**2. Synthesis and purification of phosphoramidates and phosphoric acid esters**

The reaction of phosphorus(V)-halogen compounds of the type P(O)X3-nYn (X = halide, Y = another group such as amide, alkoxide and so on, and n = 0, 1 and 2) with primary or secondary amines leads to the formation of phosphorus(V)-nitrogen compounds. The promotion of this reaction needs to the presence of an excess amount of amine as an HX scavenger or the presence of another acid scavenger such as tertiary amines [61] or pyridine [8] (Scheme 4). In this strategy, removing of the hydrohalide salt of the organic base is a challenging task in the purification process.

The purification may be performed by stirring the crude product in water to remove the amine hydrohalide or pyridinium halide and/or may be done by selecting the solvent

Some researchers focus on decontamination of such compounds under UV-irradiation or in the presence of nano-oxides or nano-photocatalysts under sun-light [5]. The flame retardancy of some phosphoric esters was studied [6] and some phosphoramidates have therapeutic applications in the treatments of HIV and cancer [7]. Some pure chemists have interested to the NMR consideration [8], chemical calculation [9] and crystallography [10] of such compounds. A few bio-inorganic chemists have worked on the prediction of the biological properties of compounds based on their structures, with the related software programs such as PASS [11], and the evaluation of some relationships between structural features and biological activities [12]. In our laboratory, we centralize on the synthesis of new phosphorus-nitrogen and phosphorus-oxygen compounds and on obtaining their

A schematic classification for the compounds having a P(O)(N)n(O)3-n (n = 1, 2, 3) skeleton is

The numbers of the reported crystal structures in each family are presented in Scheme 3. The central box (blue) indicates the overall number of phosphoramidates having a P(O)(N)n(O)3-n (n = 1, 2, 3) skeleton; the more well-studied categories of phosphoramidates are shown as green boxes in the top and bottom of the central box namely: a) phosphoric triamides (having a P(O)(N)(N)(N) or P(O)(NHC(O))(N)(N) fragment), and b) amidophosphoric acid esters (containing a P(O)(O)(N)(N) or P(O)(O)(O)(N) skeleton).

As a nitrogen bonded H atom is very important in the H-bond pattern consideration, in the sub-categories, the presence or the absence of this H atom is clarified. In the applied notation, for example, the P(O)(NH)3 and P(O)(N)3 denote to the presence of secondary and tertiary nitrogen atoms, respectively. The phosphoramidates containing a P(O)NH2 moiety

The less-studied (so far) related compounds i.e. c) the proton-transfer and phosphate salts and the acids, and d) the anhydride compounds with a P(O)(O)P(O) skeleton are shown in

In this flowchart, the skeletons of 643 compounds -which their crystal structures were deposited- have been collected. In this classification, the phosphoramidates containing the

The reaction of phosphorus(V)-halogen compounds of the type P(O)X3-nYn (X = halide, Y = another group such as amide, alkoxide and so on, and n = 0, 1 and 2) with primary or secondary amines leads to the formation of phosphorus(V)-nitrogen compounds. The promotion of this reaction needs to the presence of an excess amount of amine as an HX scavenger or the presence of another acid scavenger such as tertiary amines [61] or pyridine [8] (Scheme 4). In this strategy, removing of the hydrohalide salt of the organic base is a

The purification may be performed by stirring the crude product in water to remove the amine hydrohalide or pyridinium halide and/or may be done by selecting the solvent

phosphorus-carbon and the phosphorus-halogen bonds have not been considered.

**2. Synthesis and purification of phosphoramidates and phosphoric acid** 

suitable single crystals for the X-ray crystallography experiments [13-64].

are distinguished in the left side box directly related to the central box.

the right and the left of the central box.

challenging task in the purification process.

shown in Scheme 3.

**esters** 

Scheme 3. The classification of compounds having a P(O)(N)n(O)3-n (n = 1, 2, 3) skeleton

which the salt is as precipitate (and the product is soluble) and then the filtering off the salt. Moreover, if more than twice mole ratio of amine relative to each P-X bond is used, removing the un-reacted amine should be done in the purification process, too, which may be performed by stirring the crude product in a diluted hydrochloric acid [65].

