Configurational stability of chlorophosphines

Article abstract of DOI:10.1021/ic026128u

The configurational stability of chlorophosphines is investigated. Several mechanisms involving chlorophosphine monomer, dimers, and adducts with HCl are evaluated by density functional theory calculations. The presence of HCl in the medium is found to catalyze the P-center chiral inversion at room temperature. The reaction involves a two-step mechanism with low transition states (10 kcal·mol^-1) and a stabilized achiral intermediate (-2.6 kcal·mol^-1). Further calculations and experiments on the halogen exchange with HBr corroborate this mechanism, with bromophosphines being formed instantaneously. Finally, to avoid the racemization, the borane is found to be a very promising protecting group for the configurational stability of the P-chirogenic chlorophosphines.

Full text of DOI:10.1021/ic026128u

Inorg. Chem. 2003, 42, 420−427
Configurational Stability of Chlorophosphines
,|
Ste´phane Humbel,*,†,‡ Cyrille Bertrand,† Christophe Darcel,| Christophe Bauduin,§ and Sylvain Juge´*
Groupe Mode´lisation & Re´actiVite´ Chimique, UMR 6519, CNRS et UniVersite´ de Reims,
Moulin de la Housse, BP 1039, 51687 Reims Cedex 2, France, and Synthe`se, Catalyse et
Chiralite´, UMR 6516, CNRS et UniVersite´ de AixsMarseille III, Faculte´ des Sciences St. Jeroˆme,
AVenue Escadrille Normandie-Nie´men, 13397 Marseille Cedex 20, France, and UniVersite´ de
Cergy Pontoise, 5 Mail Gay Lussac, 95031 Cergy Pontoise Cedex, France, and Laboratoire de
Synthe`se et d’ Electrosynthe`se Organome´talliques, UMR 5632, CNRS et UniVersite´ de Bourgogne,
6 BouleVard Gabriel, BP 138, 21100 Dijon, France
Received October 23, 2002
The configurational stability of chlorophosphines is investigated. Several mechanisms involving chlorophosphine
monomer, dimers, and adducts with HCl are evaluated by density functional theory calculations. The presence of
HCl in the medium is found to catalyze the P-center chiral inversion at room temperature. The reaction involves
a two-step mechanism with low transition states (10 kcal‚mol-1) and a stabilized achiral intermediate (−2.6 kcal‚mol-1).
Further calculations and experiments on the halogen exchange with HBr corroborate this mechanism, with
bromophosphines being formed instantaneously. Finally, to avoid the racemization, the borane is found to be a
very promising protecting group for the configurational stability of the P-chirogenic chlorophosphines.
Introduction
phosphines6) have been widely used. The synthesis of these
ligands is usually performed using achiral chlorophosphines
1 (Scheme 1, R1 ) R2), either as electrophilic7 (Scheme 1a)
or nucleophilic reagents,8 in the latter case, through the
formation of phosphides (Scheme 1b).
It is interesting to note that the most commonly used
P(III)-organophosphorus ligands generally bear the chirality
on the carbon backbone. If enantiomerically enriched chlo-
During the past 3 decades, there has been considerable
development in asymmetric transition metal catalyzed reac-
tions,1 especially in the area of chiral ligands,2 where chiral
P(III)-organophosphorus derivatives (diphosphines,3 diphos-
phinites,4 aminophosphine-phosphinites,5 chelating mono-
* Authors to whom correspondence should be addressed. E-mail:
stephane.humbel@univ.u-3mrs.fr (S.H.); Sylvain.Juge@u-Bourgogne.fr (S.J.).
† CNRS et Universite´ de Reims.
‡ CNRS et Universite´ de AixsMarseille III.
(4) For recent, selected enantioselective catalysis using diphosphinite or
diphosphite ligands, see: (a) Clyne, D. S.; Mermet-Bouvier, Y. C.;
Nomura, N.; Rajanbabu, T. V. J. Org. Chem. 1999, 64, 7601-7611.
(b) Hu, W.; Yan, M.; Lau, C. P.; Yang, S. M.; Chan, A. S. C.; Jiang,
Y.; Mi, A. Tetrahedron Lett. 1999, 40, 973-976. (c) Chen, Y.; Li.
X.; Tong, S. K.; Choi, M. C. K.; Chan, A. S. C. Tetrahedron Lett.
1999, 40, 957-960. (d) Ku¨ndig, E. P.; Saudan, C. M.; Bernardinelli,
G. Angew. Chem., Int. Ed. 1999, 38, 1220-1223. (e) Reetz, M. T.;
Mehler, G. Angew. Chem., Int. Ed. 2000, 39, 3889-3890. (f) Die´guez,
M.; Pa`mies, O.; Ruiz, A.; Castillon, S.; Claver, C. Chem. Eur. J. 2001,
7, 3086-3094.
(5) (a) Agbossou, F.; Carpentier, J. F.; Hapiot, F.; Suisse, I.; Mortreux,
A. Coord. Chem. ReV. 1998, 178-180, 1615-1645. (b) Devocelle,
M.; Mortreux, A.; Agbossou, F.; Dormoy, J. R. Tetrahedron Lett. 1999,
40, 4551-4554.
(6) For a recent review on chelating monophosphines or derivative ligands,
see: Lagasse, F.; Kagan, H. B. Chem. Pharm. Bull. 2000, 48 (3), 315-
324.
§ Universite´ de Cergy Pontoise.
| CNRS et Universite´ de Bourgogne.
(1) (a) Brunner, H.; Zettlmeier, W. Handbook of EnantioselectiVe Catalysis
with Transition Metal Compounds, Products and Catalysis, Vol. 1;
VCH: Basel, Switzerland, 1993. (b) Ojima, I. Catalytic Asymmetric
Synthesis; VCH: New York, 1993. (c) Noyori, R. Asymmetric
Catalysis in Organic Synthesis; Wiley: New York, 1994. (d) Palmer,
M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045-2061. (e)
Tenaglia, A.; Heumann, A. Angew. Chem., Int. Ed. 1999, 38, 2180-
2184.
