Nucleophilic substitution reactions of benzyl- and diphenylmethylphosphonamidic chlorides with amines: Competition between the usual SN2(P) mechanism and elimination-addition with an alkylideneoxophosphorane (phosphene) intermediate

Article abstract of DOI:10.1039/b007288p

The substitution reaction of PhCH₂P(O)(NMe₂)Cl with Me₂NH or Et₂NH in CHCI₃ is very sensitive to the bulk of the nucleophile (≥ 200 times slower with Et₂NH), affords only the product derive

Full text of DOI:10.1039/b007288p

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Nucleophilic substitution reactions of benzyl- and diphenylmethyl-
phosphonamidic chlorides with amines: competition between the
usual SN2(P) mechanism and elimination–addition with an
alkylideneoxophosphorane (phosphene) intermediate
2
Martin J. P. Harger
Department of Chemistry, The University, Leicester, UK LE1 7RH
Received (in Cambridge, UK) 8th September 2000, Accepted 30th October 2000
First published as an Advance Article on the web 5th December 2000
The substitution reaction of PhCH2P(O)(NMe2)Cl with Me2NH or Et2NH in CHCl3 is very sensitive to the bulk
of the nucleophile (у200 times slower with Et2NH), affords only the product derived from Me2NH in competition
experiments, and gives largely undeuterated product with Et2ND; these features are in accord with an SN2(P)
mechanism. The corresponding reaction of Ph2CHP(O)(NMe2)Cl is relatively insensitive to the bulk of the
nucleophile (5 times slower with Et2NH), gives some of the product derived from Et2NH in competition
experiments, and gives extensively deuterated product with Et2ND; these features point to an elimination–
addition (EA) mechanism with an alkylideneoxophosphorane intermediate [Ph C᎐P(O)NMe ]. There is only a
᎐
2
2
modest (13–19 fold) increase in the rate of substitution on going to ArPhCHP(O)(NMe2)Cl (Ar = 4-NO2C6H4)
but with R2ND there is now very rapid H/D exchange at the α carbon atom. This suggests that the elimination
stage of the EA mechanism comprises rapid reversible formation of the conjugate base followed by rate-limiting
expulsion of chloride ion.
Nucleophilic substitution at phosphoryl (P᎐O) centres is
important in many areas of chemistry and makes possible the
᎐
Results and discussion
Benzylphosphonic acid derivatives
phosphoryl transfer reactions on which biological systems
depend.1 The mechanism is generally associative [SN2(P)], with
a five-coordinate intermediate or transition state.2 An altern-
ative dissociative pathway is available to substrates that have
an acidic ligand HZ (Scheme 1; X = leaving group), involving
The benzylphosphonamidic chloride 4a and its 4-nitro analogue
4b were prepared by controlled reaction of the phosphonic
dichlorides 3a and 3b with Me2NH (generated in situ from
ϩ
Me2NH2 ClϪ and Et3N) (Scheme 2). Both could be purified
by crystallisation but they hydrolyse quite readily and vacuum
distillation proved more satisfactory for the relatively volatile
and low melting compound 4a.
Scheme 1
elimination–addition and a transient three-coordinate PV
intermediate.2,3 This alternative mechanism is often important
when Z is oxygen,4 sulfur5 or nitrogen6 but not, it seems,
when Z is just a carbon atom.7 The fluoren-9-ylphosphonamidic
chloride 1 is a rare exception, undergoing substitution reactions
with amines by elimination–addition with an alkylideneoxo-
phosphorane (phosphene) intermediate 2.8 This is an extreme
case, however, since the Cα–H bond in 1 will be exceptionally
acidic because of the aromaticity of the fluorenyl anion. In
contrast are the many quite ordinary acyl and sulfonyl sub-
strates that produce ketenes9 or sulfenes10 in their reactions
with basic reagents. Is it only in extreme cases that phosphenes
are formed as intermediates in the nucleophilic substitution
Scheme 2
With Et2NH in CHCl3, and moisture carefully excluded, the
phosphonamidic chlorides formed the phosphonic diamides
5a and 5b (R = Et) (Scheme 2) over several hours at room
temperature. The reactions were monitored by 31P NMR
spectroscopy (δP 46.9 or 44.0→33.9 or 32.0) using a large excess
of a 2.0 mol dmϪ3 solution of Et2NH in CHCl3 at 30 ЊC and the
pseudo-first-order rate constants k were deduced (Table 1).†
These equate to half lives of 39 and 34 min for 4a and 4b
respectively.
reactions of P᎐O compounds? That question has prompted the
᎐
present investigation.
† In substitution reactions of phosphonamidic chlorides with amines
the amine hydrochloride by-product can accelerate the reaction slightly,
causing deviations from linearity in the first-order rate plots (ref. 8).
In the present study a small amount of the appropriate amine hydro-
chloride (Et2NH2Cl or Me2NH2Cl) (0.1 mol dmϪ3) was included in
each reaction mixture and the rate plots showed little if any curvature.
DOI: 10.1039/b007288p
J. Chem. Soc., Perkin Trans. 2, 2001, 41–47
This journal is © The Royal Society of Chemistry 2001
41

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Table 1 Pseudo-first-order rate constants (k) for reactions of phos-
phonamidic chlorides with 2.0 mol dmϪ3 amines in CHCl3 at 30 ЊC
105k/sϪ1
Substrate
Me2NH
Et2NH
4a
4b
10a
10b
~104 a
~104 a
1.04
29.7
34.4
0.21b
3.87
13.8
a Very approximate (based on 75–80% substitution in 15 s and by impli-
cation t ~ 7 s). b Some 10% of substrate formed by-products
₁
₂
(hydrolysis); value of k is for overall consumption of substrate.
Scheme 3
The corresponding reactions with Me2NH were too fast to
follow so they were quenched after just 15 s (aqueous HCl) and
the resulting mixtures were analysed by 31P NMR spectroscopy.
In both cases the diamide product 5 (R = Me) (δP 34.2 or
33.2) accounted for 75–80%, unchanged substrate 5–10%,
and by-products (most likely stemming from hydrolysis on
quenching) 10–20%. This suggests half lives of ca. 7 s for the
substitution reactions of 4a and 4b with Me2NH and implies
at least a 200-fold difference in reactivity between Et2NH and
Me2NH.