Setzer and co-workers reported the synthesis of 1,3,2-oxazaphospholane from the reaction between (lR,2R)-(-)-pseudoephedrine, phenyl dichlorophosphate and triethylamine in ethyl acetate. Triethylamine hydrochloride was filtered off and the solvent removed from the filtrate under reduced pressure [66].

Phosphoramidates: Molecular Packing and Hydrogen

further experiments.

crystal structure of [(C6H11)2NH2]+Cl-

C4H9)(C6H11)][PO2Cl2] was obtained [75].

preparation of their alkaline complexes.

Bond Strength in Compounds Having a P(O)(N)n(O)3-n (n = 1, 2, 3) Skeleton 569

synthesis. For a bulky amine such as *iso*-propylbenzyl amine or di-cyclohexyl amine as a nucleophile, it seems that a totally-dried solvent is better; of course, it needs to approve with

In the case of *iso*-propylbenzyl amine as nucleophile, the reactions with [C6H5O]P(O)Cl2, [C6H5O]2P(O)Cl or 4-F-C6H4C(O)NHP(O)Cl2 were not successful to prepare the pure [C6H5O]P(O)[N(CH(CH3)2)(CH2C6H5)]2, [C6H5O]2P(O)[N(CH(CH3)2)(CH2C6H5)] and 4-F-C6H4C(O)NHP(O)[N(CH(CH3)2)(CH2C6H5)]2; however, the crystal structures of two polymorphs of [NH2(CH(CH3)2)(CH2C6H5)]Cl were obtained [71,72]. With using this amine, the compounds [4-NO2-C6H4C(O)NH]P(O)[N(CH(CH3)2)(CH2C6H5)]2 [51], [NH2(CH(CH3)2) (CH2C6H5)][CCl3C(O)NHP(O)(O)[OCH3]] [40] and [NH2(CH(CH3)2)(CH2C6H5)][CF3C(O) NHP(O)(O)(N(CH(CH3)2)(CH2C6H5))] [73] were prepared which structurally studied, too. In the case of [NH2(CH(CH3)2)(CH2C6H5)][CCl3C(O)NHP(O)(O)[OCH3]] salt, for example, it seems that the presence of a few amount of H2O in solvent (or environment) leads to the formation of CCl3C(O)NHP(O)(OH)Cl which the proton-transfer reaction with the amine produces [NH2(CH(CH3)2)(CH2C6H5)][CCl3C(O)NHP(O)(O)Cl] and then crystallization in methanol replaces the Cl with OCH3. Moreover, from the reaction of P(O)(OC6H5)Cl2 and NH(C6H11)2, the related pure amido phosphoric acid ester was not achieved; however, the

 was obtained [74]. We are going to try to synthesize neutral phosphoramidate compounds with this and the other bulky amines. A similar feature was observed for the reaction of POCl3 with *tert*-butyl cyclohexyl amine in CHCl3 under reflux condition, where the salt [NH2(*tert*-

The moisture led to the formation of some undesirable but interesting products such as X2P(O)OP(O)X2 (X = (CH3)3CNH [76], C6H4(2-CH3)NH [48] and C6H4(4-CH3)NH [77]) from the reaction of P(O)Cl3 and corresponding amine (1 to 6 or more mole ratio) , and also formation of [3-F-C6H4C(O)NH][(CH3)3CNH]P(O)(O)P(O)[NHC(CH3)3][NHC(O)C6H4(3-F)] [78] from the reaction of 3-F-C6H4C(O)NHP(O)Cl2 and *tert*-butyl amine. Another salt, [*tert*-C4H9NH2][CF3C(O)NHP(O)(O)NH(*tert*-C4H9)].0.333CH3CN.0.333H2O, was also obtained [79]. N-methyl cyclohexyl amine showed an interesting feature in some examples which may be accidental needing to further considerations. In the reaction of 4-CH3C6H4S(O)2NHP(O)Cl2 with an excess amount of NH(CH3)(C6H11) (1:5 mole ratio), the product is a proton-transfer compound, [NH2(CH3)(C6H11)][4-CH3-C6H4S(O)2NP(O)[N(CH3)(C6H11)]2] [23]; furthermore, the crystal structures of [NH2(CH3)(C6H11)][CF3C(O)NP(O)[N(CH3)(C6H11)]2] [80] and [NH2(CH3)(C6H11)][CCl3C(O)NP(O)[N(CH3)(C6H11)]2] [81] were obtained, but in an effort to

