Nucleic Acids in Chemistry and Biology

Both C O and P O cleavage pathways (which give the same overall products) are observed. For attack
at phosphorus, associative (SN2(P): either ANDNor ANDN), mechanisms are more common than dissocia-
tive (SN1(P): DNAN) ones. The associative process is best described by invoking a 5-coordinate, trigonal
bipyramidal intermediate in which ligand positional interchange, also called pseudorotation, is usually slower
than breakdown to form products (Figure 3.44a). This leads to inversion of configuration at phosphorus. In a
fully dissociative reaction, a planar, 3-coordinate species, often described as a monomeric metaphosphate,
would be formed (Figure 3.44c). As it could capture an incoming nucleophile on either face, racemization at
phosphorus would result. However, this intermediate is not sufficiently stable to exist in aqueous solution and
real dissociative reactions involve an exploded transition state (see Section 3.2.2.4) in which the nucleophile
begins to bond with the phosphorus atom before the leaving group has fully departed (see Figure 3.52). In
between these two extremes lie concerted displacement reactions (Figure 3.44b), where bond making matches
bond breaking and the reaction involves a penta-coordinate transition state.
There has been much discussion in terms of the associativeor dissociativecharacter of transition states
for phosphoryl transfer. The associative/dissociative character is best defined according to the sum of bond

102 Chapter 3

POR'

O

B

A

R

O RO P OR'

O

AB

RO P

O

B

A

R'

O

POR'

O

B

A

R

O RO P OR'

O

AB

RO P

O

B

A

R'

O

POR'

O

B

O

+ RO

P

O

OB

RO P

O

B

O

+ R'O Solvent

• R'O
  
  
  • RO
  
  
  
  

a

b

c

Figure 3.44 Mechanisms of displacement reactions for phosphate esters. (a) Addition-elimination (ANDN)
via a pentacoordinate phosphorane intermediate; (b) synchronous displacement (SN2(P)) via a
pentacoordinate transition state; and (c) stepwise displacement (SN1(P) or DNAN) via a solvated
metaphosphate intermediate

P

O

O

O

O

R

O

P

ø

O

O

R

a b

Figure 3.43 (a) Pro-pro-chiral oxygens in a phosphate monoester; and (b) phosphate monoester chiral through
having three isotopes of oxygen

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