Nucleophilic substitution reactions of benzyl- and diphenylmethyl-phosphonamidic chlorides with amines: competition between the usual S_N2(P) mechanism and elimination–addition with an alkylideneoxophosphorane (phosphene) intermediate

Abstract

The substitution reaction of PhCH₂P(O)(NMe₂)Cl with Me₂NH or Et₂NH in CHCl₃ is very sensitive to the bulk of the nucleophile (⩾ 200 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 S_N2(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 [Ph₂C[double bond, length half m-dash]P(O)NMe₂]. There is only a 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.

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Nucleophilic substitution at phosphoryl (P[double bond, length half m-dash]O) centres is important in many areas of chemistry and makes possible the phosphoryl transfer reactions on which biological systems depend.¹ The mechanism is generally associative [S_N2(P)], with a five-coordinate intermediate or transition state.² An alternative dissociative pathway is available to substrates that have an acidic ligand HZ (Scheme 1; X = leaving group), involving elimination–addition and a transient three-coordinate P^V intermediate.^2,3 This alternative mechanism is often important when Z is oxygen,⁴ sulfur ⁵ or nitrogen ⁶ 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 alkylideneoxophosphorane (phosphene) intermediate 2.⁸ This is an extreme case, however, since the C_α–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 substrates that produce ketenes ⁹ or sulfenes ¹⁰ in their reactions with basic reagents. Is it only in extreme cases that phosphenes are formed as intermediates in the nucleophilic substitution reactions of P[double bond, length half m-dash]O compounds? That question has prompted the present investigation.

Scheme 1

Results and discussion

Benzylphosphonic acid derivatives

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 Me₂NH₂⁺Cl⁻ 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 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 (δ_P 46.9 or 44.0→33.9 or 32.0) using a large excess of a 2.0 mol dm⁻³ solution of Et₂NH in CHCl₃ at 30 °C 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.

Table 1 Pseudo-first-order rate constants (k) for reactions of phosphonamidic chlorides with 2.0 mol dm⁻³ amines in CHCl₃ at 30 °C

	10^5k/s^−1
Substrate	Me2NH	Et2NH
a Very approximate (based on 75–80% substitution in 15 s and by implication t ½ ≈ 7 s). b Some 10% of substrate formed by-products (hydrolysis); value of k is for overall consumption of substrate.
4a	≈10^4 ^a	29.7
4b	≈10^4 ^a	34.4
10a	1.04	0.21 ^b
10b	13.8	3.87

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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) (δ_P 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 S_N2(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 Bu^tNH₂,¹² and with PrⁱP(O)(NEt₂)Cl the reactivity of Me₂NH is ⩾ 200 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 of the benzylic P[double bond, length half m-dash]S substrate ArCH₂P(S)(NMe₂)Cl (Ar = 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 S_N2(P) but improbable for an EA mechanism. The acidity of the C_α–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 with the P[double bond, length half m-dash]S substrate ArCH₂P(S)(NMe₂)Cl is dramatically different: a 4-nitro substituent increases the observed reactivity towards Et₂NH by a factor of 2500, even though the unsubstituted compound reacts predominantly by S_N2(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 derivative might become more susceptible to substitution by an EA mechanism: increased acidity of the C_α–H bond, encouraging elimination–addition, and steric hindrance of attack at the phosphorus atom, discouraging competition from S_N2(P). On both counts replacing one of the benzylic hydrogen atoms by a phenyl group could have a profound effect.

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 °C) 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 of (EtO)₃P with Ph₂CHBr, but the second was obtained by an indirect route, making use of Makosza and Goliński’s vicarious substitution.¹⁴ This entailed reaction of the α-chlorobenzylphosphonate 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.

