a synthesis. The silicon chip and beads are placed in a container known as acan
that is porous to the reagents used in the synthesis. Each can is closed and
treated as though it were one bead in a mix and split synthesis. The cans are
divided into the required number of aliquots corresponding to the number of
building blocks used in the initial step of the synthesis. Each batch of cans is
reacted with its own building block and the chip is irradiated with the appropri-
ate radio signal for that building block. The mix and split procedure is followed
and at each step the chips in the batch are irradiated with the appropriate radio
signal. At the end of the synthesis the prepared library compound is cleaved
from the chip, which is interrogated to determine the history of the compound
synthesized on the chip. The method has the advantage of producing larger
amounts of the required compounds than the normal mix and split approach
because the same compound is produced on all the beads in a can.
6.4 Combinatorial synthesis in solution
The main problem with preparing libraries using solution chemistry is the diffi-
cultyofremovingunwantedimpuritiesateachstepinthesynthesis.Consequently,
many of the strategies used for the preparation of libraries using solution chemis-
try are directed to the purification of the products of each steps of the synthesis.
This and other practical problems has usually restricted the use of solution
combinatorial chemistry to synthetic pathways consisting of two or three steps.
Combinatorial synthesis in solution can be used to produce libraries that
consist of single compounds or mixtures using traditional organic chemistry.
Single compound libraries are prepared using the parallel synthesis technique
(see section 6.2.1). Libraries of mixtures are formed by separately reacting each
of the members of a set of similar compounds with the same mixture of all the
members of the second set of compounds. Consider, for example, a combinator-
ial library of amides formed by reacting a set of five acid chlorides (A
1–A
5) with
ten amines (B
1–B
10). Each of the five acid chlorides is reacted separately with
an equimolar mixture of all ten amines and each of the amines is reacted with an
equimolar mixture of all the acid chlorides (Figure 6.14). This produces a library
consisting of a set of five mixtures based on individual acid halides and 10
mixtures based on individual amines. This means that each compound in the
library is prepared twice, once from the acid chloride set and once from the
amine set. Consequently, determining the most biologically active of the mix-
tures from the acid halide set will define the acyl part of the most active amide
and similarly identifying the most biologically active of the amine based
COMBINATORIAL SYNTHESIS IN SOLUTION 127