Exploring an Umpolung strategy for quaternization of phosphorus

Article abstract of DOI:10.1080/10426507.2018.1541242

We propose a new, potentially widely-applicable, Umpolung approach for the synthesis of quaternary phosphonium salts R₃PR¹ X (X = Cl, Br) from phosphine oxides R₃PO. The new organic group R¹ is introduced via nucleophilic attack on an intermediate halophosphonium salt using a Grignard reagent R¹MgX and replaces the traditional phosphine quaternization approach. Consequently, the new method does not suffer from the limited availability of many parent phosphines and is much faster than standard quaternization.

Full text of DOI:10.1080/10426507.2018.1541242

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Exploring an Umpolung strategy for
quaternization of phosphorus
Anna C. Vetter, Kirill Nikitin & Declan G. Gilheany
To cite this article: Anna C. Vetter, Kirill Nikitin & Declan G. Gilheany (2019): Exploring an
Umpolung strategy for quaternization of phosphorus, Phosphorus, Sulfur, and Silicon and the
Related Elements, DOI: 10.1080/10426507.2018.1541242
To link to this article: https://doi.org/10.1080/10426507.2018.1541242
Published online: 22 Feb 2019.
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2018.1541242
Exploring an Umpolung strategy for quaternization of phosphorus
Anna C. Vetter, Kirill Nikitin, and Declan G. Gilheany
School of Chemistry, University College Dublin, Dublin, Ireland
ABSTRACT
ARTICLE HISTORY
We propose a new, potentially widely-applicable, Umpolung approach for the synthesis of quater-
Received 28 September 2018
Accepted 23 October 2018
1
nary phosphonium salts R PR X (X = Cl, Br) from phosphine oxides R PO. The new organic group
3
3
1
R
is introduced via nucleophilic attack on an intermediate halophosphonium salt using a
1
KEYWORDS
Grignard reagent R MgX and replaces the traditional phosphine quaternization approach.
Consequently, the new method does not suffer from the limited availability of many parent phos-
phines and is much faster than standard quaternization.
Nucleophilic substitution;
quaternary phosphonium
salts; Wittig
reagents; Umpolung
GRAPHICAL ABSTRACT
1
. Introduction
prepared by utilizing phosphine nucleophilicity in quaterni-
zation-type reactions. However, while currently being the
method of choice, this approach bears a significant disad-
The Wittig reaction enables alkene preparation by reaction
of an aldehyde or a ketone with a phosphonium ylide gener-
ated from quaternary phosphonium salts (QPS) which, in
their own right, have a multitude of applications in various
fields of chemistry. These include their use as ionic
liquids , phase-transfer and organocatalysts. However,
the most common use of QPS is likely as starting material
in the Wittig reaction. Shortly after its discovery in 1954,
its significance for synthesis was shown by its application to
the industrial synthesis of vitamin A and β-carotene and it
has continued its usefulness to this day. However, modern
economical use of the Wittig reaction requires a fundamen-
tal revision, considering economics and safety. Currently,
the entry point of phosphorus in the Wittig reaction mani-
fold is phosphine – most commonly triphenylphosphine due
to safety hazards associated with the more reactive (albeit
synthetically appealing) trialkylphosphines. After conversion
vantage: despite phosphines being effective nucleophiles,
[8–10]
these processes are typically slow
thereby limiting the
choice of reagents to active electrophiles and sterically-inno-
cent phosphines. This is particularly true for arylation of
parent phosphine structures, unless forcing conditions and/
[1]
[2]
[3]
[11]
or transition metal catalysis is employed.
[
4]
Let us suppose one desired to acquire a simple reagent, for
[12]
example MePh PCl salt
to run a standard Wittig olefina-
3
tion reaction. Currently, the choice of reagents is extremely
[
5]
narrow: use Ph P, excess of hazardous MeCl gas at elevated
3
temperate and high pressure. While an alternative all-in-one
[6]
[13]
olefination reagent has recently been proposed,
this strat-
egy is limited to just one example and, too, relies on quater-
nization under fairly harsh conditions. Conversely, we
decided to develop a totally different route to QPS by
employing an Umpolung approach, which utilizes the electro-
to QPS and exiting the Wittig reaction, phosphorus, in the philic character of a suitable accessible phosphorus-species.
form of phosphine oxide (PO), is a widely acknowledged While nucleophilic P-C bond formation (Scheme 1,
nuisance by-product. This stoichiometric by-product, com- Umpolung approach) is a common strategy for other types of
[
14]
monly Ph PO, and its disposal remain the major economic organophosphorus compounds (e.g. phosphines),
it was
and environmental drawbacks of the Wittig reaction, as well not commonly applied for the direct synthesis of QPS 5 or 6.
3
[7]
as making it a prime example of poor atom economy. The Phosphine oxides 1 and 2 depict an attractive starting mater-
QPS starting material for any Wittig reaction is traditionally ial for this approach, however, due to the lack of the suitable
CONTACT Declan G. Gilheany
declan.gilheany@ucd.ie
School of Chemistry, University College Dublin, Dublin, Ireland.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
ß 2019 Taylor & Francis Group, LLC