Scheme 3

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: δ_H 7.62 and 7.53 (both 2 H, d, J_HH 7.5). The nitro-substituted compound 10b is chiral at carbon as well as phosphorus and was obtained as a mixture of diastereoisomers, δ_P 44.6 and 44.35. The NMe₂ groups of the two diastereoisomers give distinct ¹H NMR signals, δ_H 2.68 and 2.66 (both d, J_PH 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, δ_H 2.40 (12 H, d, J_PH 9)], 12b (R = Me) is chiral at carbon [diastereotopic NMe₂ groups, δ_H 2.435 and 2.40 (both 6 H, d, J_PH 9)], 12a (R = Et) is chiral at phosphorus [diastereotopic Ph groups; ortho protons δ_H 7.66 and 7.63 (both 2 H, d, J_HH 8)], and 12b (R = Et) is chiral at both carbon and phosphorus and exists as diastereoisomers, δ_P 30.4 and 30.3 [NMe₂ groups δ_H 2.425 and 2.39 (both d, J_PH 8.5)].

Scheme 4

Reactivity in substitution reactions with Me₂NH and Et₂NH. Rates of reaction were examined as before, using 2.0 mol dm⁻³ amine in CHCl₃ at 30 °C. Even the fastest reaction (10b + Me₂NH) was now slow enough to be followed by ³¹P NMR spectroscopy (85% complete in 4 h) while the slowest (10a + 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 (k^E) than with Me₂NH (k^M) but only by a factor of about five. The difference in amine reactivity is therefore much smaller than for the benzyl compounds 4 (k^M/k^E ⩾ 200) and much less than would be expected for S_N2(P). On the other hand it is similar to the value observed with the fluorenyl substrate 1 (k^M/k^E = 4) which reacts with amines by an EA mechanism.⁸ The somewhat larger difference seen for 10a (k^M/k^E = 5.0) than for 10b (k^M/k^E = 3.6) may indicate that only the latter (nitro-substituted) substrate reacts entirely by elimination–addition. Competition from S_N2(P) will be more important with the less acidic substrate 10a and with the more nucleophilic (less hindered) amine, so the observed value of k^M for 10a with Me₂NH may well be rather greater than the value for the EA pathway alone.

A contribution from S_N2(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[double bond, length half m-dash]S substrate ArCH₂P(S)(NMe₂)Cl (>10⁴-fold).¹³ That 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).

Scheme 5

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 dm⁻³ but the solvent was changed to CDCl₃ so that the reactions could be monitored by ¹H NMR spectroscopy. Ideally the signal for the methine group [CH(D)] of the substrate 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.

Table 2 Exchange (H/D) during reactions of phosphonamidic chlorides with 2 mol dm⁻³ R₂ND (80–85 atom% D) in CDCl₃ at 30 °C

		Substrate
Reaction	Time/h	Amount (%)	CH(D) Integral
a T = 18 °C in this case.
10a + Me2ND	0.4	>95	0.9 H
	1.0	>95	0.75 H
	2.5	95	0.5 H
	9.5	80	0.2 H
10b + Me2ND	0.15 ^a	>95	0.15 H
10a + Et2ND	20	86	0.8 H
	37	78	0.6 H
	87	52	0.35 H
10b + Et2ND	0.2	>95	0.2 H

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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 bimolecular nucleophilic attack [S_N2(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 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 group of the product was 80% deuteriated (0.2 H/0.8 D by ¹H 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 + Et₂ND).‡ The other substitution reactions (10a + Me₂ND; 10b + 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.

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 [pK_a 10.68 (Me₂NH); 11.02 (Et₂NH)] ¹⁵ but it is quite large in the gas phase [R₂NH + NH₄⁺ ⇌ R₂NH₂⁺ + NH₃; ΔG ° −64.9 (Me₂NH); −84.6 (Et₂NH) kJ mol⁻¹] 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. Additional evidence for the involvement of phosphene intermediates was sought from Me₂NH–Et₂NH competition experiments. The phosphonamidic chlorides were treated with a large excess of an equimolar mixture of the amines (each 2.0 mol dm⁻³) 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 (⩾99%), in accord with an associative [S_N2(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 S_N2(P) has more chance to compete, and any of the substrate that does react by S_N2(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 S_N2(P) cannot now compete effectively with the DBU-assisted EA mechanism. The rate measurements hinted at some contribution from S_N2(P) in the reaction of 10a with Me₂NH and that is now confirmed by the outcome of the competition experiments.