(2) Brunner, H.; Zettlmeier, W. Handbook of EnantioselectiVe Catalysis
with Transition Metal Compounds, Ligands-References, Vol. 2;
VCH: Basel, Switzerland, 1993.
(3) For recent, selected examples of enantioselective catalysis using
diphosphine ligands, see: (a) Trost, B. M.; Toste, F. D. J. Am. Chem.
Soc. 1999, 121, 4545-4554. (b) Burk, M. J.; Bienewald, F.; Chal-
lenger, S.; Derrick, A.; Ramsden, J. A. J. Org. Chem. 1999, 64, 3290-
3298. (c) Blaser, H. U.; Buser, H. P.; Jalett, H. P.; Pugin, B.; Spindler,
F. Synlett 1999, 867-868. (d) Zhang, Z.; Zhu, G.; Jiang, Q.; Xiao,
D.; Zhang, X. J. Org. Chem. 1999, 64, 1774-1775. (e) Fehr, M. J.,
Consiglio, G.; Scalone, M.; Schmidt, R. J. Org. Chem. 1999, 64,
5768-5776. (f) Kuwano, R.; Ito, Y. J. Org. Chem. 1999, 64, 1232-
1237.
(7) For selected examples of the synthesis of phosphorus ligands using
chlorophosphine as an electrophilic block, see: (a) Sprinz, J.;
Helmchen, G. Tetrahedron Lett. 1993, 34, 1769-1772. (b) Deaton,
D. N. In Encyclopedia of Reagents for Organic Synthesis, Vol. 2;
Paquette, L. A., Ed.; Wiley: Chichester, U.K., 1995. (c) See also refs
4 and 5.
420 Inorganic Chemistry, Vol. 42, No. 2, 2003
10.1021/ic026128u CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/12/2002

Configurational Stability of Chorophosphines
on the racemization mechanism with acids (HCl, HBr).14 We
describe herein experimental and computational studies on
the halogen exchange between a chlorophosphine and HBr.
Scheme 1
Computational Details
The calculations were carried out using a gas-phase model with
the Gaussian 98 package.15 Cartesian D orbitals were used
throughout this study.
All geometry optimizations were done using the density func-
tional theory (DFT) approximation B3LYP.16 In a first stage, the
geometries were optimized using the CEP-31G(D) basis set. The
core electrons of the P, Cl, and Br atoms were thus described with
a “core” potential, while the other electrons were described with a
double ú basis set plus polarization function on the heavy atoms P,
Cl, Br, and C.
These geometries were then used as starting geometries for
subsequent geometry optimizations using the “all-electron” basis
set, the B3LYP/6-31+G(2d) level, which avoids the core potential
and provides, on the heavy atoms, both diffuse functions and a
double ú quality of the gaussian basis. These reoptimizations led
in fact to very small stabilizations of each structure, between 0.5
and 1.2 kcal/mol. These converging results show the good quality
of the optimization level. The stationary points were then character-
ized as minimum or transition state (TS) by analytical frequency
calculations. Corresponding unscaled zero point correction (ZPC)
and entropy are indicated in the tables. The energies obtained using
this optimization level (B3LYP/6-31+G(2d)) are denoted ∆Eopt in
the following.
The energies were then calculated within the same B3LYP
model, using the more extended basis set 6-311++G(2d,p). In this
paper, we mainly comment on the results from these “dual-level”
calculations (noted, as usual, B3LYP/ 6-311++G(2d,p)//B3LYP/
6-31+G(2D)). Those triple ú calculations provide the data for what
we called ∆ETZ. When ∆ETZ is corrected for the ZPC, it is denoted
in the following as ∆HTZZPC. Gas-phase Gibbs free energies at room
temperature ∆G298, are also indicated in the tables.
rophosphines 1 (Scheme 1, R1 * R2) were available, they
could be useful building blocks for the synthesis of a new
class of bulky, hybrid, or functionalized P-chirogenic
ligands, which would bring the chiral center close to the
metal.
Previous studies on the pyramidal inversion of chloro-
phosphines indicate that they are configurationally stable,
with even higher energy barriers than tertiary phosphines,
40.0 and 35.6 kcal‚mol-1, respectively.9 It is well-established
that this increased barrier in chlorophosphines originates from
both the σ attracting and the π donating abilities of the
chlorine substituent. Both favor the pyramidalization of the
phosphorus and hence increase the monomeric inversion
barrier.9b,10
However, only the partially enantiomerically enriched tert-
butylchlorophenylphosphine (1d) has been described to
date.11,12 This compound, which was obtained by a phos-
phonium salt decomposition at low temperature (Scheme 2a),
or by kinetic resolution, slowly racemized at room temper-
ature. The pioneering work of Horner and Jordan13 described
the formation of a racemic chlorophosphine 1e from enan-
tiomerically enriched ethylphenylaminophosphine (Scheme
2b). These authors postulated that the aminophosphine
acidolysis with HCl was stereoselective and the resulting
chlorophosphine 1e was believed to racemize by intermo-
lecular ligand exchange through the dimeric species 2e.
To date, the origin of the racemization has not been clearly
established and remains unclear. It might be due either to
the acidolysis step conditions or to the inherent configura-
tional instability of the chlorophosphines as postulated by
Horner and Jordan.13 To clarify this point, we envisaged
various racemization processes.
Results and Discussion
Computational Results. The computational investigation
was carried out using the chlorodimethylphosphine (1a,
R1 ) R2 ) Me) as a model. While this species is not chiral,
it was useful in studying the different racemization mecha-
(14) (a) For a recent high-level computational work on the SN2 reactions
of halide ions on neutral halophosphines in the gas phase, see: Sølling,
T. I.; Pross, A.; Radom, L. Int. J. Mass Spectrom. 2001, 210/211,
1-11. (b) For corresponding gas-phase measurements: Van Doren,
J. M.; DePuy, C. H.; Bierbaum, V. M. J. Phys. Chem. 1989, 93, 1130-
1134.
In the present paper, we report the results of our investiga-
tion on the configurational stability of chlorophosphines and
(15) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels,
A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone,
V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.;
Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts,
R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C.
Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.;
Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, Revision
A.7; Gaussian, Inc.: Pittsburgh, PA, 1998.
(8) For a typical synthesis of phosphorus ligands using chlorophosphine
as the phosphide source, see: Peer, M.; de Jong J. C.; Kiefer, M.;
Langer, T.; Rieck, H.; Schell, H.; Sennhenn, P.; Sprinz, J.; Steinhagen,
H.; Wiese, B.; Helmchen, G. Tetrahedron 1996, 52, 7547-7583.
(9) (a) Rauk, A.; Allen, L. C.; Mislow, K. Angew. Chem., Int. Ed. Engl.
1970, 9, 400-414. (b) Baechler, R. D.; Mislow, K. J. Am. Chem.
Soc. 1971, 93, 773-774.
(10) (a) For molecular orbital (MO) arguments, see: Levin, C. C. J. Am.
Chem. Soc. 1975, 97, 5649-5655. (b) For valence bond (VB)
arguments, see: Bent, H. A. Chem. ReV. 1961, 61, 275-311.
(11) Omelanczuk, J. J. Chem. Soc., Chem. Commun. 1992, 1718-1719.
(12) The kinetic resolution of tert-butylchlorophenylphosphine (1d) has been
described for the preparation of the (thio)phosphoryl derivative with
e.e. up to 50% in: Perlikowska, W.; Gouygou, M.; Daran, J. C.;
Balavoine, G.; Mikolajczyk, M. Tetrahedron Lett. 2001, 42, 7841-
7845.
(16) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (b) Becke, A.
D. J. Chem. Phys. 1996, 104, 1040-1046. (c) Lee, C.; Yang, W.;
Parr, R. G. Phys. ReV. B 1988, 37, 785-789. (d) Miehlich, B.; Savin,
A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157, 200-206.
(13) Horner, L.; Jordan, M. Phosphorus Sulfur 1980, 8, 235-242.
Inorganic Chemistry, Vol. 42, No. 2, 2003 421

Humbel et al.
Scheme 2
nisms under consideration. Since the racemization of P-chi-
rogenic chlorophosphines must pass through at least one TS
or one intermediate bearing an achiral phosphorus center,
we considered pathways involving such species. Conse-
quently, we envisaged the species TS2a-5a as possible
origins of this process. The monomeric planar TS3a, known
as an impossible pathway for a room-temperature chiral
inversion (vide supra), is included here for the sake of
completeness.
If we consider a mechanistic explanation involving two
molecules of 1a, two kinds of species (intermediate or
transition state) can be hypothesized: the dimeric species
2a, similar to 2e previously proposed by Horner,13 with two
chlorine atoms bridging the two phosphorus atoms, and the
pentacoordinate phosphorane 4a. In this hypervalent species,
a phosphorus-phosphorus bond is formed in the equatorial
position, and the two chlorine atoms are in apical positions.
Other stereoisomers with one or two chlorine atoms in the
equatorial position were not investigated, due to the strong
apicophilicity of this substituent.17 Finally, structure 5a results
from the HCl addition to 1a. The formation of such a
pentacoordinate phosphorus derivative could be considered
under the acidolysis conditions of the aminophosphine
precursor.
The optimized structures for the intermediates and transi-
tion states derived from 1a and their corresponding energies
are reported in Figure 1 and Table 1, respectively. The
transition state TS3a, resulting from an umbrella inversion,
is found to be 51.6 kcal‚mol-1 higher in energy than 1a
(Table 1, entry 2). Not surprisingly, the energy barrier is
much too high to consider a stereochemical path passing
through this TS at room temperature.9,10
Figure 1. B3LYP/6-31+G(2d) optimized geometries for transition states
or intermediates derived from 1a. Arrows are displayed for the transition
state structures (TS2a, TS3a, TS4a, and TS5a) to indicate the corresponding
reaction coordinates.
The bimolecular species TS2a was characterized as a
transition state rather than an intermediate (Figure 1). In this
structure, one chlorine atom is bonded to both phosphorus
atoms, while the other is further apart. The reaction
coordinate, as indicated by the arrows, clearly shows the
chlorine exchange between the phosphorus atoms. Thus,
TS2a can indeed be involved in the racemization process. It
corresponds to an intermolecular nucleophilic substitution
at the phosphorus center. The top view of TS2a shows the
important distortion of the phosphorus substituents with two
methyl groups in the plane of the square formed by the
phosphorus and the chlorine atoms, and two others in the
axial position. This distortion is attributed to the phosphorus-
phosphorus lone pair repulsion (Scheme 3a). Because this
repulsion cannot be completely avoided, the energy of TS2a
is high, 58.3 kcal‚mol-1 above the energy of the starting
(17) (a) Trippett, S. Phosphorus Sulfur 1976, 1, 89-98. (b) Thatcher, G.
R. J.; Campbell, A. S. J. Org. Chem. 1993, 58, 2272-2281. (c)
Burgada, R.; Setton, R. In The Chemistry of Organophosphorus
Compounds, Vol. 3; Hartley, F. R., Ed.; Wiley: New York, 1994.
422 Inorganic Chemistry, Vol. 42, No. 2, 2003

Configurational Stability of Chorophosphines
Scheme 3
Table 1. Energy Variations (kcal.mol-1), unless Otherwise Stated, for
the Transition States and the Intermediates Displayed in Figure 1
activation energy (≈1 kcal‚mol-1).19 Such a facile rotation
allows the inversion of the configuration at one of the
phosphorus center, through a final transition state similar to
TS4a. Meanwhile, the second chlorophosphine 1a is restored
into its original configuration (Scheme 3b).