2
A. C. VETTER ET AL.
Scheme 1. Quaternization vs Umpolung approaches for the synthesis of QPS.
3
1
3
Table 1. Interconversion of tetracoordinate ionic (TCI) and pentacoordinate phosphorane (PCP) form of R PCl2: Experimental P NMR chemical shifts and DFT
3 2
computed parameters of R PCl (3, 4, 3’ and 4’).
Solvent
3
4
3’
4’
Benzene, δ ppm
Toluene, δ ppm
THF, δ ppm
DCM, δ ppm
TCM, δ ppm
–
–
–
–
–
–
61
60
59.9
2.04
+6.8
8.5
−5.0
−3.4
–
–
–
−44.4
−46.1
−43.1
–
–
–
2.34
0
105.3
107.2
103.8
2.05
+5.3
MeCN, δ ppm
a
a
b
b
D(P-Cl), A
2.35
0
c
E
rel, kcal/mol
a
DFT B3LYP calculation in DCM.
b
DFT B3LYP calculation in toluene.
relative to the PCP form in toluene.
c
leaving group required, they cannot be directly converted into hypothesis. Cursorily, they acknowledged that in principle
QPS. We found a solution to this in intermediate chlorophos- QPS could be the product of a standard quaternization (vide
phonium salts (CPS) 3 and 4 as shown in Scheme 1. In our infra). Accordingly, the sole bona fide product of nucleo-
method, the non-reactive phosphine oxides 1 and 2 are philic attack on P, was Ph PCl, which was obtained in
4
straightforwardly converted to the highly versatile 3 and 4 via poor yield.
deoxychlorination with oxalyl chloride. The presence of the
Cl-substituent in CPS greatly augments the electrophilic char-
2. Results and discussion
acter of phosphorus while providing for a good leaving group.
Consequently, we postulated that the combination of CPS A likely reason for the lack of success in the past may be
and a suitable organometallic reagent, e.g. Grignard reagents, the complex interplay of factors that affect the structure of
[15]
should yield QPS.
While this desirable transformation has been tried in the form. We found that, in line with earlier findings,
the R PCl , adopting either an ionic or pentacoordinate
3 2
[19]
the
past, the aim was not the synthesis of QPS. Almost a cen- ionic form is present in polar solvents. For example, in
tury ago, in 1931, Grignard and Savard reported on the syn- MeCN, chloroform and dichloromethane (DCM), it is
1
13
thesis of “pentasubstituted phosphines”, the formation of clearly tetracoordinate, as can be observed by H, C and
3
1
which involved the reaction of CPS with Grignard
P NMR spectroscopy (see Table 1). In solvents of lower
In the same year, Blount recognized the vital polarity, R PCl exists as pentacoordinate form, e.g. in THF,
[16]
reagents.
role these compounds could have in understanding issues benzene and toluene, as can be seen again spectroscopically.
associated with “valency and stereochemistry”, which were Computational study of this equilibrium
also clearly dem-
However, Blount failed to onstrated that the pentacoordinate X-X-biaxial orientation
3
2
[
20]
[
17]
of great interest at the time.
isolate the products proclaimed by Grignard and Savard, of halides is the energetically preferred geometry in vacuum,
attributing the lack of success to an aqueous wash post for- and low-polar solvents, while tetracoordinate ion-pairs pos-
mation of Ph PCl when he followed their method which sess lower energy in the polar media, as also can be seen in
3
2
,
led to the conversion Ph PCl to Ph PO. Realizing that CPS Table 1.
3
2
3
were acutely moisture-sensitive, Blount repeated the experi-
Table 2 shows selected results of our initial survey of
ment yet another time using an authentic sample of reaction conditions for the reaction of 3 and 3’ with
Ph PCl . Still, not even then was he able to isolate the Grignard reagents. It can be seen that QPS 5a is obtained in
3
2
penta-substituted phosphine. Although he suspected that excellent yields in DCM and THF (entries 1–2), while a
QPS were formed instead, he was not yet able to substanti- decrease in yield is observed in case of less polar benzene
ate this. It was not until three decades later, that Denney (entry 3). The reaction of 3 with BnMgCl was strongly
[
18]
and Gross
were finally able to confirm Blount’s affected by temperature, giving, perhaps somewhat