Conclusion

The simple benzylphosphonamidic chloride 4a reacts with Me₂NH and Et₂NH by the normal associative [S_N2(P)] mechanism; there is no evidence of any appreciable competition from elimination–addition, even when the acidity of the C_α–H bonds is greatly increased by the presence of a 4-nitro substituent, as in 4b. The nitro-substituted substrate is much less reactive towards Et₂NH than is the corresponding P[double bond, length half m-dash]S compound [ArCH₂P(S)(NMe₂)Cl] for which an EA mechanism has previously been established (P[double bond, length half m-dash]O: t½ 34 min with 2.0 mol dm⁻³ Et₂NH; P[double bond, length half m-dash]S: t½ 0.6 min with 0.8 mol dm⁻³ Et₂NH). If the EA mechanism were as fast for the P[double bond, length half m-dash]O compound it would, in fact, be the preferred pathway, notwithstanding the relatively high S_N2(P) reactivity. The C_α–H bonds may be less acidic in the P[double bond, length half m-dash]O compound,¹⁷ but most evidence suggests that any difference will be marginal ¹⁸ 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 elimination of chloride from the conjugate base is more difficult for the P[double bond, length half m-dash]O compound, to form a phosphene, than for the P[double bond, length half m-dash]S compound, forming a thiophosphene.

For the diphenylmethylphosphonamidic chloride 10a the reaction with Me₂NH is in part elimination–addition and in part S_N2(P). However, the EA mechanism is dominant with Et₂NH [steric hindrance; S_N2(P) suppressed] and for both amines in the case of the 4-nitro substituted substrate 10b (enhanced C_α–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 C_α–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 S_N2(P) is clearly very severe: even though the observed rate for 10a + Me₂NH is boosted by a substantial contribution from the EA pathway it is still 10⁴ times less than the rate of the S_N2(P) reaction of 4a with Me₂NH.

Experimental

Mps were determined using a Kofler hot-stage apparatus and are uncorrected. ¹H NMR spectra were recorded on a Bruker 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 °C 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 °C 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 °C and the temperature was raised rapidly to ca. 165 °C. Heating was continued until all the Ph₂CHBr had been consumed [2–3 h; δ_H 6.26 (s) replaced by 4.38 (d, J_PH 25)]. The crude diethyl phosphonate7a (R = Et) ¹⁹ (δ_P 25.2) was hydrolysed by stirring efficiently with 48% hydrobromic acid (6 equiv.) at 130 °C until ¹H 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 acid8a (22.8 g, 92%), mp 229–231 °C (lit.,²⁰ 227–228 °C); m/z (−ES) 247 [(M − H)⁻, 100%]; δ_P(CDCl₃–MeOH, 9∶1) 25.5; δ_H(CDCl₃–MeOH, 9∶1; 250 MHz) 7.5–7.1 (10 H, m) and 4.39 (1 H, d, J_PH 26).