c
entry
∆Eopt
a
∆ZPCa ∆Sa,b ∆ETZ c ∆HTZ
∆G298 c
ZPC
1
2
3
4
5
6
7
8
1a
0.0
52.0
60.2
29.1
5.5
0.0
-0.4
-0.9 -33.9
0.7 -39.5
2.0 -40.2
1.1 -23.1 -3.8
1.1 -31.7 9.3
3.5 -32.4 -4.7
0.0
1.2
0.0
52.0
59.3
28.7
5.1
0.0
0.0
51.2
68.5
41.2
19.0
4.2
TS3a
TS2ad
TS4ad
4ad
51.6
58.3
29.4
7.0
-2.7
10.4
-1.2
From an energetic point of view, TS4a involves a much
lower energy than TS2a, ∆HTZ
) +29.4 and +58.3
ZPC
1a‚HCle -3.7
kcal‚mol-1, respectively (Table 1, entries 3, 4). This is
attributed to the smaller phosphorus-phosphorus lone pair
interaction in this biphilic mechanism. Moreover, 4a is
somewhat low in energy, with ∆HTZZPC ) +7.0 kcal‚mol-1
(entry 5). While this mechanism would appear more likely
than the monomeric “umbrella” inversion or Horner’s
mechanisms, the activation energy required to reach TS4a
is still too high for a room-temperature process. The
racemization of the chlorophosphines must still involve
another mechanism.
TS5ae
5ae
8.6
-6.2
19.9
8.5
a Geometry optimizations and related data (energy (Eopt), zero point
correction (ZPC), and entropy (S)) were obtained from B3LYP/6-31+G(2d)
calculations. b Entropy changes, ∆S, are in entropy units (cal‚mol-1‚K-1).
c The “TZ” energies are obtained from B3LYP/6-311++G(2d,p)//B3LYP/
6-31+G(2d) calculations. d Relative to two isolated chlorophosphines 1a.
e Relative to one chlorophosphine 1a and one HCl molecule.
chlorodimethylphosphine 1a (Table 1, entry 3). Since such
high activation energy is clearly unattainable at room
temperature, we rejected this pathway for the racemization.
A better mechanism, which would reduce the phosphorus-
phosphorus lone pair repulsion, should consider the phos-
phorus atoms as both nucleophilic and electrophilic centers
(biphilicity).18 In this case (Scheme 3b), the lone pair of the
phosphorus atom of one chlorodimethylphosphine 1a reacts
to displace the chlorine of the other. This leads to the
pentacoordinate intermediate 4a through the transition state
TS4a. It can be pointed out in Figure 1 that the optimized
structure 4a is asymmetric because the two P-Cl bond
lengths are not identical, 2.341 and 2.286 Å, respectively.
However, 4a easily leads to a symmetric conformer by
rotation around the P-P bond, which requires a negligible
If traces of HCl were present in the medium, for example
due to the aminophosphine acidolysis in toluene,20 the
formation of the pentacoordinate intermediate 5a could be
envisaged occurring via the transition state TS5a (Scheme
3c, Figure 1). The racemization would occur if the hydrogen
atom of the achiral pentacoordinate intermediate 5a left with
one or the other chlorine substituent, leading to a halogen
exchange between the chlorophosphine and HCl. From the
energetic point of view, this pathway requires +10.4
kcal‚mol-1, which is much lower than the energies of the
other paths previously envisaged (entry 7). In addition, the
intermediate 5a is also more stable than the pentacoordinate
species 4a, ∆HTZ
) -1.2 and +7.0 kcal‚mol-1, respec-
ZPC
tively (entries 5, 8). According to our theoretical results, the
(18) For the concept of biphilicity, which is related to dual electrophilic
and nucleophilic properties of the phosphorus center, see: (a) Ivanov,
B. E.; Zheltukhin, V. F. Russ. Chem. ReV. 1970, 39, 358-372. (b)
Smith, D. J. H. In ComprehensiVe Organic Synthesis, Vol. 2;
Sutherland, I. O., Ed.; Pergamon Press: Oxford, U.K., 1979; pp 1121-
1187.
(19) More details on this minor aspect of the mechanism are provided in
the Supporting Information.
(20) A purely ionic mechanism would require a complete charge separation
H+ + Cl- that does not occur in toluene.
Inorganic Chemistry, Vol. 42, No. 2, 2003 423

Humbel et al.
Scheme 4
Table 2. Halide Exchange with the Chlorophosphines 1b,c
R2PCl 1
exptl conditionsa
R2PBr 7
entry
R
reagent
T (°C)
time (min)
convb (%)
1
2
3
4
5
6
Ph 1b HBr (0.5 equiv) room temp
Ph 1b HBr (1 equiv) room temp
Ph 1b HBr (1 equiv) -70
45
2
2
90
90
30
7b
7b
7b
7b
7b
7c
50
100
85
40
100
100
Ph 1b LiBr (1 equiv)c room temp
Ph 1b LiBr (4 equiv)d room temp
t-Bu 1c LiBr (4 equiv)d room temp
a All reactions were performed in dry toluene. b Determined by 31P NMR.
c LiBr (1 M) in THF. d Dry LiBr.
toluene). The conversions, determined by 31P NMR, are
summarized in Table 2. With the addition of 0.5 equiv of
HBr, 1b was partially converted into the corresponding
bromo derivative 7b (entry 1).21 The proportion of the
products did not change after 30 min. When 1 equiv of HBr
was added to 1b, a complete conversion into 7b was observed
in 2 min at room temperature (entry 2). For the same reaction
performed at -70 °C, the conversion into 7b reached 85%
in 2 min, thus demonstrating the ease of the halide exchange
(entry 3). On the other hand, when 5 equiv of HCl were
added to a toluene solution of 7b, the reverse formation of
1b was less than 20% after 14 h at room temperature.
Although no intermediate species, e.g., a pentacoordinated
or a tetracoordinated phosphorus, was clearly identified by
31P NMR, we observed a facile halide exchange on the
chlorodiphenylphosphine even at -70 °C. This is in good
agreement with the HCl catalyzed racemization mechanism,
discussed in the theoretical section.
In addition, the halide exchange was studied with LiBr.
When 1 equiv of LiBr was used, 1b afforded the corre-
sponding 7b with a conversion of only 40% after 90 min at
room temperature (entry 4). The lower efficiency of LiBr
with respect to HBr could be explained by the heterogeneity
of the reaction mixture. Using 4 equiv of dry LiBr, the
conversion of 1b was complete within the same reaction time
(entry 5). When the halide exchange was carried out using
1c and LiBr (4 equiv), a complete conversion into 7c was
obtained in 30 min (entry 6).
