Concerted phosphoryl transfer

Sn2 and related concerted reactions (concerted phosphoryl transfer, concerted acyl transfer) have proven difficult to treat by NBT. The difficulty here is that... 

Fig. 8 Potential mechanisms for hydrolysis of phosphomonoester monoanions. In mechanism (a), proton transfer from the phosphoryl group to the ester oxygen (probably via the intermediacy of a water molecule) yields an anionic zwitterion intermediate. This may react in either concerted fashion (upper pathway) or via a discrete metaphosphate intermediate in a preassociative mechanism (bottom pathway). Mechanism (b) denotes proton transfer concerted with P-O(R) bond fission. As with (a), such a mechanism could either occur with concerted phosphoryl transfer to the nucleophile (upper pathway) or via a discrete metaphosphate intermediate in a preassociative mechanism (bottom pathway).

Figure 17 A transition state for a concerted phosphoryl transfer between the aspartylphosphate carrier and G6P (left), and a transition state analogue formed from /3-G6P, magnesium, and fluoride (right). ...

For acyl transfer, phosphoryl transfer, and sulfonyl transfer, the primary kind of evidence in favor of concerted mechanisms for some reactions is a linear Bronsted plot of log k versus for a range of nucleophiles, spanning p/ir/ = - p r s = 0, coupled... 

Fig. 2 The dissociative, associative, and concerted mechanistic pathways of phosphoryl transfer. The dissociative and concerted mechanisms are shown for the dianion form of a phosphomonoester. The associative mechanism is shown for a phosphotriester.

Other phosphoryl transfer mechanisms are an associative, two-step mechanism (An + Dn) and a concerted mechanism (ANDN) with no intermediate. The AN+DN mechanism is an addition-elimination pathway in which a stable pentacoordinate intermediate, called a phosphorane, is formed. This mechanism occurs in some reactions of phosphate triesters and diesters, and has been speculated to occur in enzymatic reactions of monoesters. In the concerted ANDN mechanism, bond formation to the nucleophile and bond fission to the leaving group both occur in the transition state. This transition state could be loose or tight, depending upon the synchronicity between nucleophilic attack and leaving group departure. The concerted mechanism of Fig. 2 is drawn to indicate a loose transition state, typical of phosphate monoester reactions. 

Scheme 5 A model for the mechanism of the phosphotriesterase reaction. The data do not clearly distinguish between a concerted mechanism of phosphoryl transfer, or a phosphorane intermediate in the model above the reaction is shown as a concerted process. In either case, the P-OLg bond is largely broken in the transition state, requiring that breakdown of any putative intermediate is rate-limiting for less activated substrates. For more labile substrates, such as paraoxon, a step involving proton transfer that occurs after phosphoryl transfer is rate-limiting.

Hydrolysis of Phosphates. The conclusion that phosphoryl transfer between amines is concerted does not exclude the formation of a metaphosphate intermediate in reactions with weaker nucleophiles, including water. Pyridine is a much stronger nucleophile than water and it is possible that phosphoryl transfer between pyridines is concerted because the metaphosphate ion does not have a significant lifetime in the presence of pyridine the metaphosphate ion might exist for a short time in water. However, it is much more difficult to determine whether or not the mechanism is concerted for a reaction with water than for a reaction with pyridine. 

In ah initio calculations, the species was modeled separately with MgFj and with P03 as the central moiety. " In the case of MgFj , an energy minimum was obtained with a geometry that corresponded well with the X-ray structure. When modeled as P03 the species is unstable, and resembles instead a transition state for phosphoryl transfer (with a moderate barrier of 14kcalmol ) from substrate G6P to the product glucose-1,6-diphosphate. The computationally modeled reaction is concerted with no phosphorane intermediate. ... 

Fig. 2. The dissociative and associative mechanistic extremes, and the concerted pathway for phosphoryl transfer. The concerted pathway is drawn to indicate the dissociative transition state, which is typical of phosphate monoester reactions, but in principle could have a transition state at any point between the mechanistic extremes. The sum of the bond orders to the nucleophile and leaving group is less than in the substrate in a dissociative transition state and is greater in an associative transition state.

Uncatalyzed Reactions of Phosphate Monoesters. Phosphate monoesters in physiologically relevant pH ranges exist as either the monoanion or dianion. A large body of evidence indicates that uncatalyzed phosphoryl transfer reactions of both ionic forms takes place by loose transition states that are characterized by extensive bond cleavage to the leaving group and a small degree of bond formation to the nucleophile (for reviews of the evidence, see References (3,4)). Despite loose transition states, these reactions are concerted, and free metaphosphate is not formed in protic solvents (5). 

Fig. 3. Two mechanistic possibilities for phosphoryl transfer of the monoanionic species of a phosphate monoester (a) stepwise transfer of the proton to the bridge oxygen atom in a preequilibrium step (b) proton transfer concerted with P-0 bond cleavage.

Concerted mechanisms are possible for acyl, phosphoryl, and sulfonyl transfer. By thinking about the stepwise limits for each possible concerted process, one can, even with quite crude calculations, make some judgment about the feasibility of the concerted process. This area of chemistry is as yet unsettled and will see some changes in what is now generally accepted. 

Scheme 4 Transfer of the phosphoryl group between pyridine nucleophiles - an open concerted mechanism shown also is the charge distribution in the transition structure and that expected for two putative intermediates...

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