4-Nitrophenyl(phenyl)methylphosphonic acid 8b

1-Chloro-1-phenylmethylphosphonic dichloride [δ_P(CDCl₃) 40.3] was prepared from PhCHO and PCl₃ (sealed tube; 200 °C for 8 h) as previously described ²¹ 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-phenylmethylphosphonate ²²6 (R = Me) (74%), δ_P(CDCl₃) 19.7; δ_H(CDCl₃; 90 MHz) 7.6–7.2 (5 H, m), 4.88 (1 H, d, J_PH 15), 3.76 (3 H, d, J_PH 11) and 3.52 (3 H, d, J_PH 11). Following the published procedure ¹⁴ the phosphonate 6 (R = Me) was allowed to react with nitrobenzene and NaOH in liquid NH₃ to give dimethyl 4-nitrophenyl(phenyl)methylphosphonate7b (R = Me) (77%), δ_P(CDCl₃) 25.9; δ_H(CDCl₃; 90 MHz) 8.13 (2 H, d, J_HH 9), 7.66 (2 H, dd, J_PH 2, J_HH 9), 7.6–7.2 (5 H, m), 4.51 (1 H, d, J_PH 26), 3.51 (3 H, d, J_PH 11) and 3.49 (3 H, d, J_PH 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 °C until reaction was complete (3 h) (δ_P 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 °C) afforded pure 4-nitrophenyl(phenyl)methylphosphonic acid8b as the hemihydrate (4.3 g, 75%), mp 77–80 °C; m/z (−ES) 292 [(M − H)⁻, 100%]; δ_P(CDCl₃) 27.0 br; δ_H(CDCl₃; 250 MHz) 8.1 br (3 H; OH + 0.5 H₂O), 8.04 (2 H, d, J_HH 6), 7.41 (2 H, d, J_HH 6), 7.25 (5 H, m) and 4.39 (1 H, d, J_PH 25); ν_max(Nujol)/cm⁻¹ 1520 and 1355 (NO₂) (Found: C, 52.3; H, 4.3; N, 4.4. C₁₃H₁₂NO₅P· 0.5H₂O requires C, 51.7; H, 4.3; N, 4.6%). Prolonged drying over P₂O₅ at 0.2 mmHg and 50 °C gave practically anhydrous acid.

Phosphonic dichlorides

(a) Benzylphosphonic dichloride 3a and 4-nitrobenzylphosphonic 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 °C (bath temp.) until the ³¹P NMR spectrum of the solution consisted of a single peak (δ_P ≈ 45) (1.5–3 h). Volatile material was evaporated and the residue was pumped at 0.2 mmHg. The following were obtained:

Diphenylmethylphosphonic dichloride 9a. Mp ≈ 85 °C; m/z 288, 286, 284 (M⁺, 1%) and 167 (Ph₂CH⁺, 100); m/z (CI) 306, 304, 302 [(M + NH₄)⁺, 50%]; δ_P(CDCl₃) 46.0; δ_H(CDCl₃; 250 MHz) 7.60 (4 H, m), 7.4–7.3 (6 H, m) and 4.88 (1 H, d, J_PH 20); ν_max(Nujol)/cm⁻¹ 1260 (P[double bond, length half m-dash]O).

4-Nitrophenyl(phenyl)methylphosphonic dichloride 9b. Obtained as a foam, m/z 333, 331, 329 (M⁺, 1%) and 212 (ArPhCH⁺, 100); δ_P(CDCl₃) 43.5; δ_H(CDCl₃; 250 MHz) 8.26 (2 H, d, J_HH 8), 7.82 (2 H, dd, J_PH 2.5, J_HH 8), 7.59 (2 H, m), 7.43 (3 H, m) and 5.00 (1 H, d, J_PH 20), which was used without purification.

Phosphonamidic chlorides

A solution of the phosphonic dichloride 3 or 9 (2.0 mmol) and Me₂NH₂⁺Cl⁻ (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 (δ_P 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:

N,N-Dimethyl-P-benzylphosphonamidic chloride 4a. Bp 140 °C (oven temp.) at 0.3 mmHg, mp 52–55 °C; m/z 219, 217 (M⁺, 40%), 128, 126 (M⁺−PhCH₂, 50) and 91 (100); δ_P(CDCl₃) 46.4; δ_H(CDCl₃; 250 MHz) 7.4–7.3 (5 H, m), 3.57 (2 H, ABP, δ_A 3.59, δ_B 3.55, J_AB 15, J_AP 20, J_BP 17) and 2.69 (6 H, d, J_PH 14); ν_max(Nujol)/cm⁻¹ 1240 (P[double bond, length half m-dash]O) (Found: C, 49.4; H, 6.1; N, 6.5. C₉H₁₃ClNOP requires C, 49.7; H, 6.0; N, 6.4%).