Figure 2. Thermodynamic and stereochemical pathway for the phosphorus
inversion of 1a with HCl. Energies are in kilocalories per mole.
Scheme 5
thermodynamic pathway of the inversion of configuration
for 1a can be sketched by the symmetric curve in Figure 2.
The HCl, which acts as a catalyst, is released at the end of
the reaction.
It is noteworthy that this reaction mechanism passes
through a hydrogen-bonded complex 1a‚HCl with such a
small bonding energy that it is entropically disfavored, as
shown by the enthalpy and the free energy values for the
reaction: ∆HTZ
) -2.7 kcal‚mol-1 and ∆G298 ) +4.2
ZPC
kcal‚mol-1 (entry 6). As for proton transfer from the HCl
moiety to the phosphorus, we expected 1a‚HCl to convert
into the phosphonium salt 6a before racemization via the
achiral pentacoordinate species 5a (Scheme 4). While the
ionic species 6a could not be found in the gas-phase
calculations (the optimization leads directly back to 1a‚HCl),
such a mechanism cannot be totally excluded in solution, if
the solvent favors ion pairs (polar solvent).
Finally, our theoretical studies show that acidolysis condi-
tions (HCl) catalyze the racemization of the chlorophosphines
as they are formed. The inversion of the chlorophosphine is
analogous to a halogen exchange and should thus occur with
other halides.
Chlorophosphine Halide Exchange. In this context, and
in order to illustrate this racemization, we performed
complementary computational and experimental studies on
the reaction of achiral chlorophosphines 1a-c with HBr
(Scheme 5).
Computational Studies. The computational study of this
halide exchange reaction was carried out with 1a as a model
of the chlorophosphine used experimentally (1b,c), reacting
with HBr. We applied the same levels of calculation
previously used.
The results for the halide exchange are displayed in Table
3 and Figure 3 for the energies and geometries, respectively.
After a weak preliminary hydrogen-bonded complex 1a‚HBr,
the first transition state TS8a is found to be lower in energy
Experimental Studies. Experimentally, the halide ex-
changes with diphenyl- or di-tert-butylchlorophosphines (1b
or 1c) were performed in toluene, using HBr (0.65 M in
(21) The foremost preparation of 7b by reaction of an excess of HBr with
1b has been described by: Do¨rken, C. Chem. Ber. 1888, 21, 1506-
1515.
424 Inorganic Chemistry, Vol. 42, No. 2, 2003

Configurational Stability of Chorophosphines
Table 3. Energy Variations (kcal‚mol-1), unless Otherwise Stated,
of Intermediates and Transition States for Halide Exchange between
1a and HBra
d
entry
∆Eopt b ∆ZPCb ∆Sb,c ∆ETZ d ∆HTZ
∆G298 d
ZPC
1
2
3
4
5
6
7
1a + HBr
1a‚HBr
TS8a
8a
TS8a
7a‚HCl
7a + HCl -3.2
0.0
-3.8
3.3
-8.6
5.6
0.0
1.1
1.3
3.6
1.4
1.4
0.2
0.0
-23.7 -3.2
-32.1 4.7
-32.0 -5.3
8.3
-23.8 -5.0
-0.1 -1.4
0.0
0.0
-2.1
6.0
-1.7
9.6
-3.6
-1.2
0.0
5.0
15.6
7.9
19.2
3.5
-1.1
-32.2
-7.0
a Corresponding structures are displayed in Figure 3. These energies are
relative to one chlorophosphine 1a and one HBr molecule. b Geometry
optimizations and related data (energy (Eopt), zero point correction (ZPC),
and entropy (S)) were obtained from B3LYP/6-31+G(2d) calculations.
c Entropy changes, ∆S, are in entropy units (cal‚mol-1‚K-1). d The “TZ”
energies are obtained from B3LYP/6-311++G(2d,p)//B3LYP/6-31+G(2d)
calculations.
Figure 4. Illustration of the thermodynamic pathway of halogen exchange
for 1a with HBr in the gas phase. Energies are in kilocalories per mole.
stereoselective synthesis of 1f or 1f‚BH3, by HCl acidolysis
of the diastereomerically pure aminophosphines 9, or the
borane adduct 9′‚BH3, respectively (Scheme 6). The stereo-
selectivity of the acidolysis was determined by quenching
1f (or 1f‚BH3) with methyllithium. In the first case, the
complexation of the o-anisylmethylphenylphosphine 10 was
made using BH3‚DMS and W(CO)5‚THF (DMS ) 4,6-
dimethoxybenzene-1,3-disulfonyl chloride; THF ) tetrahy-
drofuran). These complexations are well-established to
proceed with retention of the configuration.23,24 Both com-
plexes 10‚BH3 and 10‚W(CO)5 were obtained as quasi-
racemic, and this result did not depend on the reaction time
(10 min to 1 h) or the HCl concentration (0.04-0.12 M in
toluene).
Since P(III)-chirogenic compounds usually react stereo-
selectively with the organolithium reagents,25 in agreement
with our computed and experimental studies, the racemiza-
tion must originate from the reaction of the chlorophosphine
with residual HCl. However, the reaction of the chlorophos-
phine with organolithium reagent affords also LiCl as a
byproduct, and it cannot be excluded that the racemization
originates in part from the halide exchange of 1f with this
salt.
Figure 3. B3LYP/6-31+G(2d) optimized geometries for the halide
exchange between 1a and HBr. The arrows displayed on the transition-
state structures (TS8a, TS8a′) indicate the reaction coordinates.