High sensitivity to the bulk of the nucleophile is not
unreasonable for an SN2(P) mechanism, in which the four-
coordinate phosphorus atom of the substrate becomes five-
coordinate in the transition state, and it has often been noted
before.11 With PhP(O)(NMe2)Cl, for example, where
elimination–addition (EA) is not possible, PriNH2 reacts
120 times faster than the more bulky ButNH2,12 and with
PriP(O)(NEt2)Cl the reactivity of Me2NH is у200 times greater
than Et2NH.8 For an EA mechanism, however, a large steric
effect would not be expected given that the amine acts as a base
in the rate-limiting elimination stage, not as a nucleophile,
and attacks the substrate by abstraction of a proton from
the α carbon atom. Indeed, in the corresponding reactions
Scheme 4
of (EtO)3P with Ph2CHBr, but the second was obtained by
an indirect route, making use of Makosza and Golin´ski’s
vicarious substitution.14 This entailed reaction of the α-chloro-
benzylphosphonate 6 (R = Me) with nitrobenzene in liquid
NH3 containing NaOH. The key steps are nucleophilic attack
of the phosphonate anion at the para position of nitrobenzene
and, subsequently, a 1,2 shift of hydride from that position with
displacement of the chlorine from the α carbon atom.
The phosphonic acids were converted into the dichlorides 9
by heating with SOCl2 (DMF catalyst) and these on controlled
reaction with Me2NH gave the phosphonamidic chlorides 10.
The two phenyl groups in the unsubstituted compound 10a are
diastereotopic, by virtue of chirality at the phosphorus atom,
and that is reflected in a difference in the chemical shifts of
the ortho hydrogens: δH 7.62 and 7.53 (both 2 H, d, JHH 7.5).
The nitro-substituted compound 10b is chiral at carbon as
well as phosphorus and was obtained as a mixture of diastereo-
isomers, δP 44.6 and 44.35. The NMe2 groups of the two
of the benzylic P᎐S substrate ArCH P(S)(NMe )Cl (Ar =
᎐
2
2
4-NO2C6H4), which are believed to proceed by elimination–
addition, there is a mere 1.5 fold difference in reactivity between
Et2NH and Me2NH.13
The influence of the 4-nitro substituent in the substrate
4 is also reasonable for SN2(P) but improbable for an EA
mechanism. The acidity of the Cα–H bond should be greatly
increased by the NO2 group and so should the rate-limiting
formation of the phosphene intermediate, at least if it occurs by
an ElcB mechanism. In fact the nitro-substituted substrate 4b is
only marginally more reactive than 4a (Table 1). The situation
1
diastereoisomers give distinct H NMR signals, δH 2.68 and
2.66 (both d, JPH 12.5).
The phosphonamidic chlorides 10a and 10b gave the
expected diamides 12 with Me2NH and Et2NH (Scheme 4).
Of these 12a (R = Me) is achiral [equivalent NMe2 groups,
δH 2.40 (12 H, d, JPH 9)], 12b (R = Me) is chiral at carbon
[diastereotopic NMe2 groups, δH 2.435 and 2.40 (both 6 H, d,
JPH 9)], 12a (R = Et) is chiral at phosphorus [diastereotopic
Ph groups; ortho protons δH 7.66 and 7.63 (both 2 H, d, JHH 8)],
and 12b (R = Et) is chiral at both carbon and phosphorus
and exists as diastereoisomers, δP 30.4 and 30.3 [NMe2 groups
δH 2.425 and 2.39 (both d, JPH 8.5)].
with the P᎐S substrate ArCH P(S)(NMe )Cl is dramatically
᎐
2
2
different: a 4-nitro substituent increases the observed reac-
tivity towards Et2NH by a factor of 2500, even though the
unsubstituted compound reacts predominantly by SN2(P);13
for the EA pathway alone, the effect of the NO2 group must be
to increase the rate by a factor >104.
There are two ways in which a benzylphosphonic acid deriv-
ative might become more susceptible to substitution by an EA
mechanism: increased acidity of the Cα–H bond, encouraging
elimination–addition, and steric hindrance of attack at the
phosphorus atom, discouraging competition from SN2(P). On
both counts replacing one of the benzylic hydrogen atoms by a
phenyl group could have a profound effect.
Reactivity in substitution reactions with Me2NH and Et2NH.
Rates of reaction were examined as before, using 2.0 mol dmϪ3
amine in CHCl3 at 30 ЊC. Even the fastest reaction (10b ϩ
Me2NH) was now slow enough to be followed by 31P NMR
spectroscopy (85% complete in 4 h) while the slowest (10a ϩ
Et2NH) took 10 days to reach 85% completion. The values of
the pseudo-first-order rate constant k are shown in Table 1 and
correspond to half lives of 18.5 and 90 h for the unsubstituted
substrate 10a, and 1.4 and 5.0 h for the nitro compound 10b,
with Me2NH and Et2NH respectively.
As expected the reactions of both substrates are slower
with Et2NH (kE) than with Me2NH (kM) but only by a factor
of about five. The difference in amine reactivity is there-
fore much smaller than for the benzyl compounds 4 (kM/kE
у200) and much less than would be expected for SN2(P). On
the other hand it is similar to the value observed with the
Diphenylmethylphosphonic acid derivatives
Diphenylmethylphosphonic acid 8a and the related acid 8b
having a 4-nitro substituent in one of the phenyl groups were
obtained by hydrolysis (48% HBr; 130 ЊC) of the phosphonate
esters 7a (R = Et) and 7b (R = Me) (Scheme 3). The first
of these esters was prepared directly, by the Arbusov reaction
42
J. Chem. Soc., Perkin Trans. 2, 2001, 41–47

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Table
2 Exchange (H/D) during reactions of phosphonamidic
chlorides with 2 mol dmϪ3 R2ND (80–85 atom% D) in CDCl3 at 30 ЊC
Substrate
Reaction
Time/h
Amount (%)
CH(D) Integral
10a ϩ Me2ND
0.4
1.0
2.5
9.5
0.15a
20
37
87
0.2
>95
>95
95
80
>95
86
78
52
>95
0.9 H
0.75 H
0.5 H
0.2 H
0.15 H
0.8 H
0.6 H
0.35 H
0.2 H
Scheme 5
10b ϩ Me2ND
10a ϩ Et2ND
fluorenyl substrate 1 (kM/kE = 4) which reacts with amines by
an EA mechanism.8 The somewhat larger difference seen for
10a (kM/kE = 5.0) than for 10b (kM/kE = 3.6) may indicate that
only the latter (nitro-substituted) substrate reacts entirely by
elimination–addition. Competition from SN2(P) will be more
important with the less acidic substrate 10a and with the more
nucleophilic (less hindered) amine, so the observed value of
kM for 10a with Me2NH may well be rather greater than the
value for the EA pathway alone.
