-ligands HASPO 6a-6f).
Scheme 3. The formation of 6e-coordinated palladium complex 8e.
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Figure 2. ORTEP diagram of 8e. Hydrogen atoms are omitted for clarity.
Palladium-catalyzed Suzuki-Miyaura reactions using 6a-6f as pre-ligands
HASPOs 6a-6f had been employed as ligands in palladium catalyzed Suzuki-
Miyaura cross-coupling reactions of aryl halides and phenylboronic acid. To find out
the optimized condition for the reaction, several factors that affect the efficiency of
the reactions, including ligand/palladium ratios, solvent, base, temperature, time etc.,
had been screened. The designated procedure for the catalytic reaction is shown
below. Into a 20 mL Schlenk tube was placed with 1.0 mmol of arylhalides, 1.5 mmol
of phenylboronic acid, 2.0 mol% of palladium salt and 4.0 mol% of 6a-6f, 1.0 mL of
solvent, and 3.0 mmol of base. The operation was carried out under nitrogen
atmosphere. The mixture was stirred at designated temperature and reaction time and
then was followed by programmed work-up. Among all the six 6a-6f, 6a stands out as
the best choice from the preliminary screening. It is consistent with the common
observation that an adequately bulky ligand is favourable in Suzuki-Miyaura reactions
for reductive elimination, one of the three major elementary steps in cross-coupling
reactions. As known, arylchloride is less reactive than that of arylbromide due to the
stronger C(sp2)-Cl bond. The catalytic ability of 6a in Suzuki-Miyaura reaction could
be better discerned by using arylchlorides as reactant rathar than arylbromides.
Therefore, 6a is chosen as the ligand and arylchlorides as the halide sources for the
optimization of reaction condition hereafter.
It was reported that rather low reactivity was observed in the absence of base
for Suzuki-Miyaura reaction. The role played by base is probably the most ambiguous
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and unpredictable one among all the factors that affect the catalytic efficiency.[39, 97-
98] Thereby, the impact of employing different bases on the reaction yields was firstly
investigated and the results are shown in Table 1. Among all the bases screened, it
was found that KOtBu in THF is the most effective pair (Table 1, Entry 1); while
other bases such as NaOH, Na2CO3, K2CO3, Cs2CO3 and K3PO4ꢀnH2O gave poor
yields of product. As suspected, the cation of the base, besides its basicity, could be
another key factor in this reaction with arylchlorides and using 6a as ligand.
Table 1. Suzuki coupling reactions employing various bases[a].
Entry
Base
KOtBu
Conv.(%)[b][c]
Conv.(%)[b][d]
1
2
3
4
5
6
7
8
90
43
-
99
46
42
14
11
9
NaOtBu
KOH
NaOH
5
K2CO3
<5
5
Cs2CO3
Na2CO3
K3PO4ꢀnH2O
<5
<5
<5
<5
[a] Condition: 1.0 mmol 3-chlorotoluene, 1.5 mmol phenylboronic acid, 3.0
mmol base, 2 mL THF, and 2 mol % Pd(OAc)2, [Pd]:6a=1:2, 60 oC; [b] Determined
by NMR; [c] Reacted for 5 hours; [d] Reacted for 16 hours.
The solubility of substances and catalyst in a solvent is greatly affected by the
polarity of it. As a result, a proper combination of solvent/base system is crucial to the
ultimate performance of the catalytic reaction. As shown, the combination of KOtBu
with THF leads to the best result (Table 2, Entry 1). In addition, the concentration of
the reactant, by changing the amount of solvent, in fact affects the rate of the reaction.
The more concentrated solution, the better performance it will be (Table 2, Entry 2). It
was also found that higher temperature than 25 oC is required to reach its reasonably
catalytic performance (Table 2, Entry 3). This could be a characteristic for loading
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HASPO as auxiliary ligand because the HASPO-to-HAPA tautomerization is an
endothermic process.
Table 2. Suzuki coupling reactions employing various solvents.[a]
Entry
Solvent
THF
Volume (ml)
Temp (oC)
Conv.(%) [b]
1
2
3
4
5
2
1
1
2
2
60
60
25
60
60
85
94
<5
78
42
THF
THF
Toluene
1,4-dioxane
[a] Reaction condition is the same as in the footnote of Table 1 except using
3.0 mmol KOtBu as base and 3 hours for reaction; [b] Determined by NMR.