(∆HTZ
) +6.0 kcal‚mol-1; Table 3, entry 3) than the
ZPC
corresponding HCl analogue TS5a (+10.4 kcal‚mol-1; Table
1, entry 7). The rest of the reaction profile with HBr is closer
to that of the HCl analogue. The pentacoordinated intermedi-
ate 8a and the second transition state TS8a′ are only very
slightly lower in energy than those obtained with HCl (Table
3, entries 4, 5; Table 1, entries 7, 8). Finally, the reaction
goes through a weak hydrogen-bonded complex 7a‚HCl to
give the products of the halide exchange (Me)2PBr (7a) and
HCl. The thermodynamic pathway of the halide exchange
is shown in Figure 4, and it is noteworthy that the products
In the second case, the acidolysis of 9′‚BH3 leads to the
chlorophosphine borane 1f‚BH3, and, after reaction with the
(22) (a) Juge´, S.; Stephan, M.; Achi, S.; Geneˆt, J. P. Phosphorus Sulfur
1990, 49/50, 267-270. (b) U.S. Patent 5 043 465, 1989. (c) Juge´, S.;
Stephan, M.; Laffitte, J. A.; Geneˆt, J. P. Tetrahedron Lett. 1990, 31,
6357-6360. (d) Juge´, S.; Stephan, M.; Geneˆt, J. P.; Halut-Desportes,
S.; Jeannin, S. Acta Crystallogr. 1990, C46, 1869-1872. (e) Juge´,
S.; Stephan, M.; Merde`s, R.; Geneˆt, J. P.; Halut-Desportes, S. J. Chem.
Soc., Chem. Commun. 1993, 531-533. (f) Kaloun, E. B.; Merde`s,
R.; Geneˆt, J. P.; Uziel, J.; Juge´, S. J. Organomet. Chem. 1997, 529,
455-463. (g) Moulin, D.; Darcel, C.; Juge´, S. Tetrahedron: Asymmetry
1999, 10, 4729-4743. (h) Moulin, D.; Bago, S.; Bauduin, C.; Darcel,
C.; Juge´, S. Tetrahedron: Asymmetry 2000, 11, 3939-3956. (i) Uziel,
J.; Darcel, C.; Bauduin, C.; Moulin, D.; Juge´, S. Tetrahedron:
Asymmetry 2001, 12, 1441-1449.
are slightly lower in energy than the reactants: ∆HTZ
)
ZPC
-1.2 kcal‚mol-1. The computational results are thus in favor
of an easy conversion of 1a into its bromide derivative 7a
and are in good agreement with the experiments. The
thermodynamic pathways of the halogen exchange of 1a with
HCl or with HBr are very similar (Figures 2 and 4). As HBr
reacts with 1a to lead to the corresponding 7a, HCl is also
expected to perform the halide exchange and consequently
the racemization.
(23) Imamoto, T.; Kusumoto, T.; Suzuki, N.; Sato, K. J. Am. Chem. Soc.
1985, 107, 5301-5303.
(24) Brodie, N.; Juge´, S. Inorg. Chem. 1998, 37, 2438-2442.
(25) (a) Chodkiewicz, W.; Jore, D.; Wodzki, W. Tetrahedron Lett. 1979,
20, 1069-1072. (b) Mikolajzyk, M. Pure Appl. Chem. 1980, 52, 959-
972. (c) Nielsen, J.; Dahl, O. J. Chem. Soc., Perkin Trans. 2 1984,
553-558. (c) Kolodiazhnyi, O. I. Tetrahedron: Asymmetry 1998, 9,
1279-1332.
Stereochemistry of the Acidolysis with HCl in the Case
of the Diastereomerically Pure Aminophosphine 9 (or
9′‚BH3). In connection with our continued work on chiral
phosphorus borane chemistry,22 we have investigated the
Inorganic Chemistry, Vol. 42, No. 2, 2003 425

Humbel et al.
Scheme 6
butylchlorophosphine were purchased from Aldrich, Acros, and
Avocado. Commercially available 2-bromoanisole was distilled
before use. HBr in toluene was prepared by bubbling the gas
previously generated by reaction of concentrated sulfuric acid with
NaBr and titrated before use. The (Rp)-N-methyl-[(1R,2S)-(2-
hydroxy-1-phenyl)ethyl]amino-o-anisylphenylphosphine borane
(9′‚BH3) was prepared according to the litterature.22e HPLC analyses
were performed on a Gilson 305/306 or Shimadzu chromatograph
equipped with an UV detector. Flash chromatography was per-
formed on silica gel (60AC.C, 35-70 mm) or neutral aluminum
oxide (Carlo Erba; ref. 417241). All NMR spectra were recorded
on Bruker DPX 250, Avance 300-500 spectrometers, with the
deuterium signal of the solvent as the lock, tetramethylsilane (TMS)
methyllithium reagent, to the phosphine complex (S)-10‚BH3
in 80% yield and with 95% e.e. (Scheme 6b). Thus, the
complexation of the aminophosphine by the borane, used as
a protecting group, avoid fast the racemization of the
chlorophosphine during the acidolysis step.
Conclusion
In this dual experimental and computational study on the
configurational stability of the chlorophosphines, we have
shown that HCl acts as a catalyst for the inversion at the
P-center. The mechanism of the racemization is explained
by the phosphorus nucleophilic attack on H, with a concerted
backside attack by the chlorine on the phosphorus center.
The reaction intermediate, as indicated by the gas-phase
computation, is an achiral pentacoordinated phosphorus with
two chlorine atoms in the axial position. Other mono- or
dimeric mechanisms that we envisaged required too high
activation energies for a room-temperature process.
The experiments and the calculations on the HBr reaction
with chlorophosphines showed an easy halide exchange,
which corroborates the easy racemization of the P-chiro-
genic analogue. Thus, bromophosphines were easily obtained
under mild conditions by simple halide exchange, constituting
a practical method for their synthesis.
Finally, we showed that pure chlorophosphines would be
configurationally stable at the phosphorus atom but that traces
of acids (HX) or halides, which are almost unavoidable in
the experimental conditions, carry out no stereoselectivity
for the aminophosphine reaction with HX. Since the inversion
process is a simple acid-base reaction involving the lone
pair of the phosphorus, the remedy for avoiding the racem-
ization is found in the deactivation of the lone pair’s basicity,
using the borane protecting group. This opens a very
promising way for the synthetic applications of the chiral
chlorophosphine borane, as P-chirogenic building blocks.