10b ϩ Et2ND
a T = 18 ЊC in this case.
Et2NH proceeds by elimination–addition, yet with Et2ND we
observed extensive H/D exchange in the methylene group of the
substrate. With the unsubstituted benzyl substrate 4a there
was not much exchange and only a small part of the product
(<10%) contained any deuterium (EI MS).
While exchange between the substrate and R2ND is not
necessarily indicative of an EA mechanism for substitution,
incorporation of deuterium into the product in the course
of the substitution process itself would surely point to a
phosphene intermediate. It is significant, therefore, that in the
reaction of 10a with Et2ND (80–85 atom% D) the methine
A contribution from SN2(P) in the case of Me2NH and 10a
may also explain why introduction of a NO2 group into the
substrate (as in 10b) has rather less impact on the observed rate
of reaction with Me2NH (13-fold increase) than with Et2NH
(19-fold increase). More important, however, is the fact that the
NO2 group effect is so modest, regardless of the amine. It is
no longer marginal, as it was for the benzyl substrate 4, but it
is still nowhere near as great as for the EA pathway in the case
of the P᎐S substrate ArCH P(S)(NMe )Cl (>104-fold).13 That
1
᎐
2
2
group of the product was 80% deuteriated (0.2 H/0.8 D by H
being so, an EA mechanism in which removal of the proton
from the α carbon atom is rate-limiting seems untenable for
the substrates 10. If they do react by an EA mechanism, the
elimination stage must surely be E2, or reversible E1cB with
formation of the conjugate base faster (or much faster) than its
collapse (Scheme 5).
NMR) at 50% completion. At that time the methine group of
the substrate was 65% deuteriated (0.35 H/0.65 D) and most
of the product would have been derived from substrate that was
less extensively deuteriated (exchanged). So for some of the
substitution, and probably for all of it, the product must have
been formed by an EA mechanism. Then a H atom could be
removed in the elimination stage (phosphene formation) and
a D atom acquired in the addition (phosphene ϩ Et2ND).‡
The other substitution reactions (10a ϩ Me2ND; 10b ϩ Et2ND
or Me2ND) also gave highly deuteriated products but in
those cases H/D exchange in the substrate was so fast, relative
to substitution, that we could not actually demonstrate
that they were formed from less highly deuteriated starting
materials.
Reactions with Me2ND and Et2ND. The reactions of the
phosphonamidic chlorides 10 were repeated using amine in
which 80–85% of the NH group was replaced by ND (1H
NMR), looking particularly for H/D exchange at the α carbon
atom of the substrate. The amine concentration was kept at
ca. 2 mol dmϪ3 but the solvent was changed to CDCl3 so that
1
the reactions could be monitored by H NMR spectroscopy.
Ideally the signal for the methine group [CH(D)] of the sub-
strate would have been compared with that for the NMe2
group but this was often obscured by signals from the amine.
The comparison therefore had to be with the aromatic signals
of the substrate, using the 31P NMR spectrum of the reaction
mixture to ascertain the extent of reaction and hence the
proportion of the total aromatic integral attributable to the
substrate. The results in Table 2 are inevitably only approximate
but they are instructive nonetheless.
With both Me2ND and Et2ND the nitro-substituted
substrate 10b exchanged so rapidly that the integral for the
methine group had fallen close to its equilibrium value
[0.15–0.2 H; R2ND (large excess) contained 15–20% R2NH] by
the time the first spectrum had been recorded, but still before
any appreciable conversion into product had occurred. The
unsubstituted compound 10a exchanges much less quickly, as
expected, but still faster than its conversion into product or
at least as fast. It follows that substitution could proceed by
an EA mechanism in which rapid reversible formation of the
conjugate base of the substrate is followed by rate-limiting
expulsion of chloride ion and liberation of the phosphene
intermediate (Scheme 5). It does not follow that this is the
mechanism, however: unless collapse of the conjugate base is
sufficiently fast the preferred route to product will still be bi-
molecular nucleophilic attack [SN2(P)] on the substrate itself.
That, indeed, is what prevails with the nitro-substituted benzyl
substrate 4b. Little if any of its substitution reaction with
It was not possible to compare the rates of H/D exchange
with the different amines in the case of the nitro-substituted
substrate 10b—they were too fast to follow—but for 10a
it could be seen that exchange with Et2ND is some 20 times
slower than with Me2ND (Table 2). This in spite of the fact
that Et2NH is a stronger base than Me2NH. The difference in
basicity is small for aqueous solutions [pKa 10.68 (Me2NH);
11.02 (Et2NH)]15 but it is quite large in the gas phase
ϩ
[R2NH ϩ NH4
R2NH2ϩ ϩ NH3; ∆GЊ Ϫ64.9 (Me2NH);
Ϫ84.6 (Et2NH) kJ molϪ1 16 and might be in CHCl3 solution as
]
well.§ That being so, the relatively low kinetic basicity of Et2NH
seen here must be a consequence of steric hindrance. Some
steric effect is to be expected, even for abstraction of a proton,
but we had supposed it would be small. In fact it seems quite
large, reflecting, presumably, a crowded environment for the
methine hydrogen in the Ph2CHP(O) group.
Competition experiments with Me2NH and Et2NH. Addi-
tional evidence for the involvement of phosphene intermediates
was sought from Me2NH–Et2NH competition experiments.
