Study on the Atherton–Todd reaction mechanism

Abstract

A new mechanism of the Atherton–Todd reaction is discussed. The first step of the reaction between diesters of H-phosphonic acid and carbon tetrachloride in the presence of a base, commonly triethylamine, is a salt formation between carbon tetrachloride and the base [amine·Cl]⁺CCl₃⁻. The trichloromethanide anion [CCl₃⁻] deprotonates dialkyl H-phosphonate to form chloroform and dialkyl phosphonate anion [(RO)₂P(O)]⁻. The latter anion reacts with the chlorine cation to furnish dialkyl chlorophosphate. Based on these findings the reaction has been applied for the oxidation of poly(alkylene H-phosphonate)s to the corresponding poly(alkylene chlorophosphate)s via the Atherton–Todd reaction.

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1. Introduction

The Atherton–Todd reaction is one of the most characteristic reactions of diesters of H-phosphonic acid. It is a route for the oxidation of dialkyl H-phosphonates to the highly reactive dialkyl chlorophosphates.^1,2

The reaction is widely used in situ under mild conditions for the synthesis of a large number of biologically active compounds such as phosphates and amidophosphates.³ The Atherton–Todd reaction is a preferred method of synthesis of polyphosphoesters including poly[(hydroxy or alkyl)alkylene phosphate]s,⁴ poly(alkylene amidophosphate)s⁵ and polymer conjugates from poly(alkylene H-phosphonate)s.^6–9 Recently, Atherton–Todd reaction has been used for direct azidation, cyanation and thiocyanation of diethyl or dii-buthyl H-phosphonates.¹⁰ The commonly proposed mechanism of the reaction is based primarily on the early kinetic investigations done by Steinberg.¹¹ The initial step of the proposed two mechanisms involves deprotonation of dialkyl H-phosphonate (RO)₂P(O)H by a base B to give the dialkyl phosphite anion, (RO)₂PO⁻. This anion then reacts as a nucleophile with BCl⁺ to furnish the corresponding chlorophosphate (Scheme 1), or reacts with carbon tetrachloride (Scheme 2).

Scheme 1 Mechanism of Atherton–Todd reaction.¹¹

Scheme 2 Mechanism of Atherton–Todd reaction.¹¹

The validity of the deprotonation step in the above mechanism for the case of amine application is however questionable, since it has been established that amines are alkylated, but not protonated at the nitrogen by dialkyl H-phosphonates.^12–14 Based on this observation it was accepted that the first step of Atherton–Todd reaction is alkylation of base (Scheme 3).^15,16

Scheme 3 Mechanism of Atherton–Todd reaction.^15,16

According to Krutikov et al.¹⁷ the mechanism of the synthesis of phosphoramidates via the Atherton–Todd reaction is based on the primary interaction of a polyhaloalkane with the highly basic amine to form a 1 : 1 associate. Authors accepted that the subsequent attack by the associate on the tricoordinated form of dalkyl H-phosphonate lead to the formation of the target compounds in high yields. In the review of Jaffres et al.¹⁸ devoted to the Atherton–Todd reaction are discussed all proposed mechanisms and the conclusion is that they led to controversial reports over the past years. In fact, till now there are no direct evidences for the proposed mechanisms.

In this paper we provide a direct evidence for Atherton–Todd reaction mechanism according to which the first step is a complex formation between base and carbon tetrachloride.

2. Results and discussion

We did experiments between dimethyl H-phosphonate and a secondary amine. It was established that the interaction of dimethyl H-phosphonate with dibutylamine at room temperature resulted in alkylation of dibutylamine.

In the ³¹P{H}NMR spectrum of the reaction mixture there are signals for two types of phosphorus atoms at δ = 11.00 ppm and at 5.77 ppm. In the ³¹P NMR (see ESI Fig. 1†) spectrum the signal at 11.00 ppm represents a doublet of septets with ¹J(P, H) = 697.65 Hz and ³J(P, H) = 11.86 Hz and is assigned to the phosphorus atom of unreacted dimethyl H-phosphonate. Those one at 5.77 ppm appears as a doublet of quartets with ¹J(P, H) = 606.38 Hz and ³J(P, H) = 11.87 Hz. This signal can be assigned to the phosphorus atom of the mono-dealkylated H-phosphonate. The alkylation of dibutylamine is also confirmed and by ¹H NMR spectrum. Besides the signals of the unreacted dimethyl H-phosphonate (doublets at 6.64 ppm with ¹J(P, H) = 697.64 Hz and at 3.51 ppm with ³J(P, H) = 11.88 Hz for the protons in the P–H and P–OCH₃ groups, respectively) there are new signals at δ = 6.64 ppm with ¹J(P, H) = 606.35 Hz assigned to the P–H of mono-dealkylated H-phosphonate and at δ = 3.41 ppm with ³J(P, H) = 11.92 Hz attributed to the methoxy group of mono-dealkylated H-phosphonate. The singlet at 2.08 ppm can be assigned to N–CH₃ protons.

