Phosphorus nucleophiles addition-elimination

Attack by the enol at phosphorus gives an activated enol, which may further react by a nucleophilic addition-elimination process with chloride, along with formation of a P=0 containing product, which provides the driving force for the reaction. 

Now we will see how fatty acids, the other products formed from the hydrolysis of fats, are metabolized. Before a fatty acid can be metabolized, it must be activated. We have seen that a carboxylic acid can be activated in a cell by first being converted to an acyl adenylate, which occurs when the carboxylate ion attacks the a-phosphorus of ATP. The acyl adenylate then reacts with coenzyme A in a nucleophilic addition-elimination reaction to form a thioester (Section 16.23). 

Kinetic studies have shown that the enolate and phosphorus nucleophiles all react at about the same rate. This suggests that the only step directly involving the nucleophile (step 2 of the propagation sequence) occurs at essentially the diffusion-controlled rate so that there is little selectivity among the individual nucleophiles. The synthetic potential of the reaction lies in the fact that other substituents which activate the halide to substitution are not required in this reaction, in contrast to aromatic nucleophilic substitution which proceeds by an addition-elimination mechanism (see Seetion 10.5). 

In addition there are certain other methods for the preparation such compounds. Upon heating of the thionocarbonate 2 with a trivalent phosphorus compound e.g. trimethyl phosphite, a -elimination reaction takes place to yield the olefin 3. A nucleophilic addition of the phosphorus to sulfur leads to the zwitterionic species 6, which is likely to react to the phosphorus ylide 7 via cyclization and subsequent desulfurization. An alternative pathway for the formation of 7 via a 2-carbena-l,3-dioxolane 8 has been formulated. From the ylide 7 the olefin 3 is formed stereospecifically by a concerted 1,3-dipolar cycloreversion (see 1,3-dipolar cycloaddition), together with the unstable phosphorus compound 9, which decomposes into carbon dioxide and R3P. The latter is finally obtained as R3PS ... 

For example, in the instance of 9-chloroacridine, the attachment of the halogen (leaving group) at a suitably electrophilic carbon site allows the occurrence of a replacement reaction, presumably occurring via an addition-elimination procedure for phosphorus attachment, followed by the common nucleophilic displacement (ester cleavage) of the Michaelis-Arbuzov process (Figure 6.1).4... 

As well as the Bingel reaction and its modifications some more reactions that involve the addition-elimination mechanism have been discovered. 1,2-Methano-[60]fullerenes are obtainable in good yields by reaction with phosphorus- [44] or sulfur-ylides [45,46] or by fluorine-ion-mediated reaction with silylated nucleophiles [47]. The reaction with ylides requires stabilized sulfur or phosphorus ylides (Scheme 3.9). As well as representing a new route to l,2-methano[60]fullerenes, the synthesis of methanofullerenes with a formyl group at the bridgehead-carbon is possible. This formyl-group can be easily transformed into imines with various aromatic amines. 

Previous reactions in this chapter have involved only addition of the nucleophile and a hydrogen to the carbonyl group. In this reaction, addition is followed by elimination of the oxygen to form a double bond between the carbonyl carbon and the nucleophile. Such an addition-elimination reaction occurs when the nucleophile has or can generate (by the loss of a proton or a phosphorus group) a second pair of electrons that can be used to form a second bond to the electrophilic carbon. In the case of the Wittig reaction, the phosphorus and the oxygen are eliminated to form the alkene. The forma-... 

The reaction of aromatic halides with tertiary phosphines requires special reaction conditions, as they are not susceptible to the simple nucleophilic substitution reaction. Strong heating, generally in a closed pressure tube, with the tertiary phosphine in the presence of a nickel(II) halide salt allows substitution of the halogen by phosphorus, probably by way of an addition-elimination reaction. 

Bimolecular nucleophilic substitution at tetracoordinate phosphorus (Eq. (8)) may proceed by either direct (Sjq2) substitution or by an addition-elimination mechanism In the former, 16 represents a transition state, while in the... 

A few cases of nucleophilic additions to P-ketophosphonates have been reported. When the a-carbon atom to phosphorus is fully substituted, it appears unlikely that the reaction at phosphorus is competitive with the addition to carbonyl group. Thus, treatment of diethyl 1-fluoro-1-ethoxy-carbonyl-2-ethoxycarbonyl-2-oxoethylphosphonate with Grignard reagents at low temperature in THF gives an ( )/(/) mixture of a-fluoro-a,P-unsaturated diesters in 49-68% yields. The initial step is the nucleophilic attack of Grignard reagent at the carbonyl group, followed by intramolecular elimination of diethyl phosphate (Scheme 7.104). ° ... 

A novel procedure has been developed for the synthesis of phosphate esters of hindered alcohols, and was designed to avoid nucleophilic displacement reactions. It involves photolysis of the alkyl nitrite in the presence of a trialkyl phosphite and proceeds by addition of the alkoxyl radical to phosphorus followed by elimination of an alkyl group (Scheme 3). ... 

The addition-elimination reaction proceeds via addition of a nucleophile at phosphorus to generate a five-coordinate intermediate or activated complex. TTie phosphorus atom is readily able to use its d orbitals to expand its coordination number and it is argued that an attacking nucleophile such as OH" adds to the four-coordinate phosphorus to form a pentacoordinate phosphorane (143). It appears that generally the pentacoordinate intermediate will have a trigonal bipyramidal structure, although spirocyclic phosphoranes seem to favor square pyramidal structures (80). 

The major product in the reaction of the allyl anion with trimethylphosphite involves nucleophilic attack at phosphorus with subsequent elimination of methanol (equation 64) A similar series of addition/elimination reactions between several carbanions and trimethylphosphine have been observed in a flowing afterglow reactor (equation 65). In contrast, various carbanions react with trimethylphosphate via S 2 displacement at carbon (equation 66) ... 

The structural features of organophosphorus esters, which are very similar to those of the carboxylic acid esters, suggest that nucleophilic displacement at the central phosphorus atom will occur by an addition-elimination mechanism. Mechanistic studies, however, have demonstrated that hydrolysis occurs through direct nucleophilic displacement at phosphorus and does not involve formation of a pen-tavalent intermediate with H2O or OH (Hudson, 1965 Kirby and Warren, 1967). Accordingly, hydrolysis rates for phosphorus esters will be sensitive to electronic factors that alter the electrophilicity of the central phosphorus atom and steric interaetions that impede nucleophilic attack. 

There are two types of P(V) compounds, i.e., the pentacovalent and the ionic phosphonium salts. The most famUiar outcome of the attack at a pentacovalent phosphorus atom by nucleophiles is substitutive fragmentation. On the other hand, there are numerous ways for a nucleophile to attack R4P compounds direct Sn2 displacement, simple addition, and addition-elimination. Many reactions, especially the biphilic processes, involve formation of R4P compounds followed by a counterion-initiated decomposition. The Arbuzov and Perkov reactions are representative. 

Addition of phosphorus nucleophiles to electron-poor aromatic sp carbons, followed by elimination, is a basis for the reactions in which pyridylphosphonate derivatives of dinucleotides were obtained (Schemes 47.44 and 47.45). The pyridine ring can be activated to nucleophilic attack by an appropriate substituent on the nitrogen atom. When the bulky triphenylmethyl (trityl) group was used for this... 

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