‡ A control reaction showed H/D exchange between the product 12a
(R = Et) and Et2ND to be insignificant under the conditions of reaction
(no change in 1H NMR or MS during 113 h).
§ There is, however, only a small difference between Me2NH and
Et2NH in ion-pair formation with 2,4-dinitrophenol in CHCl3 (R. G.
Pearson and D. C. Vogelsong, J. Am. Chem. Soc., 1958, 80, 1038).
J. Chem. Soc., Perkin Trans. 2, 2001, 41–47
43

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The phosphonamidic chlorides were treated with a large excess
of an equimolar mixture of the amines (each 2.0 mol dmϪ3
EA pathway it is still 104 times less than the rate of the SN2(P)
reaction of 4a with Me2NH.
)
in CHCl3 and the ratio of the NMe2 and NEt2 products
was determined by 31P NMR spectroscopy. Whereas the
benzyl substrates 4a and 4b gave only the products derived
from Me2NH (у99%), in accord with an associative [SN2(P)]
mechanism in which formation of the five-coordinate transition
state is highly sensitive to steric effects, the diphenylmethyl
substrates 10a and 10b gave substantial amounts of the
products derived from Et2NH. This is easily understood in
terms of an EA mechanism since the product would then arise
by nucleophilic attack on a reactive and sterically accessible
three-coordinate phosphene intermediate and relatively little
discrimination between the amines would be expected. The
NMe2 :NEt2 product ratio was actually 3.1:1 for the nitro
compound 10b but 6.4:1 for 10a. It is possible that the
phosphene intermediate from 10a reacts more selectively but
much of the difference probably originates elsewhere. The
EA mechanism is slower for 10a than for 10b so SN2(P) has
more chance to compete, and any of the substrate that does
react by SN2(P) will give entirely the product derived from
Me2NH. When the experiments were repeated with a small
amount of the strong base 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) included in the reaction mixture (5 mol% of total
amine) the NMe2 :NEt2 product ratio was practically unchanged
for 10b (3.2:1). For 10a, however, it was reduced to 3.05:1,
presumably because SN2(P) cannot now compete effectively
with the DBU-assisted EA mechanism. The rate measurements
hinted at some contribution from SN2(P) in the reaction of
10a with Me2NH and that is now confirmed by the outcome
of the competition experiments.
Experimental
Mps were determined using a Kofler hot-stage apparatus and
are uncorrected. H NMR spectra were recorded on a Bruker
1
ARX 250 or DPX 300 spectrometer (Me4Si internal standard;
coupling constants J given in Hz) and 31P NMR spectra (1H
decoupled) were recorded on the same instruments at 101.3
or 122.0 MHz (positive chemical shifts downfield from
85% H3PO4). Mass spectra were recorded in EI mode unless
otherwise indicated on a Kratos Concept spectrometer. Amines
were distilled from KOH and amine hydrochlorides were dried
at 0.2 mmHg over P2O5. Dichloromethane was distilled from
CaH2 and chloroform was dried over 5 Å molecular sieves.
Light petroleum refers to the fraction bp 60–80 ЊC and ether
to diethyl ether. The solutions used in rate studies were made
up using dried materials and were stored over 3 Å molecular
sieves at 4 ЊC for 15–24 h before use.
Diphenylmethylphosphonic acid 8a
A mixture of Ph2CHBr (24.7 g, 0.10 mol) and (EtO)3P (22.6 g,
0.135 mol) was stirred vigorously under a gentle stream of
nitrogen. The flask was placed in an oil bath preheated to
100 ЊC and the temperature was raised rapidly to ca. 165 ЊC.
Heating was continued until all the Ph2CHBr had been con-
sumed [2–3 h; δH 6.26 (s) replaced by 4.38 (d, JPH 25)]. The
crude diethyl phosphonate 7a (R = Et)19 (δP 25.2) was hydrolysed
by stirring efficiently with 48% hydrobromic acid (6 equiv.) at
1
130 ЊC until H NMR spectroscopy showed no P–OEt signal
(5 h). After cooling the solid was filtered off, washed thoroughly
with water, and crystallised from aqueous MeOH to give
diphenylmethylphosphonic acid 8a (22.8 g, 92%), mp 229–
231 ЊC (lit.,20 227–228 ЊC); m/z (ϪES) 247 [(M Ϫ H)Ϫ, 100%];
δP(CDCl3–MeOH, 9:1) 25.5; δH(CDCl3–MeOH, 9:1; 250 MHz)
7.5–7.1 (10 H, m) and 4.39 (1 H, d, JPH 26).
