The intriguing chemical mechanism of the external transesterification by which large ribozymes (group I, group II, and spliceosomal introns) splice RNA has been found to operate in the methanolysis of ribonucleoside 2'-/3'-dimethyl phosphates in non-hydrogen-bonding organic solvents. Besides needing aprotic organic media this mechanism requires a high concentration of the attacking alcohol accounting for the binding of an external guanosine by group I introns and the use of a non-adjacent internal 2'-OH by group II and spliceosomal introns. This finding is the first example of an external non-ribozymic transesterification of ribonucleotide esters and the means by which this crucial biochemical reaction can be accelerated.