Halides, phosphorus, reactivity

Incompatibilities and Reactivities Water, combustible substances, halides, phosphorus, turpentine [Note Reacts violently in water forms chromic acid, chromic chloride, hydrochloric acid chlorine. Corrodes common metals.]... 

Again one might expect that the benzoderivatives of aromatic six-membered ring imidoyl halides have reactive halo groups. Recently, an interesting route to six-membered ring benzimidoyl chlorides has been reported ( ). Reaction of o-cyanomethylbenzoic acid (LV) with 2 moles of phosphorus pentachloride produces 1,3-dichloroisoquinoline (LVI). 

Diesters of phosphorous acid are in general neutral because the phosphorous acid exists mostly in the phosphonate form with one hydrogen directly attached to the phosphorus. But with alkali metals the H can be changed against the alkali and reactive intermediates formed. Such alkali metal derivatives of dialkyl phosphites react with alkyl halides to give dialkyl alkanephosphonates, according to Eqs. (45) and (46). 

B. Reactions.—(/) Nucleophilic Attack at Phosphorus. A reinvestigation of the reaction between phosphorus trichloride and t-butylbenzene in the presence of aluminium chloride has shown that the product after hydrolysis is the substituted phosphinic acid (11), and not the expected phosphonic acid (12). Bis(A-alkylamino)phosphines have been reported to attack chlorodiphenyl phosphine with nitrogen, in the presence of a base, to give bis-(A-alkyl-A-diphenylphosphinoamino)phenylphosphines (13). In (13), the terminal phosphorus atoms are more reactive than the central one towards sulphur and towards alkyl halides. 

B. Aryl Derivatives.—The Ph3P=N group imparts high nucleophilic reactivity to the tervalent phosphorus atom in A -(diphenylphosphino)tri-phenylphosphazene, Ph3p=N PPha- Ready reactions occur with methyl iodide, phosphorus(in) halides, and bromine ... 

In absence of diluent or other effective control of reaction rate, the sulfoxide reacts violently or explosively with the following acetyl chloride, benzenesul-fonyl chloride, cyanuric chloride, phosphorus trichloride, phosphoryl chloride, tetrachlorosilane, sulfur dichloride, disulfur dichloride, sulfuryl chloride or thionyl chloride [1], These violent reactions are explained in terms of exothermic polymerisation of formaldehyde produced under a variety of conditions by interaction of the sulfoxide with reactive halides, acidic or basic reagents [2], Oxalyl chloride reacts explosively with DMSO at ambient temperature, but controllably in dichloromethane at -60°C [3]. 

The most important derivatives of the amino acids are halides and esters. The most reactive are the halides, which, as described by Emil Fischer, can be obtained by shaking dry amino acids with phosphorus pentachloride in acetyl chloride. 

Detailed investigations of the chemical reactivity of the diketiminato-stabilized phosphenium cations like 28 (Scheme 17) are to date rare and include only two reports dealing with the substitution and reduction of P-halogen-derivatives. Thus, reaction of 28 (X=Br) with sodium hydroxide in toluene was reported to proceed with displacement of the halide substituent at phosphorus and conservation of the heterocyclic ring to give a mixture of bromide and triflate salts containing a P-hydroxy-substituted cation, both of which were isolated in small yields [89], The products are remarkable as they represent one of very few examples of a stable phosphinous acid which does not rearrange to the tautomeric secondary phosphine oxide. Potassium reduction of the P-chloro-substituted derivative 34 produced the... 

Several methods for the preparation of the parent compound in this system, tris(trimethylsilyl)phosphite, have been reported.114 118 The application of this and related reagents in reaction with alkyl halides has been reported and used for the preparation of a variety of phosphonic acid analogues of phospholipids.114119-124 Interestingly, alkyl chlorides appear to be more reactive with the silyl reagents than do alkyl iodides, a reversal of the normally observed trend with alkyl esters of the phosphorus acids. (The particular use of silyl phosphorus reagents for the synthesis of biologically significant compounds has... 

Of course, the high reactivity of the Grignard reagents can be used to good advantage for exhaustive alkylation or arylation in the preparation of a wide range of phosphorus halides and esters.43 18... 