Conclusion
The simple benzylphosphonamidic chloride 4a reacts with
Me2NH and Et2NH by the normal associative [SN2(P)] mechan-
ism; there is no evidence of any appreciable competition from
elimination–addition, even when the acidity of the Cα–H bonds
is greatly increased by the presence of a 4-nitro substituent,
as in 4b. The nitro-substituted substrate is much less reactive
4-Nitrophenyl(phenyl)methylphosphonic acid 8b
1-Chloro-1-phenylmethylphosphonic dichloride [δP(CDCl3)
40.3] was prepared from PhCHO and PCl3 (sealed tube; 200 ЊC
for 8 h) as previously described21 and was added as a CH2Cl2
solution to MeOH (large excess) containing Et3N; evaporation
of volatile material and extraction of the residue with ether
afforded dimethyl 1-chloro-1-phenylmethylphosphonate22 6 (R =
Me) (74%), δP(CDCl3) 19.7; δH(CDCl3; 90 MHz) 7.6–7.2 (5 H,
m), 4.88 (1 H, d, JPH 15), 3.76 (3 H, d, JPH 11) and 3.52 (3 H,
d, JPH 11). Following the published procedure14 the phospho-
nate 6 (R = Me) was allowed to react with nitrobenzene and
NaOH in liquid NH3 to give dimethyl 4-nitrophenyl(phenyl)-
methylphosphonate 7b (R = Me) (77%), δP(CDCl3) 25.9;
δH(CDCl3; 90 MHz) 8.13 (2 H, d, JHH 9), 7.66 (2 H, dd, JPH 2,
JHH 9), 7.6–7.2 (5 H, m), 4.51 (1 H, d, JPH 26), 3.51 (3 H, d,
JPH 11) and 3.49 (3 H, d, JPH 11). The crude phosphonate 7b
(R = Me) (6.1 g, 19.0 mmol) was hydrolysed by stirring with
48% hydrobromic acid (6 equiv.) at 130 ЊC until reaction was
complete (3 h) (δP 24.7). The mixture was diluted with water
(50 ml) and refrigerated overnight, and the precipitated solid
was collected. It could not be crystallised satisfactorily (other
than from water) but dissolution in moist ether and gradual
addition of light petroleum (bp 40–60 ЊC) afforded pure 4-
nitrophenyl(phenyl)methylphosphonic acid 8b as the hemi-
hydrate (4.3 g, 75%), mp 77–80 ЊC; m/z (ϪES) 292 [(M Ϫ H)Ϫ,
100%]; δP(CDCl3) 27.0 br; δH(CDCl3; 250 MHz) 8.1 br (3 H;
OH ϩ 0.5 H2O), 8.04 (2 H, d, JHH 6), 7.41 (2 H, d, JHH 6), 7.25
(5 H, m) and 4.39 (1 H, d, JPH 25); νmax(Nujol)/cmϪ1 1520
and 1355 (NO2) (Found: C, 52.3; H, 4.3; N, 4.4. C13H12NO5Pؒ
0.5H2O requires C, 51.7; H, 4.3; N, 4.6%). Prolonged drying
over P2O5 at 0.2 mmHg and 50 ЊC gave practically anhydrous
acid.
towards Et NH than is the corresponding P᎐S compound
᎐
2
[ArCH2P(S)(NMe2)Cl] for which an EA mechanism has
Ϫ3
₁
previously been established (P᎐O: t 34 min with 2.0 mol dm
᎐
₂

Ϫ3
₁
Et NH; P᎐S: t 0.6 min with 0.8 mol dm Et2NH). If the
᎐
2
₂
EA mechanismwere as fast for the P᎐O compound it would, in
᎐
fact, be the preferred pathway, notwithstanding the relatively
high SN2(P) reactivity. The Cα–H bonds may be less acidic in
the P᎐O compound,17 but most evidence suggests that any
᎐
difference will be marginal18 and in any case the rapid H/D
exchange seen in the reaction of 4b with Et2ND implies that the
conjugate base is formed readily. Rather, it seems that elimin-
ation of chloride from the conjugate base is more difficult for
the P᎐O compound, to form a phosphene, than for the P᎐S
᎐
᎐
compound, forming a thiophosphene.
For the diphenylmethylphosphonamidic chloride 10a the
reaction with Me2NH is in part elimination–addition and in
part SN2(P). However, the EA mechanism is dominant with
Et2NH [steric hindrance; SN2(P) suppressed] and for both
amines in the case of the 4-nitro substituted substrate 10b
(enhanced Cα–H acidity; EA promoted). The importance of
elimination–addition here, but not with the benzyl substrates 4,
is obviously a consequence of the extra phenyl group; it will
increase the thermodynamic acidity of the Cα–H bond, and
probably also the kinetic acidity, and it will hinder nucleophilic
attack on the phosphorus atom. It is not possible to assess
the effect of the extra phenyl group on acidity from our results
(H/D exchange is not competitive with substitution for 4a
and is too fast to measure for 4b) but its hindrance of SN2(P)
is clearly very severe: even though the observed rate for 10a ϩ
Me2NH is boosted by a substantial contribution from the
44
J. Chem. Soc., Perkin Trans. 2, 2001, 41–47

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Phosphonic dichlorides
(major) (total 2 H; both dd, JPH 2, JHH 8.5), 7.65–7.25 (5 H, m),
4.79 and 4.78 (major) (total 1 H; both d, JPH 18), 2.68 (major)
(a) Benzylphosphonic dichloride 3a and 4-nitrobenzylphos-
phonic dichloride 3b were prepared by literature methods.23,24
(b) The phosphonic acid 8a or 8b was converted into the
dichloride by stirring with SOCl2 (12 equiv.) and DMF
(catalyst; 0.03 equiv.) at 100 ЊC (bath temp.) until the 31P NMR
spectrum of the solution consisted of a single peak (δP ~ 45)
(1.5–3 h). Volatile material was evaporated and the residue was
pumped at 0.2 mmHg. The following were obtained:
and 2.66 (total 6 H; both d, JPH 12.5); νmax(Nujol)/cmϪ1 1525
and 1360 (NO ), 1240 (P᎐O) (Found: C, 52.85; H, 4.7; N, 7.9.
᎐
2
C15H16ClN2O3P requires C, 53.2; H, 4.8; N, 8.3%).
Phosphonamidic chloride rate studies
All materials and glassware were dried and moisture was
excluded as completely as possible. The reaction medium was
a 2.0 mol dmϪ3 solution of R2NH (R = Me or Et) in CHCl3
containing R2NH2 ClϪ (0.1 mol dmϪ3). The substrate (10–15
ϩ
Diphenylmethylphosphonic dichloride 9a. Mp ~ 85 ЊC;
m/z 288, 286, 284 (Mϩ, 1%) and 167 (Ph2CHϩ, 100); m/z (CI)
306, 304, 302 [(M ϩ NH4)ϩ, 50%]; δP(CDCl3) 46.0; δH(CDCl3;
250 MHz) 7.60 (4 H, m), 7.4–7.3 (6 H, m) and 4.88 (1 H, d,
µmol) was dissolved in the reaction medium (240 µl) and the
solution was transferred to a 4 mm NMR tube housed in a
5 mm tube containing D2O (NMR lock). Faster reactions were
conducted in the probe of the NMR spectrometer at 30 ЊC.
