Nucleophilic displacements in alkylphosphonates: P-O versus P-C bond cleavage. A combined DFT and experimental study

Article abstract of DOI:10.1080/10426507.2012.743130

Potential energy surfaces for the nucleophilic displacements at phosphorus in dimethyl methyl, chloromethyl, dichloromethyl, and trichloromethyl phosphonates have been computed by DFT methods. The results reveal that sequential introduction of chlorine substituents at the methyl group in methyl phosphonates increases the stability of transition states and intermediates, which facilitates P-C bond cleavage. While nonsubstituted dimethyl methylphosphonate may undergo exclusive P-O bond cleavage, the trichlorinated analogue reacts exclusively via P-C bond dissociation to form dichlorocarbene, which was trapped by various olefins to form the corresponding gem-dichlorocyclopropanes.

Full text of DOI:10.1080/10426507.2012.743130

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Phosphorus, Sulfur, and Silicon and the
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Nucleophilic Displacements in
Alkylphosphonates: P–O Versus P–C
Bond Cleavage. A Combined DFT and
Experimental Study
Nissan Ashkenazi a & Ravit Chen a
a Department of Organic Chemistry , IIBR-Israel Institute for
Biological Research , Ness-Ziona , Israel
Published online: 08 May 2013.
To cite this article: Nissan Ashkenazi & Ravit Chen (2013) Nucleophilic Displacements in
Alkylphosphonates: P–O Versus P–C Bond Cleavage. A Combined DFT and Experimental
Study, Phosphorus, Sulfur, and Silicon and the Related Elements, 188:1-3, 106-110, DOI:
10.1080/10426507.2012.743130
To link to this article: http://dx.doi.org/10.1080/10426507.2012.743130
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Phosphorus, Sulfur, and Silicon, 188:106–110, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.743130
NUCLEOPHILIC DISPLACEMENTS IN
ALKYLPHOSPHONATES: P–O VERSUS P–C BOND
CLEAVAGE. A COMBINED DFT AND EXPERIMENTAL
STUDY
Nissan Ashkenazi and Ravit Chen
Department of Organic Chemistry, IIBR-Israel Institute for Biological Research,
Ness-Ziona, Israel
GRAPHICAL ABSTRACT
O
O
Cl Cl
NaOMe
solvent
-10 C
OEt
OEt
OEt
OEt
+
MeO P
Cl C P
+
(2)
3
R
0
R
Abstract Potential energy surfaces for the nucleophilic displacements at phosphorus in
dimethyl methyl, chloromethyl, dichloromethyl, and trichloromethyl phosphonates have been
computed by DFT methods. The results reveal that sequential introduction of chlorine sub-
stituents at the methyl group in methyl phosphonates increases the stability of transition
states and intermediates, which facilitates P–C bond cleavage. While nonsubstituted dimethyl
methylphosphonate may undergo exclusive P–O bond cleavage, the trichlorinated analogue
reacts exclusively via P–C bond dissociation to form dichlorocarbene, which was trapped by
various olefins to form the corresponding gem-dichlorocyclopropanes.
Keywords Alkylphosphonates; DFT; potential energy surface; dichlorocarbene; gem-
dichlorocyclopropanes
Processes involving a nucleophilic attack at the phosphorus center of alkylphospho-
nic acid derivatives (i.e., esters, amides, thio esters, halides, etc.), followed by P-ligand
bond cleavage (P–O, P–N, P–S, P-Halogen, etc.), are well documented in the literature.1
In contrast, the analogous P–C bond scission is rare. As the P–C bond is polarized with a
negative charge on the carbon, these compounds might be useful in organic transformations
(e.g., transmetallation), being a potential source for carbanions activated alkylphosphonates
are known to react as carbanions only with carbonyl compounds in the Horner-Wadsworth-
Emmons reaction, via a different mechanism: nucleophilic attack of phosphoryl-stabilized
carbanion on carbonylic carbon.1 To the best of our knowledge for nonactivated alkylphos-
phonic acid derivatives (e.g., dialkyl methylphosphonates), P–C bond dissociation, which
evolves from nucleophilic displacement at the phosphorus, has never been described. Some
unique examples of P–C bond fission in activated systems are the –CF3 elimination from
Received 27 August 2012; accepted 16 October 2012.
Address correspondence to Nissan Ashkenazi, Department of Organic Chemistry, IIBR-Israel Institute for
Biological Research, P.O. Box 19, Ness-Ziona 74100, Israel. E-mail: nissan.ashkenazi@iibr.gov.il
106