Subsequently, the performances of several commonly used palladium sources
were screened for this reaction. As shown in Table 3, the best yield was obtained
while using Pd(OAc)2 as the palladium source and the ratio of 6a to palladium salt is
2:1 (Table 3, Entries 1 & 3). It is consistent with the observations reported in the
literature.[99] As known, Pd(OAc)2 is more readily to be reduced to zero-valence in
the presence of electron-rich phosphine than the halogenated palladium salt PdX2
(Table 3, Entries 4-7).[95, 100-101] Unexpectedly, rather poor performance was
observed for a zero-valence palladium source, Pd2(dba)3 (Table 3, Entry 8).
Table 3. Suzuki coupling reactions employing various Pd sources.[a]
Entry
Pd source
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(COD)Cl2
PdCl2
Pd : L
1 : 2
1 : 1
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
Time (hrs)
Conv.(%) [b]
1
2
3
4
5
6
7
2
2
3
2
3
3
2
65
48
94
<5
<5
<5
5
PdBr2
[(η3-C3H5)PdCl]2
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8
Pd2(dba)3
1 : 2
2
<5
[a] Reaction condition is the same as in the footnote of Table 1 except for
using different palladium sources; [b] Determined by NMR.
Further examination of the effect caused by substituent on arylhalides such as
substituted arylchlorides and 2-chloropyridine were carried out (Table 4). The general
observation in Suzuki-Miyaura reaction shows that a better conversion is achieved
with aryl halides bearing an electron-withdrawing than an electron-donating
group.[102] It is presumably held for the reaction while the oxidative addition process
is the rate-determining-step. Nevertheless, other unanticipated factors might perturb
this conclusion occasionally. As shown in Table 4, the catalytic performances did not
obey this rule in a regular pattern as stated above. For the cases with electron-
donating substituent, -CH3, the best performance is found for the substituent with less
steric hindrance (Entries 3 vs. 2). Relatively poor performance was observed for 1-(4-
chlorophenyl)ethanone, substance with an electron-withdrawing group (Entry 4). By
contrast, it performed rather effectively for 1-chloro-4-(trifluoromethyl)benzene
(Entry 5). Generally, poor performance has been the result for using heterocyclic ring
as halide source. Nevertheless, fair efficiency was observed for pyridyl case (Entry 6).
Finally, 92 % in yield was observed for the electron-donating case of 1-chloro-4-
methoxybenzene even after 24 hours in reaction (Entry 7).
In general, the performance of 6a as a phosphine source in Suzuki-Miyaura
coupling reactions for various aryl chlorides is better than that of its saturated
counterpart from Ackermann’s work.[84] The reactions using 7a as a phosphine
ligand took shorter time to reach better yields.
Table 4. Suzuki-Miyaura coupling reactions employing various aryl chlorides[a]
Entry
1
Aryl halide
Product
Time (h)
5
Yield(%)[b]
42
2
3
5
5
71
94
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4
5
42
5
6
7
5
5
93
81
92
24
[a] Condition: 1.0 mmol arylchloride, 1.5 mmol phenylboronic acid, 3.0 mmol KOtBu,
1 mL THF, 2 mol % Pd source, [Pd]:6c=1:2, 60 oC; [b] Yield of isolated product.
For comparison, Suzuki-Miyaura coupling reaction for 4’-bromoacetophenone
with phenylboronic acid was carried out employing selected diamines (3e-3m) and
HASPOs (6e-6f). Preliminary results showed that HASPOs exhibited better catalytic
efficiency than that of using diamines as ligands. It indicates that the active species in
the reaction while using HASPO as pre-ligand could be different from the diamine-
chelated palladium complex, although a crystal structure of this type of complex 8e
was obtained and determined from the reaction of 6e with PdBr2.
Computational Studies of electronic and steric properties
Density functional calculations (DFT)
DFT calculations were carried out to clarify the experimental observation that
HAPA 7a is superior to 7b-7f as auxiliary ligand in the Suzuki-Miyaura cross-
coupling reaction. Geometry optimization and frequency calculations were done with
the B3LYP functional in conjugation with 6-311+(3df) for phosphorus and 6-
311+(2d,p) for the other atoms. Optimized structures were confirmed to be a local
minimum on the potential energy surface by all positive elements in their
corresponding Hessian matrix.
