Developing a new class of axial chiral phosphorus ligands: Preparation and characterization of enantiopure atropisomeric phosphinines

Article abstract of DOI:10.1002/chem.200800175

Both enantiomers of the first atropisomeric phosphinine (1) have been isolated by using analytical HPLC on a chiral stationary phase. The enrichment of one enantiomer and a subsequent investigation into its racemization kinetics revealed a barrier for internal rotation of ΔG₂₉₈ ^≠ = (109.5± 0.5) kJ mol^-1, which is in excellent agreement with the theoretically predicted value of ΔG_{298 ≠} = 116 kJ mol^-1. Further analysis with UV and circular dichroism spectroscopies and density functional theory calculations led to the determination and assignment of the absolute configurations of both enantiomers. These results are the basis for future investigations into this new class of axially chiral phosphinine-based ligands and their possible applications in asymmetric homogeneous catalysis.

Full text of DOI:10.1002/chem.200800175

FULL PAPER
DOI: 10.1002/chem.200800175
Developing a New Class of Axial Chiral Phosphorus Ligands: Preparation
and Characterization of Enantiopure Atropisomeric Phosphinines
Christian Müller,*[a] Evgeny A. Pidko,[a] Antonius J. P. M. Staring,[a] Martin Lutz,[b]
[a]
Anthony L. Spek,[b] RutgerA. van Santen, [a] and DieterVogt
Dedicated to Professor Peter Jutzi on the occasion of his 70th birthday
Abstract: Both enantiomers of the first
atropisomeric phosphinine (1) have
been isolated by using analytical HPLC
on a chiral stationary phase.The en-
richment of one enantiomer and a sub-
sequent investigation into its racemiza-
tion kinetics revealed a barrier for in-
ternal rotation of DG°298 =(109.5ꢁ
0.5) kJmolꢀ1, which is in excellent
agreement with the theoretically pre-
dicted value of DG°298 =116 kJmolꢀ1.
Further analysis with UV and circular
dichroism spectroscopies and density
functional theory calculations led to
the determination and assignment of
the absolute configurations of both en-
antiomers.These results are the basis
for future investigations into this new
class of axially chiral phosphinine-
based ligands and their possible appli-
cations in asymmetric homogeneous
catalysis.
Keywords: atropisomerism · chiral-
ity · density functional calculations ·
phosphinines · phosphorus hetero-
cycles
Introduction
ality for application in asymmetric reactions.We recently
demonstrated the synthesis of various donor-functionalized
phosphinines via a pyrylium salt intermediate, which intro-
duced specific substituents into defined positions on the
l3-Phosphinines (also known as phosphabenzenes or phos-
phorins), the homologues of pyridines, have been known for
more than 40 years and have a rich and versatile coordina-
tion chemistry.[1–3] However, investigations into their suita-
bility as ligands in homogeneous catalysis only started a
decade ago, and reports are limited to just a few examples.[4]
To implement fully phosphinine-based ligands in homoge-
neous catalysis, the availability of functionalized hetero-
hetero
cyclic framework.[5] This modular approach also al-
A
lowed us to design and synthesize the first atropisomeric
phosphinine 1 (R, S) by enforcing restricted rotation around
a Caryl–Caryl’ bond (Scheme 1).[6,7] By using density functional
theory (DFT) calculations, an energy barrier for internal ro-
tation of DG°298 =116 kJmolꢀ1 for the enantiomerization of 1
was predicted, which is expected to be high enough for con-
figurational stability under ambient conditions.[8] Compound
1 was obtained as a racemic mixture, but we have already
demonstrated that both enantiomers can be detected with
cycles and their facile modification is essential to fine-tune
the stereoelectronic ligand properties and incorporate chir-
[a] Dr.C.Müller, E.A.Pidko, A.J.P.M.Staring,
Prof.Dr.R.A.van Santen, Prof.Dr.D.Vogt
Department of Chemical Engineering and Chemistry
Schuit Institute of Catalysis
Eindhoven University of Technology
5600 MB Eindhoven (The Netherlands)
Fax : (+31)402-455-054
E-mail: c.mueller@tue.nl
[b] Dr.M.Lutz, Prof.Dr.A.L.Spek
Bijvoet Center for Biomolecular Research
Crystal and Structural Chemistry
Utrecht University, Padualaan 8
3584 CH Utrecht (The Netherlands)
Scheme 1.Axially chiral phosphinine 1 (R, S).
Chem. Eur. J. 2008, 14, 4899 – 4905
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4899

sufficient separation by using analytical HPLC on a chiral
stationary phase.
