A new mechanism for nucleophilic substitution at a thiophosphoryl centre revealed by the reaction of diisopropylamine with PSCl3

Article abstract of DOI:10.1039/b502615f

The reaction of PSCl₃ with Prⁱ₂NH at 60 °C affords the disubstitution product (Prⁱ₂N) ₂P(S)Cl without first forming the monosubstitution product Pr ⁱ₂NP(S)Cl₂

Full text of DOI:10.1039/b502615f

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A new mechanism for nucleophilic substitution at a thiophosphoryl
centre revealed by the reaction of diisopropylamine with PSCl3
Martin J. P. Harger
Received (in Cambridge, UK) 24th February 2005, Accepted 7th April 2005
First published as an Advance Article on the web 22nd April 2005
DOI: 10.1039/b502615f
The reaction of PSCl3 with Pri2NH at 60 uC affords the
disubstitution product (Pri2N)2P(S)Cl without first forming the
monosubstitution product Pri2NP(S)Cl2; a PIII compound
(possibly PCl3) generated in situ seems to be a crucial
intermediate.
estimated from the rate for PSCl3 with Et2NH (t0.5 ¡ 1.25 min)
and the 40-fold greater reactivity of POCl3]. The product was the
expected amino dichloride 3 (R 5 Pri)8 (dP 11.5; t, JPH 28.5) with
no indication in the 31P NMR spectrum of any of the bis(amino)
compound 4 (R 5 Pri) (lit.,9 dP 20).
It is the quest for a more complete understanding of biologically-
important phosphoryl transfer reactions that drives the continuing
mechanistic study of nucleophilic substitution at PLO and PLS
centres.1 These reactions are usually associative [SN2(P)] with a
five-coordinate PV transition state or intermediate, although a
dissociative elimination–addition (EA) pathway may become
important when the phosphorus atom bears an acidic ligand
(OH, SH, NHR) so that a metaphosphate-like three-coordinate PV
intermediate can be formed.2
The diisopropylamino phosphorothioic dichloride 1 (R 5 Pri) is
a known compound but the ways in which it has been obtained are
not straightforward.3 We hoped it could be simply prepared by the
direct reaction of PSCl3 with Pri2NH but that proved not to be the
case.{ Since SN2(P) reactions at four-coordinate phosphoryl and
thiophosphoryl centres are very sensitive to steric effects4 it would
not have been remarkable if PSCl3 had merely failed to react with
a nucleophile as bulky as Pri2NH. It did react, however, albeit only
reluctantly, but the product was not the expected amino dichloride
1 (R 5 Pri). The identity of the product and the possible reasons
for its formation are our concern here and it is to assist our
understanding that we have made a comparative study of the
reactions of PSCl3 and POCl3 with Pri2NH and Et2NH.
In the case of PSCl3 there was no appreciable reaction with
Pri2NH (2.2 equiv., 2.0 mol dm23 in CDCl3) after 26 days at 25 uC
(31P NMR: 97% of total phosphorus accounted for by PSCl3; no
single product . 0.6%). At 60 uC reaction did occur but it showed
some unexpected features. First, there was an induction period so
that the product (dP 68.9) was barely detectable (ca. 1%) after
2 days but accounted for 9% of the total phosphorus in the
reaction mixture after 4 days and 50% after 8 days. Second,
the reaction stopped (no free amine remained) with almost half the
PSCl3 still unreacted, implying that formation of the product
consumes 4 equivalents of amine, not two. Third, the 31P NMR
signal of the product was not the triplet expected for the
monoamino compound 1 (R 5 Pri) but a quintet (JPH 22). Even
when a large excess of PSCl3 was used (solvent and reactant) the
monosubstitution product 1 (R 5 Pri) could not be detected
(dP 49.2, t, JPH 29.5 for authentic sample{). These observations
suggest that the mechanism of substitution is something other than
conventional SN2(P) and that the product is the bis(amino)
1
chloride 2 (R 5 Pri)10 (M+ 298, 300; H and 13C NMR signals
When PSCl3 (dP 31.0) was added to a solution of Et2NH
(2.5 equiv., 2.0 mol dm23) in CDCl3 at room temperature it was
rapidly converted into the amino dichloride 1 (R 5 Et)5 (dP 60.7;
indicative of diastereotopic methyls in the N-isopropyl groups). In
the same way the reaction of dicyclohexylamine with PSCl3 (large
excess) gave the bis(amino) compound 2 (R 5 C6H11) (dP 70.4,
quintet, JPH 22; M+ 458, 460).