HASPO 6a-6f and cis- and trans-rotamers of HAPA 7a-7f and 7as
Two rotamers of HAPA 7a-7f were located on the potential energy surface
during geometry optimization (Diagram 3: cis-rotamer 1 with -OH group pointing to
the same side with phosphorus lone pair electrons, while that of trans-rotamer 2
points to the opposite side).[103] 7as is the saturated HAPA counterpart of 7a. The
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relative energies of two rotamers for each HAPA 7a-7f (E = E(cis) – E(trans)) and
their corresponding Hirshfeld charges on phosphorus and two nitrogen atoms are
listed in Table S1.
Diagram 3. Model molecular structures for two rotamers of unsaturated HAPA
ligands.
As revealed, the rotamer 2 of HAPA 7a-7b, is more stable than rotamer 1 by
1.02 and 0.63 kcal/mol, respectively. On the contrary, rotamer 1 of HAPA 7c-7f is
more stable by 0.60-1.10 kcal/mol. As shown in Table S1, molecular dipole moment
of rotamer 2 is generally larger than rotamer 1 because of the orientation of -OH is
trans to the lone pair (LP) of phosphorus (Diagram 3).
The Hirshfeld charge analysis shows that phosphorus atom in rotamer 1 (less
positive) possesses more electron density than that in rotamer 2 (more positive). This
is due to the better atomic orbital interaction between π-type atomic orbital of oxygen
and σ- and π-type atomic orbitals of phosphorus in rotamer 1, and therefore a better
π-electron donating from hydroxyl group to the phosphorus atom (Table S2).[104]
Additionally, the charge density on phosphorus of HAPA 7as (0.258) is slightly larger
than that of its unsaturated counterpart 7a (0.274) Besides, all HASPO 6a-6f pre-
ligands are more stable than their HAPA 7a-7f counterparts, which is in accordance
with the previous experimental and computational observations.[105-107] With
respect to rotamer 1 of 7a-7f, the relative stabilized energies of 6a-6f are 5.72, 5.24,
7.52, 5.97, 7.38 and 6.94 kcal/mol, respectively.
Lone pair (LP) molecular orbital for HAPA 7a-7f
Recently, Martin and Buono et al. investigated the σ-donating ability of acyclic
HAPAs with HAPA-coordinated metalcarbonyls both by experimental and theoretical
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means.[108] In their study, the LP-donating ability of dialkylphosphinous acids can
actually outperform phosphines and N-heterocyclic carbenes. When two neutral
saturate five-membered heterocyclic HAPAs are examined (i.e. O-P-O and N-P-N),
the decreased LP-donating ability than their acyclic counterparts is observed based on
the stretching frequency of metal-coordinated carbonyl ligands from DFT
calculations.[109]
The HOMO and LP molecular orbitals of 7a-7b and 7c-7f are shown in Figure 3
and Figure 4, respectively. It was found LP molecular orbitals of 7a-7f are not
HOMO, which is in consistent with the Martin and Buono’s computational
results.[108] HOMOs of HAPA 7a-7f are mostly consisted of π-type atomic orbitals
from two nitrogen atoms (population > 0.13) and the two unsaturated alkenyl carbons
(population > 0.21) on the five-membered ring.
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Figure 3. Selected occupied frontier molecular orbitals for two rotamers of 7a, 7b and
7as. LP molecular orbitals are highlighted in blue.
Figure 4. Selected occupied frontier molecular orbitals for two rotamers of 7c-7f. LP
molecular orbitals are highlighted in blue.
Levin had shown that phosphine with π-donating substituent has higher-lying
LP orbital as a result of the lone pair-lone pair interaction between phosphorus atom
and the substituent.[110] The LP molecular orbital energy of 7a-7f is closely related
to the directionality of -OH substituent because a better σn-π mixing between
phosphorus and oxygen is observed in rotamer 1 of 7a-7f (Table S2). In consistent
with Levin’s theoretical calculations, we found that the better P-O σn-π mixing in the
higher lying the LP molecular orbital (Table S2). The N-alkyl substituted 7a-7b have
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LP orbitals lay at HOMO to HOMO-2 (Figure 3). LP orbital energies for HAPA 7a
are -6.75 eV (HOMO-1) in rotamer 1 and 6.99 eV (HOMO-1) in rotamer 2; for
HAPA 7as are -6.05 eV (HOMO-1) in rotamer1 and -5.92 eV (HOMO) in rotamer 2,
respectively.
