31P solid state NMR study of structure and chemical stability of dichlorotriphenylphosphorane

Article abstract of DOI:10.1002/mrc.2412

Solid state ³¹P NMR spectroscopy was used to examine, monitor and quantify the compound integrity of the chemical reagent dichlorotriphenylphosphorane. Comparison was also made with solution P NMR spectra which showed that this highly reactive

Full text of DOI:10.1002/mrc.2412

Research Article
Received: 6 November 2008
Revised: 12 January 2009
Accepted: 15 January 2009
Published online in Wiley Interscience: 5 March 2009
(www.interscience.com) DOI 10.1002/mrc.2412
31P Solid state NMR study of structure
and chemical stability of
dichlorotriphenylphosphorane
Nina C. Gonnella,∗ Carl Busacca, Scot Campbell, Magnus Eriksson,
Nelu Grinberg, Teresa Bartholomeyzik, Shengli Ma and Daniel L. Norwood
Solid state 31P NMR spectroscopy was used to examine, monitor and quantify the compound integrity of the chemical reagent
dichlorotriphenylphosphorane. Comparison was also made with solution 31P NMR spectra which showed that this highly
reactive species could be observed in dry benzene prior to conversion to the hydrolyzed product. This is the first reported
solid state NMR study of the stability and reactivity of dichlorotriphenylphosphorane and the first account of its observation
and comparison in the solution state. In the solid state, the ionic and covalent forms for dichlorotriphenylphosphorane
were observed along with hydrolyzed products, however, the degree of hydrolysis was dependent upon the rotor packing
conditions. Calculation of the relative percent composition of dichlorotriphenylphosphorane with hydrolyzed product was
made for samples prepared in air versus under nitrogen atmosphere. This information was critical in adjusting the amount of
reagent used in chemical development syntheses and scale up laboratories. All hydrolyzed products were identified, based
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upon chemical comparisons with spectra of pure materials. Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Keywords: NMR; 31P; solid state; dichlorotriphenylphosphorane; triphenylphosphine oxide; hydrolysis; quantitative comparison
Introduction
ssNMR was used to determine the reactivity of this compound and
unambiguously identify the resultant hydrolyzed products. This
information was critical in adjusting the amount of reagent used
in chemical development syntheses and scale up laboratories.
Dichlorotriphenylphosphorane (DCTP) is an efficient reagent for
alkyl halide synthesis in organic chemistry.[1] This reagent is very
sensitive to moisture, hence requires careful storage and handling
inadryatmosphere.Uponexposuretoair,DCTPrapidlyconvertsto
phosphine oxide rendering the molecule inactive as a chlorinating
agent. This rapid hydrolysis has made examination of the integrity
of the phosphorane elusive since exposure to moisture in the air
or solvent will immediately convert the reagent to hydrolyzed
product. Most analytical methods do not provide sufficient
protection from atmospheric moisture to render them viable
for monitoring the compound’s chemical state. This becomes
particularly important in batch process synthesis where product
yields are critical in compound production; hence development of
a method to assess the purity of the reactant is necessary.
For the past decade, solid state NMR (ssNMR) has emerged
as an important technology in pharmaceutical research and
development.[2] With the advent of cross polarization and magic
angle spinning (MAS),[3,4] spectra that provide the quality required
for structural identification and quantitation of inorganic, organic
and biological compounds are now possible. Unlike solution
NMR, this technology does not require use of a solvent that will
introduce moisture. Hence, materials may be examined directly
and monitored over time without external interference.
Experimental
All chemicals were purchased from either Sigma-Aldrich or Digital
Speciality Chemicals. Triphenyl phosphine oxide (TPPO) and two
different batches of dichlorotriphenylphosphorane (Batch 1 and
Batch 2) were purchased and stored in a dessicator.
Solution 31P NMR: 31PNMR spectra were acquired using a Bruker
Avance III 500 MHz NMR spectrometer (Bruker-Biospin) operating
at202.46 MHzfor 31PwithaHewlettPackardcomputerandaLinux
operating system. Spectra were acquired at 298 ◦K with a sweep
width of 80 000–100 000 Hz, relaxation delay of 1.0 s, 90◦ pulse
width of 25 µs, acquisition time of 0.4 s and 65.5 K data points.