Herein, we report the preparation, isolation, and charac-
terization of enantiopure atropisomeric phosphinines 1-R
and 1-S.Furthermore, the energy barrier for internal rota-
tion was determined experimentally and the absolute config-
urations were assigned in combination with DFT calcula-
tions.
Results and Discussion
The key intermediate for the preparation of 1 is 2,3-di-
methylpropiophenone (2; Scheme 2).[9] The use of a propio-
phenone, rather than an acetophenone, ultimately results in
Figure 1.Molecular structure of 3 determined by X-ray crystallography.
Displacement ellipsoids are shown at the 50% probability level.Selected
ꢀ
ꢀ
ꢀ
bond lengths [Š]: C1 O1 1.3509(19), O1 C5 1.3346(19), C5 C21
ꢀ
ꢀ
1.463(2), C1 C6 1.486(2), C2 C14 1.508(2); torsion angle [8]: C7-C6-C1-
C2 72.9(2).
Scheme 2.Synthesis of phosphinine 1.Reaction conditions: i) trans-ben-
zylideneacetophenone (2 equiv), HBF4·Et2O, 70 8C; ii) P
C5H5N, 1258C.
A
the placement of a methyl group at the 3-position of the het-
erocycle, which is necessary to maintain the axial chirality.[10]
Figure 2. 1H NMR (400 MHz, [D6]C6H6) spectrum of 1.Inset:
31P{1H} NMR (162 MHz, [D6]C6H6) spectrum of 1.
Treatment of
2 with of trans-benzylideneacetophenone
(2 equiv) in the presence of HBF4·Et2O gave pyrylium salt 3
as a racemic mixture, which was obtained as a yellow solid
in moderate yield (Scheme 2).[6]
Slow evaporation of the solvent from a concentrated solu-
tion of 3 in methanol gave crystals that were suitable for X-
ray diffraction.The molecular structure of 3 is illustrated in
Figure 1, along with selected bond lengths and angles.
Pyrylium salt 3 crystallizes as a racemate in the centro-
symmetric space group C2/c.This result not only confirms
the expected substitution pattern, but also shows that the
plane of the xylyl substituent in the 2-position is almost per-
pendicular (torsion angle=72.9(2)8) to the plane of the het-
erocycle as a result of the expected restricted rotation
ꢀ
teristic downfield shift of the phosphorus signal at d=
1
190.6 ppm. The H NMR spectrum shows a doublet at d=
3
7.95 ppm with a coupling constant of J
A
is characteristic of the P-heterocyclic proton (Hb) in an
asymmetrically substituted phosphinine.The doublet at d=
4
2.06 ppm with a coupling constant of J
A
assigned to the exo-heterocyclic CH3 group and the two re-
maining CH3 groups of the xylyl subsitutent were assigned
to singlets at d=2.03 and 1.98 ppm.
A very good separation of enantiomers 1-E1 (eluted first)
and 1-E2 (eluted second) was achieved by using analytical
HPLC on a chiral stationary phase with n-hexane as the
eluent (Chiralcel OD-H, t1 =17.75 min, t2 =22.98 min, 258C,
flow rate 1 mLminꢀ1).HPLC analysis of both fractions with
the same chiral column revealed that both isomers could be
obtained with an enantiopurity of 99%.Additionally, the
successful separation of the enantiomers confirmed our orig-
inal assumption that the energy barrier for internal rotation
is reasonably high (Figure 3).
around the C1 C6 bond.Thus, the molecular structure of
is similar to that of the first atropisomeric pyrylium salt we
3
recently reported.[6]
Pyrylium salt 3 was further converted into the correspond-
ing racemic phosphinine
1
by treatment with excess
[11]
P(CH2OH)3
A
in pyridine at reflux (Scheme 2).After
column chromatography, compound 1 was obtained as a
yellow powder (34% yield) and could be isolated as yellow
needles after recrystallization from hot acetonitrile or pen-
tane.Figure 2 shows the 1H and 31P{1H} NMR spectra of 1 in
[D6]C6H6.The 31P{1H} NMR spectrum illustrates the charac-
Isolation of the enantiomers also provided an opportunity
to determine the energy barrier for internal rotation experi-
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Chem. Eur. J. 2008, 14, 4899 – 4905

Axial Chiral Phosphorus Ligands
FULL PAPER
Plotting ꢀln([M]tꢀ[M]eq/[M]0ꢀ[M]eq) versus time for 1-E2
gave
a
value of k1 =kꢀ1 =(4.2ꢁ0.8)”10ꢀ7 sꢀ1 at 298 K
(Figure 5).Thus, a value of DG°298 =(109.5ꢁ0.5) kJmolꢀ1 for
Figure 3.A chromatogram of 1-E1 and 1-E2 after HPLC separation of
racemic 1.
mentally.The thermal racemization at constant temperature
of preparatively enriched 1-E1 was followed over regular
time intervals and over at least two half-lives (Figure 4).[12]
The results show that a ratio of 1-E1/1-E2 of 59:41 was
reached after 23 d at 258C, which corresponds to an enantio-
meric excess (ee) of 18% for 1-E1.