NUCLEOPHILIC DISPLACEMENTS IN ALKYLPHOSPHONATES
107
Figure 1 Transition states structures for the attack of OH– on 1. (Color figure available online).
tris(trifluoromethyl)phosphine oxide,2 P–CCl3 cleavage under nucleophilic conditions both
in phosphonates3 and in phosphinates,4 α-hydroxyphosphonate-phosphate rearrangement,5
and dephosphonylation of β-ketophosphonic acids presumably via nucleophilic addition
of water to the phosphorus.6 Elimination of CX3 moieties are of particular interest as
–
these reactions can be considered as the phosphorus equivalent of the Haloform reaction,
therefore, as dihalocarbenes source.7 Surprisingly, we found only few examples where
these commercially available compounds were used as precursors for carbenes.7 The abil-
ity to accurately elucidate reaction mechanisms involving nucleophilic transformations of
P(V) compounds using ab intio and DFT methods, both in the gas phase and in solution,
has been demonstrated many times during the last decade.8,9 Therefore, we believed that
by using this methodology and conducting a thorough study of the potential energy sur-
faces (PES), we could gain a better understanding of the structure and the reactivity of
alkylphosphonates and their nucleophilic transformations. This insight may unveil some of
the terms and conditions that dictate the reaction course and consequently the ability to ob-
tain carbanions and\or carbenes via P–C bond cleavage. To address this issue, the PES for
the nucleophilic displacements at phosphorus in the model compounds—dimethyl methyl,
chloromethyl, dichloromethyl, and trichloromethyl phosphonates—have been computed at
the B3LYP/6–31+G∗ level of theory using IEF-PCM to account for the solvent effect.9h
For dimethyl methylphosphonate (1), two different modes of attack were found:
(a) OH– approach from the opposite side to the CH3 group via the transition state 1-
–
TS1 (Figure 1) to form the distorted trigonal bipyramid (TBP) intermediate 1-INT1 and
(b) Attack opposite to the –OMe substituent (1-TS2, Figure 1) to form the corresponding
pentacoordinated TBP intermediate 1-INT2. Kinetically, the latter is favored as the required
free energy of activation is ꢀG‡ = 20.5 kcal/mol (in accordance with the experimental value
of 21.1 kcal/mol)10 and lower by 8.7 kcal/mole compared to the energy needed to obtain
1-TS1.
Furthermore, cleaving the P–C bond in 1-INT1 via the proper TS (1-TS3) demands
an activation free energy of 32.5 kcal/mol. Thus, making this step the rate determining
one and yields the initial products 1-PR1a, which are 33.9 kcal/mol higher in energy
than the starting materials. Therefore, this reaction would be strongly shifted toward the
starting materials (Equation 1), as indicated in the literature for analogous phosphoric acid
derivatives.11
O
O
OMe
OMe
+ OH-
-O OMe
1-TS1
OMe
OMe
H3C P
1-TS3
-
(1)
H3C P OH
HO P
+ CH3
1
OMe
1-INT1
1-PR1a
1-S.M.