Synthesis of such proton-transfer compounds through stirring a mixture of a few examined amines (NHR1R2) and a synthesized phosphoric triamide (CF3C(O)NHP(O)[NR1R2]2) were

Another strategy for preparation of phosphoramidate compounds is the application of

The P-N bond formation between an amide, of the type RC(O)NH2, and a phosphorus(V) site may be performed *via* a two-stages reaction, which is shown for PCl5 in Scheme 5,

sodium amide salts which produces sodium halide as a by-product [82] (Scheme 4).

not successful; however, this also needs to some further experiments.

Scheme 4. A common route for the synthesis of phosphoramidates

This method may be developed to the reaction between phenols and phosphorus-chlorine compounds. Selecting of a suitable solvent, which triethylamine hydrochloride or the other salt is low-soluble, develops the synthesis of some initial phosphorus-chlorine compounds such as [(CH3)(C6H11)N]P(O)Cl2 [67], [4-CH3C6H4NH]P(O)Cl2 [68], [C6H5O][4- CH3C6H4NH]P(O)Cl [69] and so on. For example, *para*-toluidine hydrochloride is relatively insoluble in CH3CN; so, the reaction of P(O)Cl3 or [C6H5O]P(O)Cl2 with 4-CH3-C6H4NH2 (1:2 mole ratio) respectively leads to the formation of [4-CH3C6H4NH]P(O)Cl2 [68] and [C6H5O][4-CH3C6H4NH]P(O)Cl [69] which are soluble in acetonitrile, whereas *para*-toluidine hydrochloride is simply filtered off.

Selection of a suitable solvent for such reactions leads to avoid from the time tedious purification methods such as column chromatography. Recently, we are developing this simple strategy for the synthesis of new phosphorus-chlorine compounds such as [C6H5O]P(O)[NHC6H11]Cl, CF3C(O)NHP(O)[NHC6H4(4-CH3)]Cl, [C6H11NH]P(O)Cl2 and [(C6H5CH2)2N]P(O)Cl2 [70].

With starting from P(O)Cl3 or PCl5 as initial phosphorus-chlorine compounds to reaction with an amine, surely a dry solvent is needed. A fully de-watered solvent is obtained by refluxing of a relatively dry solvent in the presence of a very efficient drying agent such as P2O5 (for CCl4 and CHCl3) or sodium (for CH3OH, C2H5OH, C6H6 and C6H5CH3) and distilling the totally dried solvent. However, it seems that the sensitivity of a YP(O)Cl2 starting material (Y = amide, alkoxy, phenoxy and so on) is very reduced to the moisture and the solvent which was dried with a moderate desiccant (such as CaCl2) is good for the

or

or

This method may be developed to the reaction between phenols and phosphorus-chlorine compounds. Selecting of a suitable solvent, which triethylamine hydrochloride or the other salt is low-soluble, develops the synthesis of some initial phosphorus-chlorine compounds such as [(CH3)(C6H11)N]P(O)Cl2 [67], [4-CH3C6H4NH]P(O)Cl2 [68], [C6H5O][4- CH3C6H4NH]P(O)Cl [69] and so on. For example, *para*-toluidine hydrochloride is relatively insoluble in CH3CN; so, the reaction of P(O)Cl3 or [C6H5O]P(O)Cl2 with 4-CH3-C6H4NH2 (1:2 mole ratio) respectively leads to the formation of [4-CH3C6H4NH]P(O)Cl2 [68] and [C6H5O][4-CH3C6H4NH]P(O)Cl [69] which are soluble in acetonitrile, whereas *para*-toluidine