Figure 5.Plot of ꢀln([M]tꢀ[M]eq/[M]0ꢀ[M]eq) versus time at 298 K for 1-
E2.
1
the free activation energy and a value of t=t = =(9.6ꢁ2.1) d
2
for the half-life were determined by using the Eyring equa-
tion [Eq.(2)] and Equation (3) to calculate the reversible
first-order kinetics for the interconversion of 1-E1 and 1-E2
(see also Table 1).[13,14]
ꢀ
ꢁ
kBT
kh
DG° ¼ RTln
ð2Þ
ð3Þ
ln 2
t ¼ t = ¼
1
2
ð2kÞ
Table 1.Experimentally and theoretically determined kinetic parameters
for phosphinine 1.[14]
DG°298 [kJmolꢀ1
]
k”10ꢀ7 [sꢀ1
4.2ꢁ0.8
]
Exptl[a]
Calcd[b]
t1/2 [d]
9.6ꢁ2.1
Figure 4.HPLC chromatograms of the thermal racemization of 1-E1 in
hexane at 298 K.
1
109.5ꢁ0.5
116
[a] Experimentally obtained value.Conditions: hexane,
T=298 K.
[b] Value obtained from DFT calculations with B3LYP/6-31G(d,p).
A
The rate constant for enantiomerization (k1 =kꢀ1) was de-
termined by using reversible first-order kinetics for the in-
terconverison of enantiomers 1-E1 and 1-E2 (see also
Scheme 1) according to Equation (1):
The experimentally determined value of DG°298 for the
energy barrier for internal rotation agrees well with the
value calculated by using DFT (DG°298 =116 kJmolꢀ1).[6]
These results also show, however suggest that configuration-
al stability is not guaranteed at higher temperatures, and
thus, under typical catalytic reaction conditions, although
the situation in the corresponding metal complexes might be
considerably different and higher free activation energies
for the interconversion of the enantiomers are expected.
Nevertheless, it demonstrates that theoretical calculations
are powerful tools for predicting and estimating physical or-
ganic properties of such systems and can help to design suit-
able ligand systems prior to synthetic work.
ꢀ
ꢁ
½MŠ ꢀ½MŠ
eq
½MŠ0t ꢀ½MŠ
ln
¼ ꢀ2kt
ð1Þ
eq
in which [M]t is the molar concentration at time t, [M]0 is
the initial molar concentration, and [M]eq is the equilibrium
molar concentration of one enantiomer.Alternatively, we
used the corresponding percentage values of the enantio-
mers obtained from the HPLC analysis described above
(Figure 4), with [M]eq =50%.
Chem. Eur. J. 2008, 14, 4899 – 4905
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C.Müller et al.
We were also interested in the possibility of assigning the
absolute configurations of 1-E1 and 1-E2.For this purpose,
the optical properties of the separated enantiomers were in-
vestigated; the experimentally recorded circular dichroism
(CD) and UV spectra of 1-E1 and 1-E2 in hexane are shown
in Figure 6a and b.The UV absorption spectra (Figure 6b)
show a shoulder at l=300 nm, followed by an absorption
maximum at lmax ꢂ260 nm.These data are typical for 2,4,6-
substituted triarylphosphinines in methanol (2,4,6-triphenyl-
phosphinine: lmax =278 nm, l=314 nm (sh); 2,4,6-triphenyl-
pyridine: lmax =254 nm, l=312 nm (sh); 2,4,6-triphenylben-
zene: lmax =254 nm).These bands were originally assigned
to an n!p* transition (long-wave absorption shoulder) and
be observed in the UV spectra and may have given rise to
the slight anomaly observed in the values of ꢀDe.
To deduce the absolute configuration of both enantio-
mers, the respective CD and UV spectra were simulated by
means of a time-dependent DFT method at the TD-B3LYP/
6-31G(d,p) level.This technique has been shown to provide
G
a reasonably accurate description of the photophysical prop-
erties of various compounds, which includes quite accurate
predictions of CD spectra.[17] We optimized the geometries
of 1-R and 1-S (see Scheme 1) at the B3LYP/6-31G(d,p)
U
level and calculated their theoretical CD and UV spectra,
which are shown in Figure 6c and d, respectively.