Waltz-16 proton decoupling was used and the total number of
transients was 16.
Samples were dissolved in either deuterated dimethylsulfoxide
or deuterated benzene as saturated solutions and placed in a
5-mm NMR tube.
Solid state 31P NMR: Solid state 31P NMR spectra were acquired
using a Bruker Avance III 400 MHz wide bore NMR spectrometer
Because ssNMR spectroscopy provides a powerful means of
chemical identification, we elected to use 31P ssNMR to examine,
monitor and quantify the compound integrity of dichlorotriph-
enylphosphorane. These studies allowed the identification of
hydrolyzed product and enabled calculation of the percent com-
position of DCTP when samples were prepared in air versus under
nitrogen atmosphere. This is the first reported study in which 31P
∗
Correspondence to: Nina C. Gonnella, Boehringer Ingelheim Pharmaceuticals
Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA.
E-mail: nina.gonnella@boehringer-ingelheim.com
Boehringer Ingelheim PharmaceuticalsInc., 900 Ridgebury Road, Ridgefield, CT
06877, USA
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Magn. Reson. Chem. 2009, 47, 461–464
Copyright ꢀ 2009 John Wiley & Sons, Ltd.

N. C. Gonnella et al.
(Bruker-Biospin) operating at 162.1 MHz for 31P. A Bruker H/X
CP/MAS probe equipped with a 4-mm rotor was used to acquire
all spectra.
Upon standing at atmospheric conditions for 16 h, dichlorot-
riphenylphosphorane was hydrolyzed to a product where the
phosphorous chemical shift is at 42.97 ppm. Since the chem-
ical shift of commercially obtained triphenylphosphine oxide
appeared at 28.65 ppm, the downfield shift of about 15 ppm
suggested a significant change in this hydrolyzed product. While
multiple polymorphs of TPPO are known to exist, their preparation
and characterization have not been reported.[20] However, be-
cause of the significant downfield shift from triphenyl phosphine
oxide, it was proposed that the unknown peak may be due to
the hydrochloride salt of TPPO as opposed to an alternate poly-
morph form. To confirm this hypothesis, the hydrochloride salt of
TPPO was prepared according to an internally developed proce-
dure. Initial attempts to prepare the hydrochloride salt of TPPO,
based upon a known procedure,[21] were unsuccessful. It was
found, however, that the desired product could be reproducibly
prepared from a ‘slurry-to-slurry’ conversion in which TPPO was
added to anhydrous 2M ethereal HCl under argon. The resultant
slurry was allowed to age overnight at ambient temperature to
yield the desired product as a solid after filtration under an inert
atmosphere. The 31P NMR spectrum showed the unknown peak
to be the hydrochloride salt of TPPO with the monohydrate as a
minor component (Fig. 2).
Solid state 31P NMR data were collected for DCTP obtained from
two different commercial batches (Batch 1 and Batch 2). The rotors
were packed in dry nitrogen atmosphere and 31P ssNMR spectra
were collected. The phosphorous ssNMR data showed a higher
composition of DCTP for the material from Batch 2, having only
3% conversion to the hydrolyzed form. The material from Batch 1,
however, showed about 8% conversion to the hydrolyzed form.
The percent of reagent and hydrolyzed impurity was determined
from the relative integrated intensities of the phosphorous peaks.
These data were in agreement with its use as a synthetic reagent
where complete conversion to product was consistently found
for material showing lower levels of hydrolysis product (internal
communication).
Samples were packed into 4-mm Zirconia rotors and sealed
with Kel-F caps. Preparation occurred either under atmospheric
conditions or under dry nitrogen. Spectra were acquired using
variable amplitude cross polarization,[4–7] magic angle spinning
(MAS)[8,9] and high power proton decoupling with two phase
pulse modulation (TPPM).[10–13] Contact time of 3 ms was used to
acquire all spectra. The MAS frequency was 15 kHz and the proton
decoupling field was approximately 49 kHz. Recycle delays, based
upon saturation of 31P signal intensity, were sufficiently long to
allow full relaxation of 31P signal. Phosphorous chemical shifts are
quoted with respect to phosphoric acid.