108
N. ASHKENAZI AND R. CHEN
Figure 2 Transition states structures for the attack of OH– on 4. (Color figure available online).
Consequently, according to our calculations, the P–CH3 bond in phosphonic acid
derivatives, such as 1, is indeed inert.
Adding chlorine substituents to the methyl group bonded to phosphorus, such as
in dimethyl chloromethyl and dichloromethyl phosphonate (2 and 3, respectively) reveals
some remarkable differences. Both paths (P–O or P–C cleavage) are less energy demanding
following the sequential addition of chlorines, although fission of the P–O bond is still
preferred. The activation barriers found for both systems are in excellent agreement with
previously reported experimental values.12 However, for all processes the initial step, attack
of the nucleophile on the phosphorus center of 2 or 3, is the rate determining step. Therefore,
for suitable systems (e.g., chloromethyl or dichloromethyl dialkyl or diaryl phosphine
oxides) a P–C cleavage of the halomethyl group should be feasible.
The calculated profiles for the reaction of dimethyl trichloromethyl phosphonate (4)
with OH– in water unveil totally different results, both structurally (Figure 2) and energeti-
cally, from those obtained for the previous systems. When the nucleophile approaches from
the opposite side to the OMe moiety, the first stationary point found was the transition state
4-TS2, which possesses square pyramid geometry in which the CCl3 fragment is in the
apical position (Figure 2), rather than the expected TBP. The formation of this transition
state requires free energy of activation of 15.7 kcal/mol and leads to the formation of an in-
termediate, which is already lower in energy than the starting materials (ca. –4.2 kcal/mol).
Intrinsic reaction coordinate (IRC) calculations confirmed that indeed 4-TS2 connects the
two minima of the starting materials and this intermediate, from which only 0.9 kcal/mol is
required in order to dissociate the CCl3 fragment. Attack from the opposite side to the CCl3
ligand is also possible as ꢀG‡
= 16.7 kcal/mol, only 1.0 kcal/mol higher than the re-
4-TS1
quired energy for 4-TS2. Moreover, once such an attack takes place, the rest of the process is
down hill in energy as the formation of the following intermediate releases 19.5 kcal/mol.
These calculations imply that the nucleophilic displacement process in 4 would follow
a SN2(P) type mechanism, as could be anticipated,13 in contrast to addition-elimination
mechanism, which was observed for systems 1–3.
O
O
Cl Cl
NaOMe
OEt
OEt
OEt
OEt
+
MeO P
Cl3C P
+
(2)
solvent
-100C
R
R
Combining the facts that P–C cleavage is the sole process observed theoretically for 4
and that trihalomethyl anions spontaneously dissociate to dihalocarbenes, we tested the
ability of a commercially available analogue, diethyl trichloromethyl phosphonate to act as
dichlorocarbene precursor. Indeed, trapping the later with various olefins formed the corre-
sponding gem-dichlorocyclopropanes.14 These manipulations were carried out in organic

NUCLEOPHILIC DISPLACEMENTS IN ALKYLPHOSPHONATES
109
Table 1 Summary of the reactions and products
Run
1
Olefin
Product
Solvent
Reference
7a, 15
Cyclohexane
Cl
Cl
Cl
Cl
2
THF
15b
3
4
THF
16
17
Cl
Cl
Cl
Cl
Cl
+
Cl
Cl
Acetonitrile
Cl
Cl
5
THF
18
Cl
O
O
solutions (in contrast to the common biphasic or the phase-transfer catalyzed reactions),14
using both acyclic and cyclic olefins and methoxide as the attacking nucleophile (Equation
2 and Table 1). The spectral data of the products were identical to those previously reported
in the literature.
In conclusion, our calculations show that the P–C cleavage in alkylphosphonates can
be achieved only if the alkyl is substituted by electronegative substituents (e.g., halogens).
This substitution increases the apicophilicity of the alkyl fragment and in turn enhances
the kinetic stability of key transition states and intermediates. These electronic properties
obviously have also a profound thermodynamic effect regarding the leaving group properties
of this fragment. Therefore, P–O cleavage is always preferred. Only for trichloromethyl
phosphonic diesters, a dramatic change is observed. In such systems, P–C bond dissociation
becomes the dominant process. In this case, the reaction is similar to the Haloform reaction
in carbonyls. Hence, these compounds are a useful source for trichloromethyl anion and
consequently as dichlorocarbene precursor.
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