It can be seen that the theoretical UV spectrum (Fig-
ure 6d) has the same qualitative features as those observed
in the experimental spectrum (Figure 6b).Moreover, the po-
sitioning of the bands in both cases is very similar.Analysis
of the calculated electronic absorption bands also reveals
that the shoulder at lꢂ300 nm should in fact be attributed
to p!p* transitions, with major contributions from
HOMO!LUMO and HOMOꢀ1!LUMO excitations.The
absorption maximum at lmax ꢂ260 nm, on the other hand,
was attributed to a combination of p!p* and n!p* transi-
1
a p!p* L(a) transition (short-wave absorption).[15,16] How-
ever, note that the lone pair located on the phosphorus
atom is not the HOMO, and therefore, it is expected to be
relatively low in energy.[15] The CD spectra (Figure 6a) show
an exciton split couplet with relatively small values of ꢀDe
ꢂ15 and ꢂ25 for 1-E1 and 1-E2, respectively, and also two
Cotton effects for each enantiomer at lꢂ275 and ꢂ210 nm.
Note that as a result of the enrichment procedure, the con-
centrations of the enantiomers are slightly different; this can
Figure 6.Experimental CD (a) and UV (b) spectra of 1-E1 (c) and 1-E2 (g) in hexane.The experimental CD spectra (gray lines) have been smooth-
ed (black lines) to reduce the high noise level.Theoretical CD (c) and UV (d) spectra of enantiomers 1-R (b) and 1-S (c).
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Axial Chiral Phosphorus Ligands
FULL PAPER
Figure 8.HPLC analysis of 1 and assignment of the absolute configura-
tions: 1-E1 =1-S, 1-E2 =1-R.
ieved by comparing the experimental CD spectra of both
enantiomers with theoretical spectra from optimized struc-
tures.Investigations on ligands with different substitution
patterns and higher rotational energy barriers are currently
in progress.Their separation on a preparative scale and the
influence of metal coordination on the free energy of activa-
tion for the interconversion of enantiomers are being inves-
tigated.These properties are of particular interest because
configurational stability at higher temperature, and thus
under typical catalytic reaction conditions, is a prerequisite
for the successful application of this new class of axially
chiral phosphorus-containing ligands in asymmetric homoge-
neous catalysis.The results presented herein provide the
basis for future investigations in this research area.
Figure 7.FMOs of phosphinine 1.
tions (see Figure 6d).The respective frontier molecular orbi-
tals (FMOs) are depicted in Figure 7.
The theoretical CD spectra (Figure 6c) of both enantio-
mers reproduce well the features of those obtained experi-
mentally (Figure 6a), in particular, the bisignate shape as
well as the sequence and positions of the negative/positive
Cotton effects.However, the intensity maxima of the theo-
retical spectra match less well and are, in general, larger
than those of the experimental spectra.Note that, even
though the rotation of the phenyl groups at the 4- and 6-po-
sitions on the heterocycle does have an influence on the
shape of the theoretical CD spectrum, the theoretically pre-
dicted and experimentally observed bisignate nature of the
spectra remains unchanged and is independent of the con-
formations of these phenyl substituents.
Experimental Section
General: The 1H and 31P{1H} NMR spectra were recorded by using a
Varian Mercury 400 spectrometer.HPLC analysis and fraction collection
was performed by using HPLC equipment that consisted of a Shimadzu
LC-20 AD pump, a Shimadzu SPD-20 A UV/Vis detector, a Spark Hol-
land Marathon autosampler, a homemade oven with a column selector,
and an LKB 2211 Superrac fraction collector.Column and analysis speci-
fications: Chiralcel OD-H (250”4.6 mm, particle size: 5 mm, purchased
from Daicel), eluent=n-hexane, column temperature=258C, flow rate=
The qualitative agreement between the experimental re-
sults and the theoretical calculations allowed us to unambig-
uously assign the 1-S configuration to 1-E1 and the 1-R con-
figuration to 1-E2, as illustrated in Figure 8.
Conclusion
1 mLminꢀ1
, pressure=34 bar, l=254 nm (UV detector), injection
volume=20 mL.