N,N-Dimethyl-P-(4-nitrobenzyl)phosphonamidic chloride 4b. (Yield 78%.) Recrystallised from Bu^tOMe, mp 93–95 °C; m/z 264, 262 (M⁺, 13%) and 128, 126 (M⁺ − ArCH₂, 100); δ_P(CDCl₃) 43.3; δ_H(CDCl₃; 250 MHz) 8.22 (2 H, d, J_HH 8.5), 7.52 (2 H, dd, J_PH 3, J_HH 8.5), 3.66 (2 H, ABP, δ_A 3.68, δ_B 3.64, J_AB 14.5, J_AP 20, J_BP 18) and 2.73 (6 H, d, J_PH 14); ν_max(Nujol)/cm⁻¹ 1515 and 1350 (NO₂), 1240 and 1230 (P[double bond, length half m-dash]O) (Found: C, 41.1; H, 4.7; N, 10.4. C₉H₁₂ClN₂O₃P requires C, 41.15; H, 4.6; N, 10.7%).

N,N-Dimethyl-P-(diphenylmethyl)phosphonamidic chloride 10a. (Yield 88%.) Mp 180–182 °C (from CH₂Cl₂–ether); m/z 295, 293 (M⁺, 2%) and 167 (Ph₂CH⁺, 100); δ_P(CDCl₃) 46.9; δ_H(CDCl₃; 250 MHz) 7.62 (2 H, d, J_HH 7.5), 7.53 (2 H, d, J_HH 7.5), 7.4–7.2 (6 H, m), 4.68 (1 H, d, J_PH 18.5) and 2.65 (6 H, d, J_PH 13); ν_max(Nujol)/cm⁻¹ 1230 (P[double bond, length half m-dash]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]phosphonamidic chloride 10b. (Yield 90%.) Mixture of diastereoisomers, mp 159–160 °C; m/z 340, 338 (M⁺, 2%), 294, 292 (M⁺ − NO₂, 5) and 212 (ArPhCH⁺, 100); δ_P(CDCl₃) 44.6 (major) and 44.35; δ_H(CDCl₃; 250 MHz) 8.19 (2 H, d, J_HH 8.5), 7.82 and 7.73 (major) (total 2 H; both dd, J_PH 2, J_HH 8.5), 7.65–7.25 (5 H, m), 4.79 and 4.78 (major) (total 1 H; both d, J_PH 18), 2.68 (major) and 2.66 (total 6 H; both d, J_PH 12.5); ν_max(Nujol)/cm⁻¹ 1525 and 1360 (NO₂), 1240 (P[double bond, length half m-dash]O) (Found: C, 52.85; H, 4.7; N, 7.9. 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 dm⁻³ solution of R₂NH (R = Me or Et) in CHCl₃ containing R₂NH₂⁺ Cl⁻ (0.1 mol dm⁻³). The substrate (10–15 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 °C. Slower reactions (sealed tubes) were maintained at 30 °C (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 ⩾9 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 ≤10%. First-order plots were linear, or practically so, and the values of k (± 6%) were deduced from the slopes of the lines (Table 1).

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 dm⁻³ 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 consequence of quenching as they were not present in reactions allowed to proceed to completion.)

Phosphonamidic chloride deuterium incorporation experiments

The salts R₂ND₂⁺Cl⁻ (R = Me or Et) were prepared by dissolving R₂NH₂⁺Cl⁻ in D₂O (2 equiv.) and evaporating to dryness, and repeating four more times.