Selection of a suitable solvent for such reactions leads to avoid from the time tedious purification methods such as column chromatography. Recently, we are developing this simple strategy for the synthesis of new phosphorus-chlorine compounds such as [C6H5O]P(O)[NHC6H11]Cl, CF3C(O)NHP(O)[NHC6H4(4-CH3)]Cl, [C6H11NH]P(O)Cl2 and

With starting from P(O)Cl3 or PCl5 as initial phosphorus-chlorine compounds to reaction with an amine, surely a dry solvent is needed. A fully de-watered solvent is obtained by refluxing of a relatively dry solvent in the presence of a very efficient drying agent such as P2O5 (for CCl4 and CHCl3) or sodium (for CH3OH, C2H5OH, C6H6 and C6H5CH3) and distilling the totally dried solvent. However, it seems that the sensitivity of a YP(O)Cl2 starting material (Y = amide, alkoxy, phenoxy and so on) is very reduced to the moisture and the solvent which was dried with a moderate desiccant (such as CaCl2) is good for the

2 NHR1R2 (or NaNR1R2)

[NH2R1R2]X (or NaX)

[NH(C2H5)3]X (or [C5H5NH]X)

NHR1R2 + N(C2H5)3 (or C5H5N)

P

Y

+

+

Scheme 4. A common route for the synthesis of phosphoramidates

<sup>X</sup> <sup>Y</sup>

P

Y

<sup>N</sup> <sup>Y</sup>

R2

hydrochloride is simply filtered off.

[(C6H5CH2)2N]P(O)Cl2 [70].

R1

O

O

synthesis. For a bulky amine such as *iso*-propylbenzyl amine or di-cyclohexyl amine as a nucleophile, it seems that a totally-dried solvent is better; of course, it needs to approve with further experiments.

In the case of *iso*-propylbenzyl amine as nucleophile, the reactions with [C6H5O]P(O)Cl2, [C6H5O]2P(O)Cl or 4-F-C6H4C(O)NHP(O)Cl2 were not successful to prepare the pure [C6H5O]P(O)[N(CH(CH3)2)(CH2C6H5)]2, [C6H5O]2P(O)[N(CH(CH3)2)(CH2C6H5)] and 4-F-C6H4C(O)NHP(O)[N(CH(CH3)2)(CH2C6H5)]2; however, the crystal structures of two polymorphs of [NH2(CH(CH3)2)(CH2C6H5)]Cl were obtained [71,72]. With using this amine, the compounds [4-NO2-C6H4C(O)NH]P(O)[N(CH(CH3)2)(CH2C6H5)]2 [51], [NH2(CH(CH3)2) (CH2C6H5)][CCl3C(O)NHP(O)(O)[OCH3]] [40] and [NH2(CH(CH3)2)(CH2C6H5)][CF3C(O) NHP(O)(O)(N(CH(CH3)2)(CH2C6H5))] [73] were prepared which structurally studied, too.

In the case of [NH2(CH(CH3)2)(CH2C6H5)][CCl3C(O)NHP(O)(O)[OCH3]] salt, for example, it seems that the presence of a few amount of H2O in solvent (or environment) leads to the formation of CCl3C(O)NHP(O)(OH)Cl which the proton-transfer reaction with the amine produces [NH2(CH(CH3)2)(CH2C6H5)][CCl3C(O)NHP(O)(O)Cl] and then crystallization in methanol replaces the Cl with OCH3. Moreover, from the reaction of P(O)(OC6H5)Cl2 and NH(C6H11)2, the related pure amido phosphoric acid ester was not achieved; however, the crystal structure of [(C6H11)2NH2]+Cl was obtained [74].

We are going to try to synthesize neutral phosphoramidate compounds with this and the other bulky amines. A similar feature was observed for the reaction of POCl3 with *tert*-butyl cyclohexyl amine in CHCl3 under reflux condition, where the salt [NH2(*tert*-C4H9)(C6H11)][PO2Cl2] was obtained [75].