Slower reactions (sealed tubes) were maintained at 30 ЊC (block
heater) and transferred to the spectrometer periodically. The
reactions of 4a and 4b with Me2NH were complete within 10
min but in other cases the 31P NMR spectrum (1H decoupled)
was recorded at regular intervals so that у9 spectra were
obtained as reaction progressed to 88% completion. For each
spectrum the relative amounts of substrate and product were
deduced from the integral. Minor by-products (hydrolysis) were
seen in some of the Et2NH reactions but in total they amounted
to р10%. First-order plots were linear, or practically so, and the
values of k ( 6%) were deduced from the slopes of the lines
(Table 1).
JPH 20); νmax(Nujol)/cmϪ1 1260 (P᎐O).
᎐
4-Nitrophenyl(phenyl)methylphosphonic
dichloride
9b.
Obtained as a foam, m/z 333, 331, 329 (Mϩ, 1%) and 212
(ArPhCHϩ, 100); δP(CDCl3) 43.5; δH(CDCl3; 250 MHz) 8.26
(2 H, d, JHH 8), 7.82 (2 H, dd, JPH 2.5, JHH 8), 7.59 (2 H, m), 7.43
(3 H, m) and 5.00 (1 H, d, JPH 20), which was used without
purification.
Phosphonamidic chlorides
A solution of the phosphonic dichloride 3 or 9 (2.0 mmol) and
Me2NH2ϩClϪ (2.4 mmol) in CH2Cl2 (5 ml) was stirred and
cooled in ice while Et3N (4.0 mmol) in CH2Cl2 (5 ml) was added
dropwise. In the case of 9b the phosphonic dichloride contained
impurities (HCl, SOCl2) that consumed some of the amine and
additional reagent was required to complete the conversion
(δP 44→46). After stirring at room temperature for 0.3 h
the mixture was concentrated and the residue, dissolved in
fresh CH2Cl2, was washed with iced water. The solvent was
evaporated and the crude product was distilled (Kugelrohr) (4a)
or crystallised from CH2Cl2–light petroleum. The following
were prepared:
When reaction was complete the volatile material was
evaporated and the residue was dissolved in CH2Cl2. The
solution was washed with water and the product was isolated
and characterised spectroscopically (see below).
The very fast reactions of 4a and 4b with Me2NH were
repeated with quenching after just 15 s by addition to an excess
of 1.0 mol dmϪ3 hydrochloric acid. The organic layer was
separated, dried over anhydrous Na2CO3, and examined by
31P NMR spectroscopy. The diamide product accounted for
75–80% of the total spectrum, implying that ca. two half lives
had elapsed before quenching. (Only 6–8% substrate remained
but the substantial by-products were supposed to be a con-
sequence of quenching as they were not present in reactions
allowed to proceed to completion.)
N,N-Dimethyl-P-benzylphosphonamidic chloride 4a. Bp
140 ЊC (oven temp.) at 0.3 mmHg, mp 52–55 ЊC; m/z 219, 217
(Mϩ, 40%), 128, 126 (MϩϪPhCH2, 50) and 91 (100); δP(CDCl3)
46.4; δH(CDCl3; 250 MHz) 7.4–7.3 (5 H, m), 3.57 (2 H, ABP,
δA 3.59, δB 3.55, JAB 15, JAP 20, JBP 17) and 2.69 (6 H, d, JPH 14);
Phosphonamidic chloride deuterium incorporation experiments
νmax(Nujol)/cmϪ1 1240 (P᎐O) (Found: C, 49.4; H, 6.1; N, 6.5.
The salts R2ND2ϩClϪ (R = Me or Et) were prepared by dis-
solving R2NH2ϩClϪ in D2O (2 equiv.) and evaporating to
dryness, and repeating four more times.
᎐
C9H13ClNOP requires C, 49.7; H, 6.0; N, 6.4%).
N,N-Dimethyl-P-(4-nitrobenzyl)phosphonamidic chloride 4b.
(Yield 78%.) Recrystallised from ButOMe, mp 93–95 ЊC;
m/z 264, 262 (Mϩ, 13%) and 128, 126 (Mϩ Ϫ ArCH2, 100);
δP(CDCl3) 43.3; δH(CDCl3; 250 MHz) 8.22 (2 H, d, JHH 8.5),
7.52 (2 H, dd, JPH 3, JHH 8.5), 3.66 (2 H, ABP, δA 3.68, δB 3.64,
JAB 14.5, JAP 20, JBP 18) and 2.73 (6 H, d, JPH 14); νmax(Nujol)/
cmϪ1 1515 and 1350 (NO ), 1240 and 1230 (P᎐O) (Found:
A solution of Me2ND in CDCl3 was obtained by adding
NaOD (6 mmol) in D2O (0.2 ml) to a stirred solution of
Me2ND2ϩClϪ (0.42 g, 5 mmol) in CDCl3 (1.9 ml) at 0 ЊC. The
organic layer was separated, shaken with solid NaCl, and dried
over anhydrous K2CO3 and then over a little 3 Å molecular
sieve. A sample was examined by 1H NMR spectroscopy
to assess the deuterium content of the amine (NH integral
0.2 H) and its concentration (Me2N integral relative to added
CH2Cl2; 1.9 mol dmϪ3).¶
᎐
2
C, 41.1; H, 4.7; N, 10.4. C9H12ClN2O3P requires C, 41.15;
H, 4.6; N, 10.7%).
A solution of Et2ND in CDCl3 was obtained by shaking
Et2NH (1.1 g, 15 mmol) in CDCl3 (5 ml) with D2O (20 mmol)
containing a little NaCl. The organic layer was collected and
the process was repeated four more times. The resulting solu-
tion was dried and analysed as above (NH integral 0.15 H;
amine concentration 2.5 mol dmϪ3 but 2.0 mol dmϪ3 after
dilution with more CDCl3).¶
The behaviour of the phosphonamidic chlorides 4 and 10
(12–16 µmol) with R2ND (R = Me or Et) in CDCl3 (containing
0.1 mol dmϪ3 R2ND2ϩClϪ) was examined using the solutions
obtained above (65 µl portions) in capillary NMR tubes. At
N,N-Dimethyl-P-(diphenylmethyl)phosphonamidic chloride
10a. (Yield 88%.) Mp 180–182 ЊC (from CH2Cl2–ether);
m/z 295, 293 (Mϩ, 2%) and 167 (Ph2CHϩ, 100); δP(CDCl3)
46.9; δH(CDCl3; 250 MHz) 7.62 (2 H, d, JHH 7.5), 7.53 (2 H, d,
JHH 7.5), 7.4–7.2 (6 H, m), 4.68 (1 H, d, JPH 18.5) and 2.65 (6 H,
d, JPH 13); νmax(Nujol)/cmϪ1 1230 (P᎐O) (Found: C, 61.2; H, 5.8;
᎐
N, 4.75. C15H17ClNOP requires C, 61.3; H, 5.8; N, 4.8%).