A solution of Me₂ND in CDCl₃ was obtained by adding NaOD (6 mmol) in D₂O (0.2 ml) to a stirred solution of Me₂ND₂⁺Cl⁻ (0.42 g, 5 mmol) in CDCl₃ (1.9 ml) at 0 °C. 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 dm⁻³).¶

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 solution was dried and analysed as above (NH integral 0.15 H; amine concentration 2.5 mol dm⁻³ but 2.0 mol dm⁻³ 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 dm⁻³ R₂ND₂⁺Cl⁻) was examined using the solutions obtained above (65 μl portions) in capillary NMR tubes. At 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 °C (or 18 °C for 10b + Me₂ND) but no attempt was made to obtain precise rate data. Selected results are shown in Table 2.

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 dm⁻³) in CHCl₃ (containing Me₂NH₂⁺Cl⁻ and Et₂NH₂⁺Cl⁻, each 0.05 mol dm⁻³) (150–250 μl) at ca. 30 °C. 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 dm⁻³) present in the reaction medium (amine hydrochloride omitted).

Phosphonamidic chloride reaction products

The identities of the phosphonic diamide products 5 and 12 from the rate studies were confirmed as detailed below (crystallised from CH₂Cl₂–light petroleum unless indicated otherwise).

From 4a and Me₂NH, product5a (R = Me), mp 78–80 °C (lit.,²⁵ 79.5–80.5 °C); m/z 226 (M⁺, 20%) and 135 (M⁺ − CH₂Ph, 100); δ_P(CDCl₃) 34.2; δ_H(CDCl₃; 250 MHz) 7.4–7.2 (5 H, m), 3.21 (2 H, d, J_PH 17) and 2.54 (12 H, d, J_PH 9.5); ν_max(melt)/cm⁻¹ 1210 and 1190 (P[double bond, length half m-dash]O).

From 4a and Et₂NH, product5a (R = Et), bp 150 °C (oven temp.) at 0.2 mmHg, solidifies at room temperature; m/z 254 (M⁺, 11%) and 163 (M⁺ − CH₂Ph, 100); δ_P(CDCl₃) 33.3; δ_H(CDCl₃, 250 MHz) 7.4–7.15 (5 H, m), 3.18 (2 H, d, J_PH 16.5), 2.97 (4 H, m), 2.54 (6 H, d, J_PH 9.5) and 1.00 (6 H, t, J_HH 7); ν_max(melt)/cm⁻¹ 1220 (P[double bond, length half m-dash]O) (Found: M⁺, 254.1548; C₁₃H₂₃N₂OP requires M, 254.1548).

From 4b and Me₂NH, product5b (R = Me), mp 132–134 °C; m/z 271 (M⁺, 13%), 151 (14) and 135 (M⁺ − ArCH₂, 100); δ_P(CDCl₃) 32.3; δ_H(CDCl₃; 250 MHz) 8.17 (2 H, d, J_HH 8.5), 7.50 (2 H, dd, J_PH 2, J_HH 8.5), 3.30 (2 H, d, J_PH 17) and 2.57 (12 H, d, J_PH 10); ν_max(Nujol)/cm⁻¹ 1520 and 1350 (NO₂), 1210 and 1190 (P[double bond, length half m-dash]O) (Found: M⁺, 271.1085. C₁₁H₁₈N₃O₃P requires M, 271.1086).

From 4b and Et₂NH, product5b (R = Et), mp 114–116 °C (from ether); m/z 299 (M⁺, 15%) and 163 (M⁺ − ArCH₂, 100); δ_P(CDCl₃) 31.4; δ_H(CDCl₃; 250 MHz) 8.18 (2 H, d, J_HH 8.5), 7.53 (2 H, dd, J_PH 2, J_HH 8.5), 3.28 (2 H, d, J_PH 17), 2.97 (4 H, m), 2.58 (6 H, d, J_PH 9.5) and 1.03 (6 H, t, J_HH 7); ν_max(Nujol)/cm⁻¹ 1515 and 1350 (NO₂), 1215 and 1200 (P[double bond, length half m-dash]O) (Found: M⁺, 299.1398. C₁₃H₂₂N₃O₃P requires M, 299.1399).