The moisture led to the formation of some undesirable but interesting products such as X2P(O)OP(O)X2 (X = (CH3)3CNH [76], C6H4(2-CH3)NH [48] and C6H4(4-CH3)NH [77]) from the reaction of P(O)Cl3 and corresponding amine (1 to 6 or more mole ratio) , and also formation of [3-F-C6H4C(O)NH][(CH3)3CNH]P(O)(O)P(O)[NHC(CH3)3][NHC(O)C6H4(3-F)] [78] from the reaction of 3-F-C6H4C(O)NHP(O)Cl2 and *tert*-butyl amine. Another salt, [*tert*-C4H9NH2][CF3C(O)NHP(O)(O)NH(*tert*-C4H9)].0.333CH3CN.0.333H2O, was also obtained [79].

N-methyl cyclohexyl amine showed an interesting feature in some examples which may be accidental needing to further considerations. In the reaction of 4-CH3C6H4S(O)2NHP(O)Cl2 with an excess amount of NH(CH3)(C6H11) (1:5 mole ratio), the product is a proton-transfer compound, [NH2(CH3)(C6H11)][4-CH3-C6H4S(O)2NP(O)[N(CH3)(C6H11)]2] [23]; furthermore, the crystal structures of [NH2(CH3)(C6H11)][CF3C(O)NP(O)[N(CH3)(C6H11)]2] [80] and [NH2(CH3)(C6H11)][CCl3C(O)NP(O)[N(CH3)(C6H11)]2] [81] were obtained, but in an effort to preparation of their alkaline complexes.

Synthesis of such proton-transfer compounds through stirring a mixture of a few examined amines (NHR1R2) and a synthesized phosphoric triamide (CF3C(O)NHP(O)[NR1R2]2) were not successful; however, this also needs to some further experiments.

Another strategy for preparation of phosphoramidate compounds is the application of sodium amide salts which produces sodium halide as a by-product [82] (Scheme 4).

The P-N bond formation between an amide, of the type RC(O)NH2, and a phosphorus(V) site may be performed *via* a two-stages reaction, which is shown for PCl5 in Scheme 5,

Phosphoramidates: Molecular Packing and Hydrogen

Scheme 7. A bicyclic phosphoric triamide

N

N

Nu

N H

alcoholysis

N P

Ar O

Nu

Ar

**3. Crystallization of phosphoramidates** 

at room temperature after slow evaporation of the solvent.

**4. General features of phosphoramidate compounds** 

*Compounds with formula RC(O)NHP(O)[NR1R2]2 and RC(O)NHP(O)[NHR1]2*

N

O

Ar

RHN Base-promoted alcoholysis

P

Bond Strength in Compounds Having a P(O)(N)n(O)3-n (n = 1, 2, 3) Skeleton 571

P

N N

<sup>O</sup> Ar Ar

N

Scheme 8. The obtained products from the solvolysis of 1-oxo-2,8-diphenyl-2,5,8-triaza-1 λ5-

The convenient solvents for obtaining suitable single crystals for the studied compounds may be CH3C(O)CH3, CHCl3, CHCl3/n-C7H16, CH2Cl2, CH3CN, CH3CN/CH3OH, CH3CN/CHCl3, CH3OH, CH3OH/H2O, C2H5OH/n-C6H14, (CH3)2CHOH/n-C6H14, (CH3)2NC(O)H/CHCl3, (CH3)2NC(O)H/CH3OH and n-C6H14. The crystal may be obtained

The four different groups linked to the P atom result in a distorted tetrahedral configuration; as one instance, the bond angles around the P atom of P(O)[NHC(O)CF3][NHCH2C6H4(2-Cl)]2 range from 102.67(12)° to 117.60(12)° [87]. In the

phosphabicyclo[3.3.0]octane under base-promoted alcoholysis and acid-catalyzed

Acid-catalyzed alcoholysis

showing the reaction of PCl5 with an amide and then the treatment of HCOOH. Moreover, a few efforts have been devoted to the synthesis of RS(O)2NHP(O)Cl2 by a similar procedure [23].