Results and Discussion
The31PNMRchemicalshiftsofdichlorotriphenylphosphorane,and
its hydrolyzed products obtained from both ssNMR and solution
NMR are given in Table 1. The ssNMR data show that dichloro-
triphenylphosphorane exists in the pseudo-trigonal bipyramidal
form as evidenced by the peak at −43.44 ppm and in the ionic
quasi-phosphonium salt appearing at 63.62 ppm.[14,15] Multiple
peaks for the dichlorotriphenylphosphorane at −43.44 ppm and
63.62 ppm are due to 31P, 35,37Cl dipolar coupling in 31P MAS
spectra.[16,17] Measured 31P–35Cl isotropic (J) scalar couplings for
the peaks at −43.44 and 63.62 ppm were approximately 230 and
317 Hz with quadrupole-perturbed dipolar and anisotropic scalar
distortions of approximately +14 Hz and −179 Hz, respectively.[18]
Because of the phosphorane’s susceptibility to hydrolysis on
exposure to moisture, this compound required handling in a
dry atmosphere. When NMR rotors were packed under a dry
nitrogen atmosphere, the monohydrate phosphine oxide, at
27.04 ppm, was present in the phosphorane spectrum as the
only hydrolyzed product. The identity of the monohydrate was
confirmed via a preparation, according to a known procedure.[19]
The 31P NMR data, comparing the dichlorotriphenylphosphorane
spectrum with the hydrolyzed monohydrate spectrum are shown
in Fig. 1. The hydrolyzed product was also evident from the loss of
dipolarcouplingofchlorinewithphosphorousthatischaracteristic
of a 31P–35Cl bond.
When the rotors were packed in the laboratory atmosphere,
the exposure to air for a short duration of several minutes
increased the amount of hydrolyzed product to about 30%. This
hydrolyzedproductconsistedofthemonohydrateat27.04 ppm[19]
and hydrochloride salt at 42.97 ppm. Spectra of DCTP prepared
underdrynitrogenatmosphereandunderlaboratoryatmospheric
conditions are shown in Fig. 1 (b–d).
A comparison of solution NMR with solid state NMR was
also carried out. The 31P NMR solution spectrum of the
dichlorotriphenylphosphorane was difficult to acquire because
of the almost instant conversion to the hydrolyzed form upon
dissolution in solvent. This was found to be the case in DMSO
where the chemical shift of the phosphorane showed complete
conversion to the hydrolyzed form with the 31P chemical shift at
39.96 ppm which is identical with the 31P solution NMR chemical
shift of the purchased TPPO. In benzene, however, it was possible
to trap the covalent form long enough to get a spectrum of the
dichlorotriphenyphosphorane (Fig. 3). The spectrum showed that
the covalent dichlorotriphenylphosphorane phosphorous atom
resonates at −29.6 ppm and ionic dichloride at 69.8 ppm. Peaks
consistent with the hydrolyzed forms appear between 38.8 and
40.8 ppm. Upon standing in solution, complete conversion to the
TPPO was observed. All solution NMR chemical shifts appeared
downfield relative to that in the solid state.
Table 1. Phosphorous-31 NMR chemical shifts for dichlorotri-
phenylphosphorane and hydrolyzed products
Compound
ss NMR δ31P/(ppm)a
solution NMR δ31P/(ppm)
Ph3PCl+Cl−
Ph3PCl2
63.62
−43.44
28.65
69.8b
−29.8b
Ph3PO
38.96c
(38.87–40.81)b
(38.87–40.81)b
40.81b
Ph3PO · H2O
Ph3PO · HCl
27.04
42.97
44.40d
a Referenced from 85% H3PO4.
b Dichlorotriphenylphosphorane and hydrolyzed products (Batch 1)
acquired in benzene-d6.
c Triphenylphosphine oxide (purchased material) spectrum acquired in
DMSO-d6.
d Hydrolyzed product of dichlorotriphenylphosphorane (Batch 1) after
standing in benzene-d6 for 1 h.