From 10a and Me₂NH, product12a (R = Me), mp 182–184 °C; m/z 302 (M⁺, 7%) and 135 (M⁺ − Ph₂CH, 100); δ_P(CDCl₃) 32.2; δ_H(CDCl₃; 250 MHz) 7.64 (4 H, d, J_HH 7), 7.35–7.15 (6 H, m), 4.345 (1 H, d, J_PH 15) and 2.40 (12 H, d, J_PH 9); ν_max(Nujol)/cm⁻¹ 1200 and 1185 (P[double bond, length half m-dash]O) (Found: M⁺, 302.1548. C₁₇H₂₃N₂OP requires M, 302.1548).

From 10a and Et₂NH, product12a (R = Et), mp 152–154 °C; m/z 330 (M⁺, 8%) and 163 (M⁺ − Ph₂CH, 100); δ_P(CDCl₃) 31.7; δ_H(CDCl₃; 250 MHz) 7.66 (2 H, d, J_HH 8), 7.63 (2 H, d, J_HH 8), 7.3–7.15 (6 H, m), 4.33 (1 H, d, J_PH 16), 2.86 (4 H, m), 2.39 (6 H, d, J_PH 9) and 0.86 (6 H, t, J_HH 7); ν_max(Nujol)/cm⁻¹ 1185 (P[double bond, length half m-dash]O) (Found: M⁺, 330.1861. C₁₉H₂₇N₂OP requires M, 330.1861).

From 10b and Me₂NH, product12b (R = Me), mp ca. 190 °C (softens at 180 °C); m/z 347 (M⁺, 11%), 196 (65), 166 (50), 165 (40) and 135 (M⁺ − ArPhCH, 100); δ_P(CDCl₃) 31.0; δ_H(CDCl₃; 250 MHz) 8.15 (2 H, d, J_HH 9), 7.86 (2 H, d, J_HH 9), 7.61 (2 H, d, J_HH 7), 7.35–7.2 (3 H, m), 4.47 (1 H, d, J_PH 15), 2.435 (6 H, d, J_PH 9) and 2.40 (6 H, d, J_PH 9); ν_max(Nujol)/cm⁻¹ 1520 and 1355 (NO₂), 1180 (P[double bond, length half m-dash]O) (Found: M⁺, 347.1398. C₁₇H₂₂N₃O₃P requires M, 347.1399).

From 10b and Et₂NH, product12b (R = Et), mixture of diastereoisomers (melts 153–166 °C); m/z 375 (M⁺, 8%), 212 (15), 196 (55), 179 (25) and 163 (M⁺ − ArPhCH, 100); δ_P(CDCl₃) 30.4 and 30.3 (ratio 1.2∶1); δ_H(CDCl₃; 250 MHz) 8.15 (2 H, d, J_HH 9), 7.88 (major) and 7.85 (total 2 H; both d, J_HH 9), 7.60 and 7.59 (major) (total 2 H; both d, J_HH 7), 7.35–7.2 (3 H, m), 4.46 and 4.45 (major) (total 1 H; both d, J_PH 15), 2.88 (4 H, m), 2.425 and 2.39 (major) (total 6 H; both d, J_PH 8.5), 0.90 (major) and 0.87 (total 6 H; both t, J_HH 7); ν_max(Nujol)/cm⁻¹ 1515 and 1350 (NO₂), 1170 (P[double bond, length half m-dash]O) (Found: M⁺, 375.1712. 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.

References

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Footnotes

† 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 hydrochloride (Et₂NH₂Cl or Me₂NH₂Cl) (0.1 mol dm⁻³) was included in each reaction mixture and the rate plots showed little if any curvature.

‡ 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).

¶ The deuterium content was not as high as expected, apparently because some D/H exchange occurred with the molecular sieve.

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