Scheme 5. Synthesis of RC(O)NHP(O)Cl2

The simple mentioned methods for the preparation of phosphoramidates from the reaction of phosphorus-chlorine compounds and amines may be extended to the diamines or amino alcohols to produce cyclic [83] or bridged compounds [61].

The preparation of some compounds containing the P-Cl bonds, such as 4- CH3C6H4OP(O)Cl2 and [(CH3)2N]P(O)Cl2, were performed through the reaction between corresponding phenol derivatives or amine hydrochloride salts [for example *para*-cresol or dimethylamine hydrochloride salt for the mentioned phosphorus-chlorine compounds] with an excess amount of POCl3 and then the removal of the remaining POCl3 in a reduced pressure [32,47].

Some compounds were synthesized by the reaction of P-H compounds (such as dimethylphosphine oxide, (CH3)2P(O)H and *N*,*N*-disubstituted derivatives of 5,6-benzo-2H-2-oxo-1,3,2λ4-diazaphosphorinan-4-one, Scheme 6) with ketones [84].

Scheme 6. 5,6-benzo-2H-2-oxo-1,3,2λ4-diazaphosphorinan-4-one

Wan and Modro developed the synthesis of a bicyclic phosphoric triamide (Scheme 7) *via*  the base-promoted cyclization of the corresponding 3-(2-chloroethyl)-2-oxo-1-aryl-2 arylamino-1,3,2-diazaphospholidine [85].

Mbianda and co-workers reported the solvolysis of 1-oxo-2,8-diphenyl-2,5,8-triaza-1 λ5 phosphabicyclo[3.3.0]octane under base-promoted alcoholysis and acid-catalyzed alcoholysis. Scheme 8 shows the two different products of such solvolysis reactions [86].

Scheme 7. A bicyclic phosphoric triamide

showing the reaction of PCl5 with an amide and then the treatment of HCOOH. Moreover, a few efforts have been devoted to the synthesis of RS(O)2NHP(O)Cl2 by a similar procedure

**RC(O)NPCl3**

The simple mentioned methods for the preparation of phosphoramidates from the reaction of phosphorus-chlorine compounds and amines may be extended to the diamines or amino

The preparation of some compounds containing the P-Cl bonds, such as 4- CH3C6H4OP(O)Cl2 and [(CH3)2N]P(O)Cl2, were performed through the reaction between corresponding phenol derivatives or amine hydrochloride salts [for example *para*-cresol or dimethylamine hydrochloride salt for the mentioned phosphorus-chlorine compounds] with an excess amount of POCl3 and then the removal of the remaining POCl3 in a reduced

Some compounds were synthesized by the reaction of P-H compounds (such as dimethylphosphine oxide, (CH3)2P(O)H and *N*,*N*-disubstituted derivatives of 5,6-benzo-2H-

N

Wan and Modro developed the synthesis of a bicyclic phosphoric triamide (Scheme 7) *via*  the base-promoted cyclization of the corresponding 3-(2-chloroethyl)-2-oxo-1-aryl-2-

Mbianda and co-workers reported the solvolysis of 1-oxo-2,8-diphenyl-2,5,8-triaza-1 λ5 phosphabicyclo[3.3.0]octane under base-promoted alcoholysis and acid-catalyzed alcoholysis. Scheme 8 shows the two different products of such solvolysis reactions [86].

CH3

C

O

P

O

N

R

H

**HCOOH**

**O**

**P HN Cl**

**R O**

**Cl**

[23].

**PCl5 + RC(O)NH2**

pressure [32,47].

Scheme 5. Synthesis of RC(O)NHP(O)Cl2

alcohols to produce cyclic [83] or bridged compounds [61].

2-oxo-1,3,2λ4-diazaphosphorinan-4-one, Scheme 6) with ketones [84].

Scheme 6. 5,6-benzo-2H-2-oxo-1,3,2λ4-diazaphosphorinan-4-one

arylamino-1,3,2-diazaphospholidine [85].

Scheme 8. The obtained products from the solvolysis of 1-oxo-2,8-diphenyl-2,5,8-triaza-1 λ5 phosphabicyclo[3.3.0]octane under base-promoted alcoholysis and acid-catalyzed alcoholysis