LP orbitals of 7c-7f are lying even lower (HOMO-5). The low-lying LP
orbitals of 7c-7f corresponding nicely to the poor catalytic performance in Suzuki-
Miyaura reactions as shown in our preliminary screening catalytic experiments, since
the coordination of such phosphine ligands to soft transition metals are kinetically
unfavourable. On the contrary, higher LP orbital of HOMO-1 in HAPA 7a is the
reason for its best catalytic performance among all six HAPA 7a-7f. Although LP
orbitals of 7c-7f are very low-lying, we note that the anionic deprotonated form of 7c-
7f, i.e. monomeric [P-O]- or dimeric [P-O…H…O-P]- bi-dentate ligands,[111-112]
could be a remedy and could have better performance in cross-coupling
reactions.[108] The better P-O- σn-π mixing can be expected in [P-O]- or dimeric [P-
O…H…O-P]- because p-type atomic orbital energy on the negatively charged oxygen
will be higher than that on the -OH group.[109] Hence, [P-O]- or dimeric [P-O…H…O-
P]- could be equipped with higher LP molecular orbital.
Steric effects estimated with percent buried volume (%Vbur)
Based on the definition of Clavier and Nolan,[113] the steric effect of
phosphines quantified by percent buried volume (%Vbur) can be roughly classified
into three categories when a putative metal is 2.28 Å away from phosphorus atom. It
is regarded as sterically rather hindered ligand while %Vbur > 35.0 %; a middle or
normal range for 35.0 % > %Vbur > 30.0 %; low steric effect for %Vbur < 30.0 %.
Accordingly, P(tBu)3 locates at the lower limit of the large steric hindrance, while
PCy3 near the lower limit of middle range, respectively (Table S3). Note that P(tBu)3
and PCy3 are two commonly used auxiliary phosphine ligands for Suzuki-Miyaura
cross-coupling reactions.
HAPA 7c and 7e reveals significant steric hindrance (%Vbur > 42.0 %), much
larger than P(tBu)3 and PCy3. Although neutral 7d (%Vbur ~ 34.0 %) and 7f has similar
quantified steric property to PCy3 (%Vbur ~ 32.0 %), its LP orbital (HOMO-5) is too
low-lying to be an effective ligand. The low catalytic performance for 7c and 7e as
ligands can also be attributed to the same reason, while their high steric ranking could
17

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be a merit for reductive elimination in the Suzuki-Miyaura catalytic cycle. On the
contrary, the very low steric hindrance offered by 7b (%Vbur ~ 24.0 %), could be one
of the reasons for its lower catalytic performance than 7a (i.e. LP orbital of 7b lies in
HOMO-1 of rotamer 1 and HOMO-2 of rotamer 2, respectively.)
Compound 7a is the tautomer of pre-ligand 6a, and is the best ligand for
Suzuki-Miyaura reactions carried out in this study. This is due not only to HAPA 7a
(%Vbur ~ 32.0 %) has nearly identical steric effect as PCy3 but also to it owns the
highest-lying LP molecular orbital (i.e. HOMO-1) among 7a-7f. Considering steric
and electronic effects as a whole, it is rational to comment that employing 7a as
ligand shows the best catalytic yield in our screening tests. Model ligand, 7as, is the
saturated analogue of 7a. Although 7as may not be superior to 7a, based on the
previous two facts, we anticipate that 7as could be as effective as 7a in the Suzuki-
Miyaura reactions at least.
Conclusion
In this study, six new HASPO 6a-6f pre-ligands have been synthesized and
characterized, and crystal structures for three of them (6a, 6c, 6e) have been well
resolved. 6a-6f can undergo tautomerization to 7a-7f as genuine phosphine ligands.
Diimine-coordinated (3e-coordinated) mono-palladium complex was obtained
unexpectedly during the reaction of 6e and PdBr2. Moreover, attempting to synthesize
6c-coordinated palladium complex was not successful. Instead, an intriguing di-
palladium complex bridged by two phosphide- ligands was obtained. These two
complexes were characterized by X-ray studies. In our preliminary screening of using
6a-6f as pre-ligands in Suzuki-Miyaura cross-coupling reactions, only 6a gave
satisfactory catalytic performance. Therefore, further catalytic conditions were
optimized for 6a. The optimized catalytic conditions are summarized as the
combination of 6a/Pd(OAc)2/KOtBu/THF/60 oC. At room temperature, the poor
catalytic yield could reflect that the chemical equilibrium of HASPO-to-PA
tautomerization favours HASPO.