Unlike solution NMR, the solid state phosphorous NMR spectra
showthatdichlorotriphenylphosphoranedoesnotrapidlyconvert
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Copyright ꢀ 2009 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2009, 47, 461–464

31P Solid state NMR study of dichlorotriphenylphosphorane
Cl
P
Cl
P
P
O
Cl
H
P
O
Cl
H
Cl
O
H
58.8%
37.6%
43.4%
Batch 2 / Glove Box
Batch 1 / Glove Box
Atm preparation
3.6%
8.2%
14%
(d)
(c)
48.4%
25.6%
44.4%
16%
(b)
(a)
Figure 1. 31P CP/MAS NMR spectra (B0 = 9.4 T, vrot = 15 000 Hz). (a) Triphenyl phosphine oxide monohydrate prepared according to reported
procedure.[19] (b) Dichlorotriphenylphosphorane (Batch 1) prepared in laboratory atmosphere shows the presence of 30% TPPO hydrolyzed products;
existing as 14% monohydrate and 16% hydrochloride salt. (c) Dichlorotriphenylphosphorane (Batch 1) prepared under dry nitrogen atmosphere shows
the presence of 8.2% TPPO monohydrate. (d) Dichlorotriphenylphosphorane (Batch 2) prepared under dry nitrogen atmosphere shows the presence of
3.6% TPPO monohydrate.
Figure 2. (a)31P CP/MAS NMR spectrum of triphenyl phosphine oxide hydrochloride (B0 = 9.4 T, vrot = 15 000 Hz) shows the trace amounts of the TPPO
monohydrate present. (b) 31P CP/MAS NMR spectrum of dichlorotriphenylphosphorane (B0 = 9.4 T, vrot = 15 000 Hz) after exposure to atmosphere for
16 h. The spectrum shows nearly complete conversion to the hydrochloride salt with trace amounts of triphenylphosphine oxide.
to hydrolyzed product when packed in a rotor, since spectra of the
compound remained virtually unchanged for weeks. Clearly the
packed rotor protects the compound from exposure to moisture in
theatmosphereandpreventstheformationofhydrolysisproducts.
Hence insights into the appropriate handling of this material could
be readily ascertained from the solid state NMR spectra.
of the covalent form of DCTP to the hydrolyzed form consists of
transition through an intermediate ionic state. The data also show
that the conversion to hydrolyzed products is initiated with the
formation of the monohydrate followed by final formation of the
hydrochloride salt.
The data do, however, show that the samples with the lowest
concentration of hydrolyzed product have the highest amount of
covalent DCTP reagent. As the conversion to hydrolyzed product
increases, the ionic form of the material becomes more prevalent
(Fig. 1 (b–d)). This suggests that the mechanism for conversion
Conclusion
31P Solid state NMR spectroscopy proved to be a valuable
technology for monitoring the physical characteristics and
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Magn. Reson. Chem. 2009, 47, 461–464
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N. C. Gonnella et al.
Cl
P
P
O
Cl
Cl
P
Cl
Figure 3. 31P NMR spectrum (202.46 MHz) of dichlorotriphenylphosphorane in dry benzene-d6. Upon standing in solution, the compound rapidly
converts to a broad peak at 44.4 ppm.
chemical integrity of highly reactive reagents. These results
enabled chemists to accurately estimate the relative excess of
reagent to allow reactions to go to completion. This becomes
particularlyimportantinlargeproductionscaleupreactionswhere
associated costs of materials and time become significant.
Our data also provided insight into the structural forms of
dichlorotriphenylphosphorane, indicating that both the ionic and
covalent forms of the molecule coexist and suggesting that
the ionic form represents an intermediate in the transition to
hydrolyzed product.
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Magn. Reson. Chem. 2009, 47, 461–464