1
as the internal reference for H (250 MHz) and 13C NMR (62.9
MHz), and 85% phosphoric acid as the external reference for 31P
NMR (101.3 MHz). The 31P NMR chemical shifts (δ) are calculated
as negative values upfield of phosphoric acid. IR spectra were
recorded on a Perkin-Elmer 1600 FT or a Bruker Equinox 55 or
Vector 22 spectrometer. Melting points were measured on a Bu¨chi
melting point apparatus and are uncorrected. Optical rotation values
were determined at 20 °C on a Perkin-Elmer 241 polarimeter. Mass
spectral analyses were performed on a JEOL MS 700 and KRATOS
Concept S, at the Mass Spectroscopy Laboratories of ENS Paris
and Burgundy University (Dijon). Elemental analyses were mea-
sured with a precision superior to 0.4% at the Microanalysis
Laboratories of P. & M. Curie (Paris) and Burgundy (Dijon)
Universities.
(Rp)-(-)-N-Methyl-N-[(1S,2R)-(1-acetoxy-2-methyl-1-phenyl-
prop-2-yl)]amino-o-anisylphenylphosphine (9). This compound
was obtained by decomplexation from its borane complex, previ-
ously prepared from (+)-ephedrine according to the published
procedure.22i In a two-necked flask equipped with a reflux
condenser, a magnetic stirrer, and an argon inlet, 500 mg (1.15
mmol) of borane complex and 515 mg (4.6 mmol) of diazabicy-
clooctane were dissolved in 10 mL of dry and degassed toluene.
The mixture was heated at 50 °C for 10 h. The crude product was
rapidly filtered off on a neutral alumina column (15 cm height, 2
cm diameter) using 9:1 toluene/AcOEt as eluent, to give 444 mg
of 9 (yield, 91%; colorless viscous oil). 1H NMR (CDCl3): δ 0.5-
Experimental Section
3
2.0 (3H, br, BH3), 1.30 (3H, d, JHH ) 7, CHCH3), 1.93 (3H, s,
CH3CO), 2.22 (3H, d, 3JHH ) 3, NCH3), 3.60 (s, OCH3), 3.90 (1H,
m, 3JHH ) 3JPH ) 7, 3JHH ) 8, NCH), 5.75 (1H, d, 3JHH ) 8, PhCH),
6.54 (1H, m, H arom), 7.84-7.34 (13H, m, H arom). 13C NMR
(CDCl3): δ 15.9 (d, 3JPNCC ) 6, CHCH3), 21.2 (CH3CO), 31.9 (d,
2JPNC ) 9, NCH3), 55.1 (OCH3), 63.5 (d, 2JPNC ) 40, NCH), 78.4
All reactions were carried out under an argon or nitrogen
atmosphere in dried glassware. THF and toluene were dried and
freshly distilled under a nitrogen atmosphere over sodium/ben-
zophenone. Hexane and ethanol for HPLC were of chromatographic
grade and were used without further purification. n-Butyllithium,
2-bromoanisole, (+)-ephedrine, BH3‚S(CH3)2, 1,4-diazabicyclo-
[2.2.2]octane (DABCO), chlorodiphenylphosphine, and di-tert-
3
(d, JPNCC ) 9, CHO), 109.9 (C arom), 120.6 (C arom), 125.2-
129.9 (C arom), 131.3 (d, JPC ) 19, C arom), 131.8 (d, JPC ) 3,
426 Inorganic Chemistry, Vol. 42, No. 2, 2003

Configurational Stability of Chorophosphines
C arom), 138.1 (d, JPC ) 7, C arom), 139.1 (C arom), 160.4 (d,
JPC ) 17, C arom), 170.1 (C arom). 31P NMR (CDCl3): δ +56.
HCl Acidolysis of 9 into the o-Anisylchlorophenylphosphine
(1f). In a 100 mL two-necked flask equipped with a magnetic stirrer,
an argon inlet, and a rubber septum, 600 mg of 9 (0.95 mmol) was
dissolved in 32.5 mL of toluene. A solution of HCl in toluene (0.37
M, 5.3 mL, 2 mmol) was added at room temperature with stirring.
After 1 h, the ephedrine hydrochloride was filtered off on a
Millipore 4 µm filter, and the solution of 1f was used immediately
without further purification.
JP-C ) 12.9, C arom), 132.0 (d, JP-C ) 2.6, C arom), 134.6 (d,
JP-C ) 14.3, C arom), 135.5 (d, JP-C ) 1.8, C arom), 161.1 (d,
1
JP-C ) 2.4, C arom). 31P NMR (CDCl3): δ +91.9 (brd, JP-B
)
51.4).
Correlation of 1f‚BH3 into (R)-(-)-Phosphine Borane (10•BH3).
The methyllithium reagent (2.5 equiv.) is slowly added at -78 °C
to the toluene solution of 1f‚BH3 freshly prepared as described
above. The mixture is allowed to warm to room temperature and
then hydrolyzed with 20 mL of water. The aqueous layer is
extracted twice with dichloromethane. The combined organic phase
is dried over magnesium sulfate and condensed under reduced
pressure. The residue is purified over silica gel using 7:3 toluene/
petroleum ether as eluent, giving (R)-(-)-10‚BH3 in 80% yield,
with satisfactory analytical data.22f The enantiomeric excesses have
been determined by HPLC analysis on a Chiralcel OK Daicel
column, as described above.
Halide Exchange with the Chlorophosphines 1b,c. Typical
Procedure for HBr Reaction: Preparation of the Bromodiphen-
ylphosphine (7b). In a 50 mL two-necked flask equipped with a
magnetic stirrer, an argon inlet, and a rubber septum, 0.9 mL of
freshly distilled 1b [5 mmol; 31P NMR (CDCl3): δ +82] was added
to 14 mL of HBr in toluene (0.65 M, 9 mmol). After stirring at
room temperature for 15 min, 31P NMR analysis revealed complete
conversion into 7b. After removal of the solvent under vacuum,
the orange oily residue was distilled under vacuum (0.08 mbar) to
give 700 mg as the main fraction (isolated yield, 53%).