Enrichment and determination of racemization kinetics of 1-E1: Phosphi-
nine 1 was prepared according to a previously reported procedure[6] and
recrystallized from hot, degassed, dry acetonitrile to give 1 as bright
yellow needles.Racemate 1 (1 mg, 8.2”10ꢀ6 mol) was dissolved in de-
gassed n-hexane (1 mL), prior to HPLC enrichment.Enantiomer 1-E1
was eluted and collected under an argon atmosphere and the solvent was
evaporated.This procedure was performed twelve times, and the com-
bined residues of 1-E1 were redissolved in degassed n-hexane (6.0 mL) to
give a final concentration of approximately 1”10ꢀ4 m.This solution was
stirred at 258C and aliquots (0.7 mL) were analyzed by using HPLC at
time intervals of t=0, 3, 6, 10, 16, and 23 d.
We have demonstrated the successful separation of enantio-
mers of the first axially chiral phosphinine 1 by means of an-
alytical HPLC on a chiral stationary phase.The atropisom-
ers were isolated with an enantiopurity of 99% and an
energy barrier for internal rotation of DG°298 =(109.5ꢁ
0.5) kJmolꢀ1 was experimentally determined by thermal rac-
emization and showed a very good agreement with the theo-
retically predicted value of DG°298 =116 kJmolꢀ1.The assign-
ment of the absolute configurations 1-R and 1-S was ach-
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C.Müller et al.
UV and CD analysis: UV/Vis and CD spectroscopic measurements were
performed at 258C by using a Jasco J-815 spectropolarimeter.Appropri-
ate settings were chosen for the sensitivity, time constant, and scan rate
and 0.1 cm cuvettes were used.
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(1 mL), prior to HPLC separation.Enantiomers 1-E1 and 1-E2 were
eluted and collected under an argon atmosphere and the solvent was
evaporated.This procedure was performed three times and the combined
residues of 1-E1 and 1-E2 were each redissolved in degassed hexane
(0.6 mL) to give final concentrations of approximately 2.7·10ꢀ4 m.The
UV and CD spectra were recorded immediately.
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Crystallographic data: C26H23O·BF4; Mr =438.25; yellow block; 0.37”
0.27”0.22 mm3; monoclinic; C2/c (no.15); a=35.478(3), b=7.7312(5),
c=15.8455(11) Š;
b=99.877(2)8;
V=4281.9(2) Š3;
Z=8;
1=
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1.360 gcmꢀ3; m=0.104 mmꢀ1.37605 reflections were measured by using a
Nonius Kappa CCD diffractometer with a rotating anode (graphite mon-
ꢀ1
ochromator, l=0.71073 Š) up to a resolution of (sinq/l)max =0.61 Š at
a temperature of 150 K.The reflections were corrected for absorption
and scaled on the basis of multiple measured reflections by using the
SADABS program[18] (0.70–0.97 correction range). 3987 reflections were
unique (Rint =0.027). The structures were solved with SHELXS-97[19] by
using direct methods and refined with SHELXL-97[19] on F2 for all reflec-
tions.Non-hydrogen atoms were refined by using anisotropic displace-
ment parameters.All hydrogen atoms were located by using difference
Fourier maps and refined with a riding model.292 parameters were re-
fined with no restraints. R1/wR2 [I>2s(I)]: 0.0404/0.0973, R1/wR2 (all
reflns): 0.0503/0.1030, S=1.042, residual electron density was between
ꢀ0.28 and 0.55 eŠꢀ3.Geometry calculations and checks for higher sym-
metry were performed with the PLATON program.[20]
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CCDC-675769 (3) contains the supplementary crystallographic data for
this paper.These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Computational details: Quantum chemical calculations were carried out
with DFT by using the Gaussian 03[21] program at the B3LYP/6-31G
(d,p)
G
level.Full geometry optimizations were performed for compounds 1-R,
1-S, and the transition state of racemization.The nature of the stationary
points was tested by analyzing the analytically calculated harmonic
normal modes.The local minimum structures did not show imaginary fre-
quencies, whereas the transition-state structure showed a single imagina-
ry frequency that corresponded to an eigenvector along the reaction
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ꢀ
path, that is, internal rotation about the Caryl Caryl’ bond.The theoretical
˙
ˇ
ˇ
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UV/Vis spectra were calculated at the same level as the geometry optimi-
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Acknowledgements
The authors would like to thank Dr.Subi Jacob George (TU/e, Laborato-
ry of Macromolecular Chemistry) for recording the CD and UV spectra
and Joost van Dongen for valuable advice on HPLC analysis.This work
was supported in part (ML, ALS) by the Council for the Chemical Scien-
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Axial Chiral Phosphorus Ligands
FULL PAPER
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Received: January 28, 2008
Published online: April 9, 2008
Chem. Eur. J. 2008, 14, 4899 – 4905
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4905