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
1
Table 2. Reaction conditions for QPS synthesis from dichlorides R
3
PCl
2
and
Table 3. Preparation of QPS from CPS and Grignard reagents (R -MgX) vs for-
Grignard reagents.
mation of phosphine.
1
Entry
3
R PCl
2
R
Solvent
T, °C
QPS
Yield
1
2
3
4
5
6
3
3’
3’
3
3
3
Et
Et
Et
Bn
Bn
Bn
DCM
THF
Benzene
DCM
DCM
DCM
0
r.t.
r.t.
r.t.
0
5a
5a
5a
5b
5b
5b
100
95
79
55
74
94
b
Products
1
a
Entry
CPS
R -MgX
QPS
%
Phosphine
%
1
2
3
4
5
6
7
8
3
4
3
4
3
3
4
4
4
3
MeMgCl
5c
6a
5c
6a
5d
5e
6b
6c
6d
5f
97
7
8
7
8
7
7
8
8
8
7
0
0
0
42
0
30
46
96
75
0
MeMgCl
MeMgBr
MeMgBr
>99
95
58
95
62
48
0
−83
iso-BuMgCl
sec-BuMgCl
iso-BuMgCl
sec-BuMgCl
Neophyl-MgCl
PhMgCl
counterintuitively, better yields of QPS 5b at lower tempera-
tures (entries 4–6). Having optimized reaction conditions,
we explored the scope of Grignard reagents. From Table 3 it
can be seen that reactions of tributyl and triphenyl CPS 3 10
and 4 with MeMgCl afforded the respective QPS 5c and 6a
in excellent yields (entries 1–2). On switching to MeMgBr
c
9
0
>99
a
1
using 2 equivalents of R MgX.
b
31
by P NMR of reaction mixture: balance largely phosphine oxide derived
from unreacted CPS.
c
(entries 3–4), the yield of 5c remained virtually unaffected,
reaction time 42 h, reaction temperature 30 °C.
however, reaction of CPS 4 with MeMgBr led to the forma-
tion of phosphine 8 at the expense of QPS 6a. Increasing
the steric bulk in R -MgCl was generally tolerated better by
3. Conclusions
1
tributyl CPS 3 (entries 5/6 vs 7/8), affording QPS 5d in A high-yielding nucleophilic preparation of QPS, e.g. tet-
excellent yield (entry 5), while on moving the branching raalkyl, and alkyl-aryl series from phosphine oxides is now
point adjacent to the reaction center a decrease in yield of realized. The corresponding chlorophosphonium species,
5
e due to formation of 7 was observed (entry 6). This trend CPS, are excellent intermediate synthons for this transform-
is even more pronounced for the reactions of CPS 4 (entries ation. The new methodology is another implementation of a
and 8) with use of secondary sec-BuMgCl completely sup- general Umpolung strategy, whereby both reacting partners
7
pressing QPS formation. Most importantly, reaction of 3 have been subjected to inversion of polarity with respect to
with PhMgCl gave QPS 5f almost quantitatively (entry 9), a standard quaternization. Mechanistically, the ionic tetracoor-
drastic improvement compared to the virtually impossible dinate form of CPS in the presence of strongly nucleophilic
traditional quaternization of 7 with chlorobenzene.
Formation of QPS (Scheme 2, red) is viewed as fast
nucleophilic attack (termed here the P-attack) of the R -
group of the Grignard reagent on the phosphonium center
via an axial transition state (10-TS) or an alternative far less
likely equatorial route (not shown). The formation of phos-
phine by-product is attributed to a different nucleophilic
pathway (Scheme 2, blue) where the covalently bonded Cl of
Grignard reagents undergoes two principal reactions: P-
attack leading to the desired QPS or Cl-attack leading to
side-product phosphine. Our new method is a very practical
alternative to the existing routes to QPS based on alkylation/
quaternization of highly nucleophilic, and therefore readily
oxidized, phosphines because it does not require synthesis/
handling of such substrates.
1
1
the chlorophosphonium cation is attacked by the R -group
via a different transition state (the Cl-attack, 11-TS). The
Cl-attack can also be considered a reductive process, as it
yields the parent phosphine and the derived alkyl halide 12.
To confirm this latter point, we used the bulky branched
Grignard reagent derived from 2-methyl-2-phenylpropyl
chloride (12a neophyl chloride, Table 3 entry 9). The reac-
tion with 4 was very sluggish and, as expected, phosphine 8,
but not the respective QPS, was formed. The fact that the
parent 12a was also isolated strongly supports our mechan-
istic hypothesis. Aside from the principal mechanistic path-
ways (Scheme 2, red & blue), a multitude of other processes
4
. Experimental
Methyltriphenylphosphonium chloride, 6a. To a DCM solu-
tion of 4 (0.2 M in DCM, 25.00 mL, 5.00 mmol) a solution
of MeMgCl (3.0 M in THF, 3.35 mL, 10.05 mmol) was added
at 0 °C and the mixture was stirred at 0 °C for 1 hour after
which time it was quenched by HCl (2.0 M in Et O,
2
5
.00 mmol), concentrated in vacuo to yield an oily residue
which was treated with DCM (50 mL) and aqueous NaCl
2.0 M, 2 × 10 mL). The DCM layer was washed with an
equal volume of saturated aqueous NaCl. The organic layer
(
can be contemplated (Scheme 2, gray), resulting partly from was eluted through sodium sulfate (10 g) and concentrated
the introduction of adventitious water/air into the reaction in vacuo to yield a clear oily residue, which crystallized on
manifold. Although in the examples above most of the side standing. Recrystallization from chloroform/ethyl acetate
processes have been avoided, work is underway on establish- afforded 6a (1.53 g, 98%) as fine white crystals: MP
+
ing the conditions for successful preparation of the desired 219–221 °C, HRMS (ES+) m/z: calculated for C19
QPS in more challenging cases. 277.1146, found 277.1135.
H P
18