Correlation of 1f into o-Anisylmethylphenylphosphine Com-
plexes 10‚BH3 and 10‚W(CO)5. The previous filtrate was then
cooled to -78 °C, and 2.2 mL of MeLi (1.33 M) was added. The
reaction was kept at this temperature for 30 min, after which the
cooling bath was removed and the temperature allowed to warm
to room temperature. Half of the reaction mixture was quenched
by 0.5 mL of BH3‚DMS (10 M; DMS ) dimethyl sulfide). After
hydrolysis, the solvent was removed under reduced pressure and
the aqueous layer was extracted with 3 × 25 mL of CH2Cl2. The
combined extracts were dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by chromatography on
a short column of silica gel with a 7:3 toluene/petroleum ether
22f
mixture as eluent to give 50 mg of 10‚BH3 (43% yield). The
enantiomeric excess of the phosphine borane complex 10‚BH3 (e.e.
3%) was determined by HPLC on a Chiralcel OK Daicel column
with 70:30 hexane/EtOH as eluent (flow rate, 1 mL‚ min-1; (R)
enantiomer tR ) 11.1 min; (S) enantiomer tR ) 21.4 min).
The second half of the reaction mixture (∼20 mL) was quenched
by 8.5 mL of a freshly prepared solution of W(CO)5‚THF (0.05
M). After 2 h, the reaction mixture was hydrolyzed and the solvent
removed under reduced pressure. After extraction of the aqueous
layer with 3 × 25 mL of CH2Cl2, the combined extracts were dried
over MgSO4 and then concentrated. The residue was purified by
chromatography on a column of silica gel with a 15:1 cyclohexane/
AcOEt mixture as eluent to give 96 mg of 10‚W(CO)5 (36%
1H NMR (CDCl3): δ 7.33-7.36 (6H, sl, H arom), 7.57-7.65
(4H, sl, H arom). 13C NMR (CDCl3): δ 128.5 (d, 2JPCC ) 7, Cortho),
130.2 (s, Cpara), 132.5 (d, 3JPCCC ) 24, Cmeta), 137.0 (d, 1JPC ) 36,
C
ipso). 31P NMR (CDCl3): δ +72; lit.26 +72.4.
Typical Procedure for LiBr Reaction: Preparation of the
Bromodi-tert-butylphosphine (7c).
In a 50 mL two-necked flask equipped with a magnetic stirrer,
an argon inlet, and a rubber septum, 0.5 mL of freshly distilled 1c
[2.9 mmol; 31P NMR (CDCl3): δ +146], and 1.05 g of LiBr (11.6
mmol, 4 equiv) was added to 3 mL of dry toluene (0.65 M, 9 mmol).
After stirring at room temperature for 30 min, 31P NMR analysis
revealed complete conversion into 7c.
20
20
yield): o.p. <2%; [R]D ) -0.95 (c 0.5, CHCl3); lit.24 [R]D
)
-77 (c 2.3, CHCl3).
HCl Acidolysis of 9′‚BH3 into (S)-(-)-o-Anisylchlorophos-
phine Borane (1f‚BH3). In a 50 mL two-necked flask, equipped
with a magnetic stirrer, an argon inlet, and a rubber septum, 2 mmol
of 9′‚BH3 was introduced. A solution of HCl in toluene (0.38 M,
11.05 mL, 4.2 mmol, 2.1 equiv) was then added at room temperature
under stirring, without previous solubilization of 9′‚BH3. After 1
h, the precipitate of ephedrine hydrochloride was filtered off with
a Millipore 4 µm filter. The excess of HCl was then removed by
several vacuum/argon cycles, and the toluenic solution of 1f‚BH3
directly used for its reaction with the methyllithium reagent (vide
infra). The analysis was realized after purification by filtration on
31P NMR (CDCl3): δ +150; lit.27 +152.
Acknowledgment. This work was supported by a sub-
stantial allocation of computing time from CRIHAN-Plan
Interre´gional du Bassin Parisien-Poˆle interre´gional de mod-
e´lisation en sciences pour l’inge´nieur, Project 2001-2003,
and by the computational center of the University of Reims
ChampagnesArdenne. The authors gratefully acknowledge
also the Regions Champagne Ardennes (Fellowship for C.B.)
and Bourgogne, the ministry of research, and the CNRS for
their financial support.
a short column of silicagel, with toluene as eluent22h
(
20
yield, 99%; colorless viscous oil). Rf ) 0.8 (toluene). [R]D
)
-11.1 (c 8.6, CHCl3). e.e. ) 95 ( 5%. IR (NaCl, ν cm-1): 3058-
3010 (C-H), 2941-2839 (C-H), 2394 (B-H), 1589, 1575, 1478,
Supporting Information Available: Computational results,
XYZ coordinates, and absolute energies for all the computed
structures. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
1433, 1280, 1252, 1181, 1165, 1136, 1055, 1020, 900. H NMR
(CDCl3): δ 0.40-2.20 (3H, m, BH3), 3.63 (3H, s, OCH3), 6.91
(1H, dd, J ) 4.6, J ) 8.3, H arom), 7.11 (1H, td, J ) 2.6, J ) 7.6,
H arom), 7.39-7.61 (4H, m, H arom), 7.72-7.82 (2H, m, H arom),
7.95 (1H, ddd, J ) 1.6, J ) 7.7, J ) 14.9, H arom). 13C NMR
(CDCl3): δ 55.7 (OCH3), 112.0 (d, JP-C ) 4.4, C arom), 117.6 (d,
1JP-C ) 47.7, C arom), 121.1 (d, JP-C ) 12.3, C arom), 128.5 (d,
IC026128U
(26) Lindner, E.; Dieter Merkle, D. Hiller, W.; Fawzi, R. Chem. Ber. 1986,
119, 659-668.
(27) Du Mont, W.-W.; Schumann, H. J. Organomet. Chem. 1977, 128,
99-114.
1
JP-C ) 11.5, C arom), 128.7 (d, JP-C ) 50.8, C arom), 131.1 (d,
Inorganic Chemistry, Vol. 42, No. 2, 2003 427