The essential observation is the acceleration of both ring closure and ring opening. Furthermore, exo-
cyclic P O bond cleavage is also accelerated in five-membered cyclic esters (Figure 3.49).
How can ring strain accelerate both endocyclic and exocyclic substitution at phosphorus? The hydroly-
sis of ethylene phosphate shows incorporation of isotopic label from H 218 O solvent into P O bonds in both
acidic and alkaline conditions, and these reactions must involve an ANDN(i.e.an associative) process
(Figure 3.44a). It is generally agreed that a transient penta-coordinated phosphorane intermediate is both
stabilized and made kinetically more accessible relative to its acyclic counterpart because of the geometry
of the five-membered ring. It is then reasonable to invoke topoisomerism (in this case the pseudorotation
of the trigonal bipyramidal species) to explain most of the phenomena associated with this remarkably
enhanced reactivity (Figure 3.50).
This phenomenon is clearly important in the hydrolysis of RNA by alkali and ribonucleases. In both
cases, the 5-membered 2,3-cyclic phosphates of nucleosides are formed by the displacement of the
Nucleosides and Nucleotides 105
Table 3.1 Some rate constants for the hydrolysis of phosphate esters (25°C) and patterns of bond
cleavage
PhosphateH 2 O Phosphate monoanion PhosphateHO
kw(s^1 )H 2 O kw(s^1 ) kOH(M^1 s^1 )(MeO) 3 PO 2 10 ^8 (C O) — 2 10 ^4 (P O)
(MeO) 2 PO 2 H5 10 ^10 (C O) 2 10 ^147 10 ^12 (C O)
1 10 ^10 (P O) 1 10 ^15 (P O)138
(MeO)PO 3 H 2 1 10 ^10 (C O) 3 10 ^10 (P O) 2 10 ^20 (P O) †139
(PhO) 3 PO — — 5 10 ^3 (P O)^140
(PhO) 2 PO 2 H— 5 10 ^15 (P O)^1412 10 ^7 (P O)142
(PhO)PO 3 H 2 —2 10 ^8 (P O)^1431 10 ^13 (P O)†138
UpU^86 —— 2 10 ^3 (P O)‡
7 10 ^5 (P O)§,¶ 5 10 ^6 (P O)¶ 5 (P O)¶
Ethylene phosphate — — 5 10 ^4 (P O)144
- monoanion.
†pH-independent reaction of dianion, s (^1).
‡intramolecular transesterification at phosphate diester monoanion.
§intramolecular attack by 2OH.
¶at 90°C.
H 218 O
O
O
H
P
O
OR
OR
O
P
O
O
OR
O
P
O
OR
O
O
O
H
P
O
OH
OR
O
P
O
O
OH
exchange
ring cleavage
endocyclic exocyclic
Figure 3.49 Accelerated P O cleavages associated with 5-membered ring phosphate esters in acidic and in
alkaline solution