When dimethyl H-phosphonate was added to in advanced mixed dibutylamine with carbon tetrachloride the NMR data showed that there proceeded the Atherton–Todd reaction (see ESI Fig. 2†). The reaction is highly exothermic and the corresponding amidophosphate is formed.

In the ³¹P{H}NMR spectrum (see ESI Fig. 2†) of the reaction mixture there are signals for two types of phosphorus atoms at δ = 13.73 ppm and at 11.02 ppm. In the ³¹P NMR spectrum the signal at 13.73 ppm represents 11 lines with ³J(P, H) = 11.18 Hz and can be assigned to the phosphorus atom of dimethyl dibutylamidophosphate. The one at 11.02 ppm appears as a doublet of septets with ¹J(P, H) = 698.16 Hz and ³J(P, H) = 11.85 Hz and can be assigned to the phosphorus atom of dimethyl H-phosphonate. There is no signal in the range between 5 ppm and 6 ppm which is characteristic for the mono-dealkylated H-phosphonate. Expected dealkylation of dimethyl H-phosphonate did not occur.

The formation of complex between carbon tetrachloride and base (triethylamine) was confirmed by ¹H NMR spectroscopy (See ESI Fig. 3†).

The signals for CH₃ and CH₂ protons in ¹H NMR spectrum of the complex are shifted to low field compared to pure triethylamine. The triplet for CH₃ protons and quartet for CH₂ protons of pure triethylamine appears at 1.030 ppm and 2.524 ppm, those one of the complex appear at 1.035 ppm and 2.532 ppm, and in the salt at 1.042 ppm, and 2.543 ppm, respectively. Shifting for CH₃ and CH₂ protons of pure triethylamine compared to salt is 0.005 ppm (6.66 Hz) and 0.011 ppm (10.42 Hz), respectively.

Based on these results the following mechanism of Atherton–Todd reaction can be proposed (Scheme 4).

Scheme 4 Reaction mechanism of oxidation of dimethyl H-phosphonate via Atherton–Todd reaction.

It can be assumed that the first step of the reaction is a salt formation between carbon tetrachloride and the base. Obviously, the formation of this salt is the main reason dibutylamine do not participate in a dealkylation reaction. Trichloromethanide anion [CCl₃⁻] deprotonates dialkyl H-phosphonate to form chloroform and a dialkyl phosphonate anion [(RO)₂P(O)]⁻. The latter anion takes the chlorine cation to furnish dialkyl chlorophosphate.

According to the proposed mechanism the Atherton–Todd reaction can be applied for oxidation of poly(alkylene H-phosphonate)s to the corresponding poly(alkylene chlorophosphate)s (Scheme 5).

Scheme 5 Reaction mechanism of the oxidation of poly(alkylene H-phosphonate)s via Atherton–Todd reaction.

In the ³¹P{H}NMR spectrum of the mixture (See ESI Fig. 4a†) poly(oxyethylene H-phosphonate), triethylamine and CCl₄ (Atherton–Todd reaction conditions) measured after 4 h, there are signals for the phosphorus atom in the repeating units at 9.85 ppm, a doublet of quintets (See ESI Fig. 4b†), and at 5.89 ppm, new one, a; quintet for the phosphorus atom connected with a chlorine atom (10% conversion). It can be accepted that the active species in the oxidation of poly(alkylene H-phosphonate)s via Atherton–Todd reaction to the corresponding poly(alkylene chlorophosphate)s is the phosphonate anion. The formation of the phosphonate anion can be formed via deprotonation of the poly(alkylene H-phosphonate) by the trichloromethanide anion.

3. Experimental

Materials

Dimethyl H-phosphonate, dibutylamine and triethylamine were purchased from Sigma-Aldrich and distilled prior to use. Carbon tetrachloride was obtained from Sigma-Aldrich, dried over P₂O₅ and distilled prior to use. All NMR spectra were measured on Bruker Avance II+ 600 NMR spectrometer in CDCl₃.

The poly(oxyethylene H-phosphonate) was obtained via polytransesterification of dimethyl H-phosphonate and poly(ethylene glycol) with number average molecular weight 600 g mol⁻¹ (PEG 600) following a procedure described in ref. 4.

Interaction of dimethyl H-phosphonate with dibutylamine

1 ml of dimethyl H-phosphonate (0.0109 mol) and 1.84 ml dibutylamine (0.0109 mol) were mixed at room temperature under inert atmosphere (gentle flow of dry argon). After stirring the mixer for 48 h, sample was taken without further isolation for NMR analysis in CDCl₃.

³¹P{H}NMR (CDCl₃), δ ppm: 11.00 ppm (content 39.5%); 5.77 ppm (content 60.5%).