4
A. C. VETTER ET AL.
1
1
Scheme 2. Bold/red/blue: Mechanistic hypothesis illustrating competing pathways: axial attack of R MgCl at P (red) leading to QPS and attack of R MgCl at Cl
blue) to give phosphine. Grey: Plausible mechanistic pathways (for the tetracoordinate ionic form).
(
Phenyltributylphosphonium chloride (5f) was prepared in
[8] Henderson, W. A.; Buckler, S. A. The Nucleophilicity of
Phosphines. J. Am. Chem. Soc. 1960, 82, 5794–5800.
[9] Methotand, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346,
1035–1050.
10] Honaker, M.; Hovland, J.; Salvatore, R. N. The Synthesis of
Tertiary and Secondary Phosphines and Their Applications in
Organic Synthesis. COS 2007, 4, 31–45.
11] Tappe, F.; Trepohl, V.; Oestreich, M. Transition-Metal-
Catalyzed C-P Cross-Coupling Reactions. Synthesis 2010, 2010,
3037–3062.
a similar fashion from 3 and PhMgCl: transparent crystalline
+
sheets (yield 95%): MP 138–140 °C; HRMS (ES ): calculated
+
for C H P = 279.2242, found 279.2247.
1
8
32
[
Funding
[
This work was supported by Science Foundation Ireland through the
SFI-funded Synthesis & Solid State Pharmaceutical Centre 12/RC/2275
Grant to D. G. G. We also thank Dr Kamalraj Rajendran for prelimin- [12] The commercial sources offer this salt at extortionate prices,
ary studies.
e.g. 5.68 €/mmol.
[
13] Cattelan, L.; Noè, M.; Demitri, N.; Selva, M.; Perosa, A.
Methyltriphenylphosphonium Methylcarbonate, An All-In-One
Wittig Vinylation Reagent. ChemSusChem 2015, 8, 3963–3966.
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Boca Raton, 1988.
15] Vetter, A. C.; Nikitin, K.; Gilheany, D. G. Long Sought
Synthesis of Quaternary Phosphonium Salts from Phosphine
Oxides: inverse Reactivity Approach. Chem. Commun. 2018, 54,
5843–5846.
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