A range of mechanisms is possible for the acidolysis of phosphorus amides, depending on the nucleophilicity of the departing amine. A recent study of phosphinic amides (160) in acidic media demonstrated that, when R2 is aryl, the presence of an o-Me group reduced the hydrolysis rate significantly, and also that the mechanism appears to be of an associative type.128 The phosphinic halides (161 X = Cl or F R = Me) are more reactive, probably for steric reasons, than the corresponding halides (161 R = Bu1) in 5 n2(P) solvolyses with aqueous acetone and with alkali. In the case of the t-butyl compounds, the fluoride is more reactive to OH- than is the chloride.129... 

Reaction of 2-methylpyridine iV-oxide with p-toluenesulfonyl chloride or phosphorus oxychloride gives 2-pyridylmethyl chloride (Scheme 47), and related reactions with reactive halides have also been studied (62JOC3856, 81JHC939). 

Antimony(III) halides are chemically reactive, but less so than their phosphorus or arsenic analogues. Antimony(III) chloride forms a clear solution with water, and there is no evidence for Sb3+ ions dilution results in precipitation of insoluble oxychlorides of various compositions, e.g. SbOCl, Sb405a2, SbsOuCl2. Some reactions of SbCl3 are shown in Scheme 3. Antimony(III) fluoride is an important fluorinating agent. 

The reactive 3-carbonyl group in compounds of type (279) undergoes aldol condensation with active methylene compounds such reactions of isatin with indoxyl, oxindole (Section 3.3.2.5.4) and with thiophenes (Section 3.3.1.5.7.ii) have already been mentioned. These compounds also react with Grignard reagents and phosphorus halides as expected, e.g. isatin (279 Z = NH) with MeMgBr and PC13 yields (285) and (286), respectively. 

In contrast to the inertness of carbon halides, the halides of silicon and phosphorus are extremely reactive with water, to the extent that they must be protected from atmospheric moisture. A clue to the reactivity of these halides is provided hy the somewhat Similar reactivity of acid halides which readily react with water... 

A number of other metallic halide salts have been found to condense with ethylene oxide, propylene oxide, or epichlorohydrin in a similar fashion (Eq. 662). Among them are phosphorus trichloride/ 7- a 17 bismuth trichloride,1SM arsenic trichloride,1000 silicon tetrachloride/7 1 titanium tetrachloride/ 09 16,7 beryllium chlorido/189 and Won trifluoride.401 Depending on their reactivity, on the reactant ratio, and... 

Peptidomimetics in which one amide bond is replaced by a phosphinic acid (R-P(0H)(=0)-R phosphinic peptides ) are of interest as potential protease inhibitors [17-19]. These compounds have been prepared either from orthogonally protected phosphorus-containing monomers [17,18,20], or by forming the phosphorus-containing fragments on solid phase, as sketched in Figure 11.4 [19,21], Phosphinic acids have been prepared on solid phase mainly by reaction of carbon electrophiles with monoalkylphosphinates. As carbon electrophiles, acrylates, aldehydes, reactive alkyl halides, or a, 3-unsaturated ketones can be used. 

Acylation. Acylation is the most reliable means of introducing a 3-substituent on the indole ring. Because 3-acyl substituents can be easily reduced to 3-alkyl groups, a two-step acylation—reduction sequence is often an attractive alternative to direct 3-alkylation. Several kinds of conditions have been employed for acylation. Very reactive acyl halides, such as oxalyl chloride, can effect substitution direcdy without any catalyst. Normal acid chlorides are usually allowed to react with the magnesium (15) or zinc (16) salts. The Vilsmeier-Haack conditions involving an amide and phosphorus oxychloride, in which a chloroiminium ion is the active electrophile, frequendy give excellent yields of 3-acylindoles. 

This variation of the Wittig reaction uses ylides prepared from phosphonates.12 The Horner-Wadsworth-Emmons method has several advantages over the use of phosphoranes. These ylides are more reactive than the corresponding phosphoranes, especially when substituted with an electron withdrawing group. In addition the phosphorus product is a phosphate ester and soluble in water - unlike the Ph3PO product of the Wittig reaction - which makes it easy to separate from the olefin product. Phosphonates are also cheaper than phosphonium salts and can easily be prepared by the Arbuzov reaction from phosphanes and halides. 

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