The effectiveness of 6a and disability of 6b-6f as pre-ligands are fully
supported by DFT studies together with the quantified steric property. Based on the
DFT calculations, the highest occupied molecular orbital of 7a-7c is not LP molecular
orbital. Rather, LP orbital is HOMO-1 or HOMO-2 for 7a-7b and HOMO-5 for 7c-7f,
respectively. Notably, the steric property quantified by %Vbur reveals that 7a
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(tautomer of 6a) is as bulky as PCy3 (a useful ligand for Suzuki-Miyaura cross-
coupling reactions). The higher-lying LP orbital together with adequate steric
property provided by 7a account for the satisfactory catalytic performance. To
improve the catalytic performance, we suggest employing the anionic deprotonated
form of 7c-7f (i.e. monomeric [P-O]- or dimeric bi-dentate [P-O…H…O-P]- as ligands
for future development of HASPO). It is because the anionic form would result in
higher-lying LP molecular orbitals, which is essential for phosphines as effective
auxiliary ligands in catalytic reactions, via better σn-π mixing of P-O-.
Experimental Section
General Procedures
All reactions were carried out under a nitrogen atmosphere using standard
Schlenk techniques or in a nitrogen-flushed glove box. Freshly distilled solvents were
used. All processes of separations of the products were performed by Centrifugal Thin
Layer Chromatography (CTLC, Chromatotron, Harrison model 8924) or column
chromatography. GC-MS analysis was performed on an Agilent 5890 gas
chromatograph (Restek Rtx-5MS fused silica capillary column: 30m, 0.25mm,
0.5µm) with an Agilent® 5972 mass selective detector. Routine 1H NMR spectra were
recorded on a Varian-400 spectrometer at 400.441 MHz. The chemical shifts are
reported in ppm relative to internal standards TMS (δ = 0.0). 31P and 13C NMR
spectra were recorded at 162.1 and 100.7 MHz, respectively. The chemical shifts for
the former and the latter are reported in ppm relative to internal standards H3PO4 (δ =
0.0) and CHCl3 (δ = 77), respectively. Mass spectra were recorded on JOEL JMS-
SX/SX 102A GC/MS/MS spectrometer. Electrospray ionization-high resolution mass
spectra (ESI-HRMS) were recorded on a Finnigan/Thermo Quest Mat 95 XL mass
spectrometer.
Synthesis and characterization of 3a-3f and 6a-6f
Procedures for the preparations of 3a-3f were modified from literature.[114] In
the same measure, preparations of 6a-6f were followed the modified procedures of
reports elsewhere.[52, 115-116]
Synthesis and characterization of 3a and 3b
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Similar procedures as the previous one for the preparation of 3a and 3b were
carried out. Into a 250 mL round-bottomed flask was placed 70.0 mmol (7.42 ml) tert-
butylamine or tert-cyclohexylamine (100.0 mmol, 11.45 ml) in 50 mL deionized
water. In ice bath, then, the solution of Glyoxal (4.01 ml, 40 wt % in H2O, 35.0 mmol
or 5.73 g, 40 wt % in H2O, 50.0 mmol) was added slowly to the flask. White
participation was observed in the bottom of the flask. The solution was stirred for 45
minutes at room temperature. It was then filtered through frit at 0 °C The collected
product was washed by ethanol/H2O mixed solution at 0 °C. A white solid 3a (5.01 g,
29.79 mmol, 85 %) or 3b (10.24 g, 46.50 mmol, 93 %) was obtained after solvent was
removed by vacuum.
‡ Selected spectroscopic data for 3a, 1H NMR (CDCl3, δ/ppm): 1.22 (s, 18 H,
CH3), 7.90 (s, 2H, NCH); 13C NMR (CDCl3, δ/ppm): 157.8 (N-C), 58.1 (ipso-CtBu),
29.3 (CtBu).
‡ Selected spectroscopic data for 3b, 1H NMR (CDCl3, δ/ppm): 7.93 (s, 2 H,
NCH), 3.15 (m, 2 H, NCH), 1.19-1.82 (m, 10H, CH2); 13C NMR (CDCl3, δ/ppm):
160.0 (N-C), 24.5, 25.4, 33.9, 69.4 (Ccy).
Synthesis and characterization of 3c and 3d
Into a 500 mL round-bottomed flask was placed 60.0 mmol (10.63 g) 2,6-
diisopropylaniline (or 60.0 mmol 2,4,6-trimethylaniline) in 130 ml ethanol. Then, the
solution of Glyoxal (4.35 g, 40 wt % in H2O, 30.0 mmol) was added slowly to the
flask which was placed in ice bath beforehand. The colour of solution changed to
golden-yellow. It was then refluxed for 12 hours before cooling down to room
temperature. The volume of the solution was then reduced to 100 mL under vacuum.