³¹P NMR (CDCl₃), δ ppm: 11.00 dseptets, ¹J(P, H) = 697.65 Hz, ³J(P, H) = 11.86 Hz, CH₃OP(O)(H)OCH₃; 5.77 ppm, dq, ¹J(P, H) = 606.38 Hz, ³J(P, H) = 11.87 Hz, CH₃OP(O)(H)O⁻NHCH₃⁺(C₄H₉)₂.

¹H NMR (CDCl₃), δ ppm: 0.80 ppm, t, CH₃–CH₂–, ³J(H, H) = 7.2 Hz; 1.14–1.39 ppm, –CH₂–CH₂–CH₃; 1.48–1.60 ppm, –CH₂CH₂–CH₂–; 2.08 ppm, –N–CH₃; 2.51–2.63 ppm, N–CH₂–CH₂–; 3.41 ppm, d, P–OCH₃, ³J(P, H) = 11.92 Hz; 3.65 ppm, d, P–OCH₃, ³J(P, H) = 11.88 Hz; 6.64 ppm, P–H, d, ¹J(P, H) = 606.35 Hz, CH₃OP(O)(H)O⁻NHCH₃⁺(C₄H₉)₂; 6.64 ppm, ¹J(P, H) = 697.64 Hz, d, CH₃OP(O)(H)OCH₃.

Oxidation of dimethyl H-phosphonate via Athertton–Todd reaction

To a solution of 1.84 ml dibutylamine (0.0109 mol) in carbon tetrachloride (2.5 ml, 0.027 mol) at room temperature under inert atmosphere and stirring was added drop-wise 1 ml of dimethyl H-phosphonate (0.0109 mol). When dimethyl H-phosphonate was added to in advanced mixed dibutylamine with carbon tetrachloride, the reaction is highly exothermic. After stirring the mixer for 24 h, sample was taken without further isolation for NMR analysis in CDCl₃ and dibutylamine were mixed (gentle flow of dry argon).

³¹P{H}NMR (CDCl₃), δ ppm: 13.73 ppm (content 59.5%); 11.02 ppm (content 41.5%).

³¹P NMR (CDCl₃), δ ppm: 13.73 ppm, 11 lines, ³J(P, H) = 11.18 Hz, (CH₃O)₂P(O)N(C₄H₉)₂; 11.02 ppm, dseptets, ¹J(P, H) = 698.16 Hz, ³J(P, H) = 11.86 Hz, CH₃OP(O)(H)OCH₃.

¹H NMR (CDCl₃), δ ppm: 0.86 ppm, t, 3J(H, H) = 7.2 Hz, CH₃–CH₂–; 1.16–1.40 ppm, –CH₂–CH₂–CH₃; 1.71–1.84 ppm, –CH₂CH₂–CH₂–; 2.72–2.93 ppm, P–N–CH₂–CH₂–; 3.57 ppm, d, P–OCH₃, ³J(P, H) = 11.1 Hz, (CH₃O)₂P(O)N(C₄H₉)₂; 3.69 ppm, d, P–OCH₃, ³J(P, H) = 11.88 Hz, (CH₃O)₂P(O) (H); 6.68 ppm, d, ¹J(P, H) = 697.80 Hz, (CH₃O)₂P(O)(H).

Oxidation of poly(oxyethylene H-phosphonate) via Athetton–Todd reaction

The mixture of 0.035 g poly(oxyethylene H-phosphonate) based on PEG600 (0.054 mmol repeating units), 0.01 ml triethylamine (0.072 mmol) and 0.017 ml carbon tetrachloride (0.175 mmol) were mixed at room temperature under inert atmosphere (gentle flow of dry argon). After stirring the mixer for 24 h, sample was taken without further isolation for NMR analysis in CDCl₃.

³¹P{H}NMR (CDCl₃), δ ppm: 9.87 ppm (content 88.4%); 5.89 ppm (content 11.6%).

³¹P NMR (CDCl₃), δ ppm: 9.87 ppm, dquintets, ¹J(P, H) = 715.84 ppm, ³J(P, H) = 9.11 Hz, –CH₂O–P(O)(H)OCH₂–; 5.89 ppm, quintet, ³J(P, H) = 9.11 Hz, –CH₂O–P(O) (Cl)OCH₂–;

Interaction of triethylamine with carbontetrachloride

60 mg of triethylamine (0.00059 mol) and 90 mg of carbon tetrachloride (0.00059 mol) were mixed at room temperature. After stirring for 48 h, the solid sample was taken without further isolation for NMR analysis in CDCl₃.

¹H NMR (CDCl₃), δ ppm: 1.042 ppm, t, CH₃–, ³J(H, H) = 7.2 Hz; 2.53–2.56 ppm, N–CH₂–CH₃.

Acknowledgements

Financial support of this work was provided by the National Science Fund of Bulgaria (National Center for Advanced Materials (UNION) Module 2 “New materials in medicine and pharmacy” Contract DCVP 02-2/2009.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra10228b

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