quintet, JPH 18.5), reaction being complete inside 5 min (t0.5
¡
1.25 min).{ Addition of more Et2NH (2.0 equiv.) caused further
substitution and formation of the bis(amino) chloride 2 (R 5 Et)5
(dP 83.0; 9 lines, JPH 15) but this was at least 700 times slower
(t0.5 y 15 h at 25 uC).
It is hard to imagine further reaction of the monosubstitution
product 1 (R 5 Pri) being competitive with its formation by
SN2(P) let alone so fast that it does not accumulate enough to be
detected. In any case when some authentic 1 (R 5 Pri) was
included in the PSCl3 (neat)–Pri2NH reaction mixture it remained
unchanged, neither increasing nor decreasing, as the amine reacted
with PSCl3 to give the bis(amino) product 2 (R 5 Pri). The
conclusion must be that Pri2NH can convert PSCl3 into the
disubstitution product 2 (R 5 Pri) without passing through
the monosubstitution product 1 (R 5 Pri).§
Using POCl3 as the substrate the reaction with Et2NH (2.0 mol
dm23 in CDCl3) to give the amino dichloride 3 (R 5 Et)6 (dP 16.1;
quintet, JPH 16.5) was so fast as to be quite violent; in a
competition experiment (limited Et2NH) POCl3 was found to be
ca. 40 times as reactive as PSCl3. Here too, further substitution to
give the bis(amino) chloride 4 (R 5 Et)7 (dP 26.7; 9 lines, JPH 13.5)
was relatively slow (t0.5 y 20 min) though again some 45 times
faster than the corresponding PLS transformation.
In looking for an explanation we were mindful of the high
reactivity of PIII compounds towards nucleophiles, in particular
the ready reaction of PCl3 with Pri2NH (in CHCl3) to give
(Pri2N)2PCl,11 and of the tendency of PIII compounds to abstract
The reaction of POCl3 with Pri2NH (2 mol dm23 in CDCl3) was
sluggish at room temperature (t0.5 y 26 h at 25 uC) and at least
5 6 104 times slower than its reaction with Et2NH [t0.5 ¡ 2 s,
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sulfur from PSCl3.12 Control experiments showed that under the
conditions of our PSCl3–Pri2NH reactions (at 60 uC) PCl3 is
rapidly transformed into (Pri2N)2PCl (dP 138) and that this is then
gradually converted into the PLS compound 2 (R 5 Pri). They also
showed that addition of a little PCl3 (0.1 equiv.) eliminated the
induction period and greatly increased the rate of the reaction of
PSCl3 with Pri2NH to give 2 (R 5 Pri).13 It would therefore be
possible for a catalytic amount of PCl3 to cause the reaction of
PSCl3 with Pri2NH to give the disubstitution product 2 (R 5 Pri)
without the monosubstitution product 1 (R 5 Pri) ever being
formed (Scheme 1, R 5 Pri).
Martin J. P. Harger
Department of Chemistry, University of Leicester, Leicester, UK, LE1
7RH. E-mail: mjph2@le.ac.uk; Fax: +44(0)116 2523789;
Tel: +44(0)116 2522127
Notes and references
{ A straightforward route to 1 (R 5 Pri) was subsequently found viz.
addition of Pri2NH (2 equiv.) to PCl3 in ether and thiation of the crude
product using a concentrated solution of sulfur in boiling toluene.
{ Reactions were carried out in NMR tubes using distilled PSCl3 or POCl3
and dried amine. Values of t0.5 are an indication of the time taken to reach
50% completion but are not true half lives as the amine was not in large
excess. The products have previously been reported but in some cases with
little data; they were provisionally identified in reaction mixtures by their
1H-coupled 31P NMR signals and definitively after isolation by their 1H
and 13C NMR (CDCl3) and mass spectra. J values are in Hz.
1 (R 5 Et), dH 3.50 (4H, dq, JPH 18.5, JHH 7) and 1.24 (6H, t, JHH 7), dC
42.7 (d, JPC 3.5) and 13.7 (d, JPC 3.5), M+ 205, 207, 209 (10%).