Subsequently, the solution was filtered through frit at 0 °C. The collected product was
washed with ethanol/H2O mixed solution at 0 °C. A golden-yellow solid 3c (6.89 g,
18.31 mmol, 61 %) or 3d (6.87 g, 23.51 mmol, 47 %) was obtained after all solvent
was removed by vacuum.
‡ Selected spectroscopic data for 3c, 1H NMR (CDCl3, δ/ppm): 1.22 (d, JH-
H=7.1 Hz, 24H, CH(CH3)2), 2.96 (m, JH-H=6.7 Hz, 4H, CH(CH3)2), 7.20 (m, 6H,
overlapping C6H3), 8.12 (s, 2H, NCH); 13C NMR (CDCl3, δ/ppm): 163.0 (N-C), 147.9
(ipso-CMes), 136.6 (o-CMes), 125.0 (m-CMes), 123.1 (p-CMes), 27.9 (iPr CH), 23.3 (iPr
CH3).
20

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‡ Selected spectroscopic data for 3d, 1H NMR (CDCl3, δ/ppm): 2.15 (s, 12 H,
2,6-(CH3)2-C6H2), 2.29 (s, 6H, 4-CH3-C6H2), 6.90 (s, 4H, C6H2), 8.09 (s, 2H, NCH);
13C NMR (CDCl3, δ/ppm): 163.3 (N-C), 147.3 (ipso-CMes), 126.4 (o-CMes), 128.9 (m-
CMes), 134.1 (p-CMes), 18.1 (o-CH3), 20.6 (p-CH3).
Synthesis and characterization of 3e-3f
Into a 100 mL round-bottomed flask was placed 120.0 mmol (22.9 mL) 2,6-
diisopropylaniline in 50 ml methanol. Then, formic acid (6.9 mL) was added slowly.
The colour of solution changed to pale coffee. It was then added 2,3-butanedione
(60.0 mmol, 5.32 mL) and stirred for 0.5~1.0 hour till yellow participation was
observed. Gold-yellow solid participate was ready to be isolated after 2 hours of
stirring. Firstly, the solution was cooled to 0 °C and filtered through frit at that
temperature. The solvent was removed completely under vacuum. The collected
product was washed with methanol/H2O mixed solution at 0 °C. A golden-yellow
solid 3e (13.68 g, 56 %) was obtained after all solvent was removed by vacuum.
Similar procedures were taken for the preparation of 3f. The yield of the yellow
product of 3f is 58 % (11.15 g).
‡ Selected spectroscopic data for 3e, 1H NMR (CDCl3, δ/ppm): 1.18 (d, J =
7.2 Hz, 24H), 2.71 (septet, J=6.4 Hz, 4H), 7.17 (m, 6H), 2.07 (s, 6H); 13C NMR
(CDCl3, δ/ppm): 16.57, 22.69, 22.97, 28.47, 122.97, 123.71, 135.04, 146.13, 168.16.
‡ Selected spectroscopic data for 3f, 1H NMR (CDCl3, δ/ppm): 1.98 (s, 12H),
2.00 (s, 6H), 2.27 (s, 6H), 6.87 (4H); 13C NMR (CDCl3, δ/ppm): 15.82, 17.79, 20.78,
124.55, 128.64, 132.41, 145.95, 168.37.
Synthesis and characterization of 6a-6f
A 100 mL round-bottomed flask contained 2 mmol of corresponding diimine
3a-3f, 5 mL dichloromethane and 6 mmol cyclohexene. Another flask in Glove box
was placed with 2 mmol PBr3 and 5 mL dichloromethane; it was then placed in ice
bath till reached 0° C. The solution of the first flask was transferred slowly into the
second one and stirred at room temperature for 12 hours. Presumably, 4a-4f were
formed by judging from their large down-fielded shift in 31P NMR, ranges from
170~200 ppm around. Without further purification, 1.00 molar equivalent of HNEt2
was subsequently added into the flask. The color of solution changed to yellow. Then,
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the solvent was removed completely after stirring at room temperature for 2 hours.