N,N-Dimethyl-P-[4-nitrophenyl(phenyl)methyl]phosphon-
amidic chloride 10b. (Yield 90%.) Mixture of diastereoisomers,
mp 159–160 ЊC; m/z 340, 338 (Mϩ, 2%), 294, 292 (Mϩ Ϫ NO2,
5) and 212 (ArPhCHϩ, 100); δP(CDCl3) 44.6 (major) and 44.35;
δH(CDCl3; 250 MHz) 8.19 (2 H, d, JHH 8.5), 7.82 and 7.73
¶ The deuterium content was not as high as expected, apparently
because some D/H exchange occurred with the molecular sieve.
J. Chem. Soc., Perkin Trans. 2, 2001, 41–47
45

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intervals the 31P and 1H NMR spectra were recorded and from
them the extent of reaction and the deuterium content of
the substrate (and sometimes the product) were estimated
(see Results and discussion). The temperature was generally
maintained at ca. 30 ЊC (or 18 ЊC for 10b ϩ Me2ND) but no
attempt was made to obtain precise rate data. Selected results
are shown in Table 2.
1355 (NO ), 1180 (P᎐O) (Found: Mϩ, 347.1398. C H N O P
᎐
2 17 22 3 3
requires M, 347.1399).
From 10b and Et2NH, product 12b (R = Et), mixture of
diastereoisomers (melts 153–166 ЊC); m/z 375 (Mϩ, 8%), 212
(15), 196 (55), 179 (25) and 163 (Mϩ Ϫ ArPhCH, 100);
δP(CDCl3) 30.4 and 30.3 (ratio 1.2:1); δH(CDCl3; 250 MHz)
8.15 (2 H, d, JHH 9), 7.88 (major) and 7.85 (total 2 H; both d,
JHH 9), 7.60 and 7.59 (major) (total 2 H; both d, JHH 7), 7.35–7.2
(3 H, m), 4.46 and 4.45 (major) (total 1 H; both d, JPH 15), 2.88
(4 H, m), 2.425 and 2.39 (major) (total 6 H; both d, JPH 8.5),
0.90 (major) and 0.87 (total 6 H; both t, JHH 7); νmax(Nujol)/
cmϪ1 1515 and 1350 (NO ), 1170 (P᎐O) (Found: Mϩ, 375.1712.
Phosphonamidic chloride competition experiments
The phosphonamidic chloride 4 or 10 (10–15 µmol) was added
to an equimolar mixture of Me2NH and Et2NH (each 2.0 mol
dmϪ3) in CHCl3 (containing Me2NH2ϩClϪ and Et2NH2ϩClϪ,
each 0.05 mol dmϪ3) (150–250 µl) at ca. 30 ЊC. After several
hours (days for 10a; reaction conducted in sealed ampoule)
volatile material was evaporated and the residue was dissolved
in CDCl3. The NMe2 :NEt2 product ratio was determined by
31P NMR spectroscopy. The experiments with 10a and 10b
were also carried out with 1,8-diazabicyclo[5.4.0]undec-7-ene
(0.2 mol dmϪ3) present in the reaction medium (amine hydro-
chloride omitted).
᎐
2
C19H26N3O3P requires M, 375.1712). Prior to crystallisation
the highfield 31P NMR diastereoisomer was in excess (ratio
ca. 1:2).
Acknowledgements
The assistance of Danny Paige and Mark Fielding is gratefully
acknowledged.
Phosphonamidic chloride reaction products
References
The identities of the phosphonic diamide products 5 and 12
from the rate studies were confirmed as detailed below (crystal-
lised from CH2Cl2–light petroleum unless indicated otherwise).
From 4a and Me2NH, product 5a (R = Me), mp 78–80 ЊC
(lit.,25 79.5–80.5 ЊC); m/z 226 (Mϩ, 20%) and 135 (Mϩ Ϫ
CH2Ph, 100); δP(CDCl3) 34.2; δH(CDCl3; 250 MHz) 7.4–7.2
(5 H, m), 3.21 (2 H, d, JPH 17) and 2.54 (12 H, d, JPH 9.5);
1 D. E. C. Corbridge, Phosphorus: An Outline of its Chemistry,
Biochemistry and Technology, Elsevier, Amsterdam, 1995; Chemistry
of Organophosphorus Compounds, ed. F. R. Hartley, Wiley,
Chichester, 1996, vol. 4.
2 G. R. J. Thatcher and R. Kluger, Adv. Phys. Org. Chem., 1989, 25,
99; D. M. Perreault and E. V. Anslyn, Angew. Chem., Int. Ed. Engl.,
1997, 36, 433; A. Blasko and T. C. Bruice, Acc. Chem. Res., 1999, 32,
475.
νmax(melt)/cmϪ1 1210 and 1190 (P᎐O).
᎐
3 Multiple Bonds and Low Coordination in Phosphorus Chemistry,
ed. M. Regitz and O. J. Scherer, Thieme, Stuttgart, 1990, Section E.
4 For more recent work and references see: E. S. Lightcap and
P. A. Frey, J. Am. Chem. Soc., 1992, 114, 9750; J. M. Friedman,
S. Freeman and J. R. Knowles, J. Am. Chem. Soc., 1988, 110, 1268;
L. D. Quin and S. Jankowski, J. Org. Chem., 1994, 59, 4402.
5 For more recent work and references see: P. M. Cullis and R. Misra,
J. Am. Chem. Soc., 1991, 113, 9679; S. P. Harnett and G. Lowe,
J. Chem. Soc., Chem. Commun., 1987, 1416; I. E. Catrina and
A. C. Hengge, J. Am. Chem. Soc., 1999, 121, 2156. See also
L. D. Quin, P. Hermann and S. Jankowski, J. Org. Chem., 1996, 61,
3944.