2 (R 5 Et), dH 3.28 (8H, dq, JPH 14, JHH 7) and 1.19 (12H, t, JHH 7), dC
41.0 (d, JPC 4) and 13.7 (d, JPC 4), M+ 242, 244 (50%).
3 (R 5 Et), dH 3.34 (4H, dq, JPH 16.5, JHH 7) and 1.23 (6H, t, JHH 7), dC
41.2 (d, JPC 4) and 13.6 (d, JPC 3), M+ 189, 191, 193 (20%).
4 (R 5 Et), dH 3.18 (8H, dq, JPH 14, JHH 7) and 1.17 (12H, t, JHH 7), dC
40.3 (d, JPC 4) and 13.8 (d, JPC 3.5), (M + H)+ (ES) 227, 229 (100%).
1 (R 5 Pri) (authentic) dH 3.98 (2H, d 6 sept, JPH 29, JHH 7) and 1.43
(12H, d, JHH 7), dC 51.4 (d, JPC 4.5) and 22.2 (d, JPC 2), M+ 233, 235, 237
(4%).
2 (R 5 Pri), dH 3.79 (4H, d 6 sept, JPH 22, JHH 7), 1.42 (12H, d, JHH 7)
and 1.38 (12H, d, JHH 7), dC 48.7 (d, JPC 4.5), 22.5 (d, JPC 2.5) and 22.1 (d,
JPC 2.5), M+ 298, 300 (8%).
If PCl3 is responsible it seems it must be generated in the
reaction mixture, not only because of the induction period but also
because the same behaviour was seen using PSCl3 that had been
washed with water to destroy (by hydrolysis) any PCl3 impurity
that might be present. We do not know how PCl3 could be formed
but perhaps Pri2NH is so bulky it does not act as a nucleophile at
the P atom of PSCl3 but attacks at the S atom instead. There are
many examples of amines and other nucleophiles attacking at a
two-coordinate bivalent sulfur atom, notably in the substitution
reactions of sulfenic acid derivatives.14 Nucleophilic attack at a
one-coordinate bivalent sulfur (as in R2CLS) is much less common
except with organometallic reagents (which probably react by
electron transfer)15 but it has been reported16 for (CF3)2CLS and
Cl2CLS and seems plausible for Cl3PLS. That being so, the crucial
PIII species may not be PCl3 itself but some related species such as
5 (Scheme 2, R 5 Pri)." The extended induction period could be
due to traces of moisture in the reaction mixture so that any PCl3
(or related PIII species) that is generated is at first destroyed by
hydrolysis [vP5Cl A vP(O)H]. Only when the water has been
consumed can the reaction with Pri2NH (Scheme 1, R 5 Pri) make
substantial headway.
3 (R 5 Pri), dH 3.71 (2H, d 6 sept, JPH 29, JHH 7) and 1.38 (12H, d, JHH
7), dC 49.5 (d, JPC 5) and 22.0 (d, JPC 2), (M + H)+ (ES) 218, 220 (100%).
§ Had Pri2NP(S)Cl2 proved to be more reactive than PSCl3 the possibility
of dissociative reaction by an SN1(P) mechanism, with a phosphorylium ion
intermediate (X2P+LS; X 5 Cl or Pri2N), might have merited consideration
(cf. ref. 17).
" Another possibility for the reactive PIII species is ClSPCl2 resulting from
nucleophilic attack of chloride ion at the S atom of PSCl3 (Scheme 2 with
Cl2 in place of R2NH).
In principle PIII species could be involved in many substitution
reactions of thiophosphoryl compounds but in practise they will
probably be important only when nucleophilic attack at the
phosphorus atom is severely hindered or the nucleophile is
especially thiophilic.
1 D. E. C. Corbridge, Phosphorus—An Outline of its Chemistry,
Biochemistry and Uses, Elsevier, Amsterdam, 5th edn., 1995, ch. 11.