Presumably, the corresponding 5a-5f were formed. The residue was extracted twice
by ethylacetate and separated by column chromatography. The hydrolyzed products
(6a, 6b, 6c, and 6d) are in the yield of 39 % for 6a (0.17 g, 0.78 mmol), 30 % for 6b
(0.16 g, 0.60 mmol), 29 % for 6c (0.25 g, 0.59 mmol), 35 % for 6d (0.24 g, 0.70
mmol), 35 % for 6e (1.27 g, 2.22 mmol), 30 % for 6f (0.88 g, 2.39 mmol).
‡ Selected spectroscopic data for 6a, 1H NMR (CDCl3, δ/ppm): 8.67 (d, JP-
H=648.0 Hz, 1H), 7.34-7.18 (m, 6H), 5.93 (dd, 2H), 3.68 (m, JH-H=6.7 Hz, 1H), 3.18
(m, JH-H=6.7 Hz, 2H), 1.34 (d, JH-H=6.3 Hz, 6H), 1.27 (d, JH-H=7.1 Hz, 6H), 1.25 (d,
JH-H=7.1 Hz, 6H), 1.24 (d, JH-H=6.7 Hz, 6H); 13C NMR (CDCl3, δ/ppm): 117.1/117.2
(N-C), 123.8/124.5/128.9/132.3/147.9/149.8 (arene), 28.3/28.6 (iPr CH),
24.0/24.0/24.9/25.2 (iPr CH3); 31P NMR (CDCl3, δ/ppm): 4.8 ppm (JP-H = 648.0 Hz).
‡ Selected spectroscopic data for 6b, 1H NMR (CDCl3, δ/ppm): 2.29/2.27 (s,
12H, o-CH3), 2.4 (s, 6H, p-CH3), 6.92/6.96 (s, 4H, C6H2), 5.90 (d, JH-H=16.39, 2H,
NCH), 8.73 (d, 1H, JP-H = 649.2, PH); 13C NMR (CDCl3, δ/ppm): 115.7/115.9 (N-C),
128.9/129.6/132.4/136.8/138.0/139.0 (arene), 18.3/18.5 (o-CH3), 20.9 (p-CH3); 31P
NMR (CDCl3, δ/ppm): 1.3 ppm (JP-H = 649.2 Hz).
‡ Selected spectroscopic data for 6c, 1H NMR (CDCl3, δ/ppm): 1.43 (s, 18 H,
CH3), 5.95 (dd, JH-H=16.01, 2H, NCH), 8.60 (d, 1H, JP-H=647.91, PH); 13C NMR
(CDCl3, δ/ppm): 110.2/110.3 (N-C), 53.3 (ipso-CtBu), 29.9 (CtBu); 31P NMR (CDCl3,
δ/ppm): 4.0 ppm (JP-H = 647.91 Hz).
‡ Selected spectroscopic data for 6d, 1H NMR (CDCl3, δ/ppm): 5.84 (dd, 2 H,
NCH), 1.07-2.01 (m, 11 H, C6H11), 8.64 (d, 1H, JP-H=640.4, PH); 13C NMR (CDCl3,
δ/ppm): 111.1/111.2 (N-C), 25.5/33.2/33.9/54.5 (Ccy); 31P NMR (CDCl3, δ/ppm): 6.1
ppm (JP-H = 640.4 Hz).
‡ Selected spectroscopic data for 6e, 1H NMR (CDCl3, δ/ppm): 1.24 (d, J =
6.80, 12H), 1.25 (d, J = 7.20, 6H), 1.61 (s, 6H), 3.16 (septet, 2H), 3.55 (septet, 2H),
7.18 (d, J = 7.60, 2H), 7.25 (d, J = 8.39, 2H), 7.35 (t, 2H), 8.54 (d, J = 635.2, 1H); 13C
NMR (CDCl3, δ/ppm): 11.07, 24.21, 24.31, 25.09, 25.27, 28.20, 28.37, 117.48,
117.59, 123.79, 124.58, 128.82, 130.37, 148.53, 150.80; 31P NMR (CDCl3, δ/ppm):
5.23 ppm, JP-H = 635.2 Hz.