6 A. F. Gerrard and N. K. Hamer, J. Chem. Soc. (B), 1968, 539;
A. F. Gerrard and N. K. Hamer, J. Chem. Soc. (B), 1969, 369;
S. Freeman and M. J. P. Harger, J. Chem. Soc., Perkin Trans. 2, 1988,
81; S. Freeman and M. J. P. Harger, J. Chem. Soc., Perkin Trans. 1,
1988, 2737; M. J. P. Harger, J. Chem. Soc., Perkin Trans. 2, 1991,
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9 F. I. Luknitskii and B. A. Vovsi, Russ. Chem. Rev., 1969, 38, 487;
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10 J. F. King, Acc. Chem. Res., 1975, 8, 10; J. F. King, J. Y. L. Lam and
S. Skonieczny, J. Am. Chem. Soc., 1992, 114, 1743; J. F. King and
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their Derivatives, ed. S. Patai and Z. Rappoport, Wiley, Chichester,
1991, ch. 17; T. Kataoka and T. Iwama, Synlett, 1994, 1017.
11 L. Keay, J. Org. Chem., 1963, 28, 329; I. Dostrovsky and
M. Halmann, J. Chem. Soc., 1953, 511; A. Kanavarioti, M. W.
Stronach, R. J. Ketner and T. B. Hurley, J. Org. Chem., 1995, 60,
632.
From 4a and Et2NH, product 5a (R = Et), bp 150 ЊC (oven
temp.) at 0.2 mmHg, solidifies at room temperature; m/z 254
(Mϩ, 11%) and 163 (Mϩ Ϫ CH2Ph, 100); δP(CDCl3) 33.3;
δH(CDCl3, 250 MHz) 7.4–7.15 (5 H, m), 3.18 (2 H, d, JPH 16.5),
2.97 (4 H, m), 2.54 (6 H, d, JPH 9.5) and 1.00 (6 H, t, JHH 7);
νmax(melt)/cmϪ1 1220 (P᎐O) (Found: Mϩ, 254.1548; C H -
᎐
13 23
N2OP requires M, 254.1548).
From 4b and Me2NH, product 5b (R = Me), mp 132–134 ЊC;
m/z 271 (Mϩ, 13%), 151 (14) and 135 (Mϩ Ϫ ArCH2, 100);
δP(CDCl3) 32.3; δH(CDCl3; 250 MHz) 8.17 (2 H, d, JHH 8.5),
7.50 (2 H, dd, JPH 2, JHH 8.5), 3.30 (2 H, d, JPH 17) and 2.57
(12 H, d, JPH 10); νmax(Nujol)/cmϪ1 1520 and 1350 (NO2), 1210
and 1190 (P᎐O) (Found: Mϩ, 271.1085. C H N O P requires
᎐
11 18
3
3
M, 271.1086).
From 4b and Et2NH, product 5b (R = Et), mp 114–116 ЊC
(from ether); m/z 299 (Mϩ, 15%) and 163 (Mϩ Ϫ ArCH2, 100);
δP(CDCl3) 31.4; δH(CDCl3; 250 MHz) 8.18 (2 H, d, JHH 8.5),
7.53 (2 H, dd, JPH 2, JHH 8.5), 3.28 (2 H, d, JPH 17), 2.97 (4 H,
m), 2.58 (6 H, d, JPH 9.5) and 1.03 (6 H, t, JHH 7); νmax(Nujol)/
cmϪ1 1515 and 1350 (NO ), 1215 and 1200 (P᎐O) (Found:
᎐
2
Mϩ, 299.1398. C13H22N3O3P requires M, 299.1399).
From 10a and Me2NH, product 12a (R = Me), mp 182–
184 ЊC; m/z 302 (Mϩ, 7%) and 135 (Mϩ Ϫ Ph2CH, 100);
δP(CDCl3) 32.2; δH(CDCl3; 250 MHz) 7.64 (4 H, d, JHH 7), 7.35–
7.15 (6 H, m), 4.345 (1 H, d, JPH 15) and 2.40 (12 H, d, JPH 9);
νmax(Nujol)/cmϪ1 1200 and 1185 (P᎐O) (Found: Mϩ, 302.1548.
᎐
C17H23N2OP requires M, 302.1548).
From 10a and Et2NH, product 12a (R = Et), mp 152–154 ЊC;
m/z 330 (Mϩ, 8%) and 163 (Mϩ Ϫ Ph2CH, 100); δP(CDCl3) 31.7;
δH(CDCl3; 250 MHz) 7.66 (2 H, d, JHH 8), 7.63 (2 H, d, JHH 8),
7.3–7.15 (6 H, m), 4.33 (1 H, d, JPH 16), 2.86 (4 H, m), 2.39 (6 H,
12 S. Freeman and M. J. P. Harger, J. Chem. Soc., Perkin Trans. 1, 1987,
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d, JPH 9) and 0.86 (6 H, t, JHH 7); νmax(Nujol)/cmϪ1 1185 (P᎐O)
᎐
(Found: Mϩ, 330.1861. C19H27N2OP requires M, 330.1861).
From 10b and Me2NH, product 12b (R = Me), mp ca. 190 ЊC
(softens at 180 ЊC); m/z 347 (Mϩ, 11%), 196 (65), 166 (50), 165
(40) and 135 (Mϩ Ϫ ArPhCH, 100); δP(CDCl3) 31.0; δH(CDCl3;
250 MHz) 8.15 (2 H, d, JHH 9), 7.86 (2 H, d, JHH 9), 7.61 (2 H,
d, JHH 7), 7.35–7.2 (3 H, m), 4.47 (1 H, d, JPH 15), 2.435 (6 H,
d, JPH 9) and 2.40 (6 H, d, JPH 9); νmax(Nujol)/cmϪ1 1520 and
46
J. Chem. Soc., Perkin Trans. 2, 2001, 41–47

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J. Chem. Soc., Perkin Trans. 2, 2001, 41–47
47