For recent work and references, see: I. E. Catrina and A. C. Hengge,
J. Am. Chem. Soc., 2003, 125, 7546; P. K. Grzyska, P. G. Czyryca,
J. Purcell and A. C. Hengge, J. Am. Chem. Soc., 2003, 125, 13106.
2 G. R. J. Thatcher and R. Kluger, Adv. Phys. Org. Chem., 1989, 25, 99;
R. S. Edmundson, in The Chemistry of Organophosphorus Compounds,
ed. F. R. Hartley, Wiley, 1996, vol. 4, pp. 598–630.
3 Y. W. Li, M. G. Newton and R. B. King, J. Organomet. Chem., 1995,
488, 63; V. Kumar, D. W. Lee, M. G. Newton and R. B. King,
J. Organomet. Chem., 1996, 512, 1.
4 See, for example: M. P. Coogan and M. J. P. Harger, J. Chem. Soc.,
Perkin Trans. 2, 1994, 2101 [Et2NH reacts 200 times less readily than
Me2NH with PhP(S)(NMe2)Cl].
Scheme 1
5 F. L. Scott, R. Riordan and P. D. Morton, J. Org. Chem., 1962, 27, 4255;
see also: E. C. F. Ko and R. E. Robertson, Can. J. Chem., 1973, 51, 597.
6 R. F. Borch and R. R. Valente, J. Med. Chem., 1991, 34, 3052.
7 M. H. Lyttle, A. Satyam, M. D. Hocker, K. E. Bauer, C. G. Caldwell,
H. C. Hui, A. S. Morgan, A. Mergia and L. M. Kauver, J. Med. Chem.,
1994, 37, 1501.
8 E. J. Cabrita, C. A. M. Afonso and A. G. Santos, Chem. Eur. J., 2001,
7, 1455 (presumed intermediate in preparation of 3-N-benzyl-2-
diisopropylamino-1,3,2-l5-oxazaphospholidine-2-one). Also ref. 9.
9 A.-M. Caminade, F. El Khatib, A. Baceiredo and M. Koenig,
Phosphorus, Sulfur Relat. Elem., 1987, 29, 365.
10 N. Burford, R. E. v. H. Spence and R. D. Rogers, J. Chem. Soc., Dalton
Trans., 1990, 3611 have prepared 2 (R 5 Pri) by heating (Pri2N)2PCl
with sulfur and AlCl3.
11 Although formation of (Pri2N)2PCl from PCl3 and Pri2NH is apparently
slow in boiling hexane (R. B. King and P. M. Sundaram, J. Org. Chem.,
1984, 49, 1784) or ether (S. Hamamoto and H. Takaku, Chem. Lett.,
1986, 1401) it is quite fast in CHCl3 even at room temperature
(t0.5 y 7 min).
Scheme 2
2864 | Chem. Commun., 2005, 2863–2865
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12 I. B. Johns and H. R. DiPietro, J. Org. Chem., 1964, 29, 1970;
R. S. Edmundson, in The Chemistry of Organophosphorus Compounds,
ed. F. R. Hartley, Wiley, Chichester, 1996, vol. 4, p. 413.
14 The Chemistry of Sulphenic Acids and their Derivatives, ed. S. Patai,
Wiley, Chichester, 1990, ch. 5, 6, 10 and 18; L. Senatore, E. Ciuffarin
and L. Sagramora, J. Chem. Soc. B, 1971, 2191.
13 The added PCl3 is converted into (Pri2N)2PCl (dP 138). The proportion
of this in the reaction mixture remains more or less constant while the
PSCl3–Pri2NH (2 equiv.) reaction is proceeding but it is replaced by
Pri2NPCl2 (dP 169) when no free amine remains [(Pri2N)2PCl + PCl3
2 Pri2NPCl2; cf. J. R. Van Wazer and L. Maier, J. Am. Chem. Soc.,
1964, 86, 811].
15 A. Ohno, K. Nakamura, M. Uohama, S. Oka, T. Yamabe and
S. Nagata, Bull. Chem. Soc. Jpn., 1975, 48, 3718.
16 W. J. Middleton and W. H. Sharkey, J. Org. Chem., 1965, 30, 1384;
N. H. Nilsson, C. Jacobsen and A. Senning, J. Chem. Soc. D, 1970, 658.
17 Z. Skrzpczynski, J. Phys. Org. Chem., 1990, 3, 23; Z. Skrzpczynski,
J. Phys. Org. Chem., 1990, 3, 35.
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