‡ Selected spectroscopic data for 6f, 1H NMR (CDCl3, δ/ppm): 1.57 (s, 6H),
2.21 (s, 6H), 2.29 (s, 6H), 2.43 (s, 6H), 6.90 (s, 2H), 6.95 (s, 2H), 8.57 (d, J = 637.22,
1H); 13C NMR (CDCl3, δ/ppm): 10.63, 18.25, 18.95, 20.98, 116.53, 116.65, 128.86,
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129.52, 130.88, 137.61, 137.78, 140.10; 31P NMR (CDCl3, δ/ppm): 0.57 ppm, JP-H
=
637.22 Hz.
General procedure for the Suzuki-Miyaura cross-coupling reactions
Suzuki-Miyaura cross-coupling reactions were performed according to the
following procedures. The four reactants, palladium source, ligand, boronic acid and
base, were placed in a suitable oven-dried Schlenk flask. It was evacuated for 0.5 hour
and backfilled with nitrogen gas before adding solvent and aryl halide through a
rubber septum. The aryl halides being solids at room temperature were added prior to
the evacuation/backfill cycle. The flask was sealed with a rubber septum and the
solution was stirred at the required temperature for designated hours. Then, the
reaction mixture was diluted with ethyl acetate (3 mL) and the cooled solution poured
into a separatory funnel. The mixture was washed with aqueous NaOH (1.0 M, 5 mL)
and the aqueous layer was extracted with ethyl acetate (2 x 5 mL). The combined
organic layer were washed with brine and dried with anhydrous magnesium sulfate.
The dried organic layer was concentrated in vacuo. The residue was purified by
column chromatography to give the desired product.
X-ray crystallographic studies
Suitable crystals of 6a, 6c, 6e, and 8e were sealed in thin-walled glass
capillaries under nitrogen atmosphere and mounted on a Bruker AXS SMART 1000
diffractometer. Intensity data were collected in 1350 frames with increasing ω (width
of 0.3° per frame). The absorption correction was based on the symmetry equivalent
reflections using SADABS program. The space group determination was based on a
check of the Laue symmetry and systematic absences, and was confirmed using the
structure solution. The structure was solved by direct methods using a SHELXTL
package.[117] All non-H atoms were located from successive Fourier maps and
hydrogen atoms were refined using a riding model. Anisotropic thermal parameters
were used for all non-H atoms, and fixed isotropic parameters were used for H
atoms.[118] Crystallographic data for the structural analysis have been deposited in
the Cambridge Crystallographic Data Center, CCDC no. 900104, 900105, 900106,
and 900107 for 6a, 6c, 6e, and 8e, respectively.
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Computational Details
All calculations were performed with Gaussian 09 quantum-chemistry
packages.[119] Geometry optimizations (Gaussian keyword: opt) were carried out
with the B3LYP density functional in conjugation with 6-311+(2d,p) for oxygen,
nitrogen, carbon and hydrogen atoms and 6-311+(3df) for phosphorus atom. All
optimized geometries were confirmed to be local minima by frequency calculations
(Gaussian keyword: freq=noraman). Hirshfeld charge analysis was used to analyse
the population of electron density (Gaussian keyword: pop=hirshfeld).[120] In
addition, orbital analysis was done to identify the atomic orbital contributions to
HOMO and LP molecular orbitals (Gaussian keyword:
pop=(orbitals,threshorbitals=3)). Contributions from atomic orbitals greater than 3 %
will be printed out, and the threshold value is adequate for our purposes.
Percent Buries Volume (%Vbur)
Due to the success of the percent buried volume (%Vbur) in addressing the
steric hindrance of NHC and phosphine ligands,[113, 121] we employed this
approach to access the bulkiness of the HAPA ligands for qualitative mutual
comparison. Cartesian coordinates of HAPA are obtained from the DFT-optimized
geometries. Noteworthy, %Vburs are linearly proportional to the values estimated with
the definition of Tolman cone angle for commonly used phosphine ligands.[113]
SambVca is a web application for such purpose established by Cavallo et al.[122-
123] %Vbur is estimated from the percent ratio between the ligand occupied space and
the sum of ligand unoccupied free space and ligand occupied space in a hemisphere
centered on a putative metal center (TM) (sphere radius is fixed as 3.5 Å). In our
study, the TM-Lignad bond lengths were set to 2.00 and 2.28 Å, respectively, along
the axis including phosphorus and the center of the three atoms (N, N and O) bonded
to phosphorus. Hydrogen atoms are excluded in our calculations. More computational
details regarding how to estimate %Vbur can be found in the original paper and the
SambVca website.
Acknowledgements
The authors thank the Ministry of Science and Technology of the ROC (Grant
MOST 104-2119-M-005-014) for financial support. We are also grateful to the
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National Center for High-performance Computing (NCHC) for providing precious
computing time and facilities.
Appendix A.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/.
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