This thesis describes the synthesis of uniform, heterobifunctional poly(ethylene glycol) via organic
solvent nanofiltration, a scalable and cost-effective membrane-based technology that allows reactions
and purifications to be carried out in liquid medium throughout and provides access to oligomers of
commercially relevant length. This membrane-based strategy contrasts with established routes via
chromatography, extraction and solid phase synthesis.
The preparation of uniform oligomers relies on the stepwise addition of building blocks, one at a time,
over many synthetic extension cycles. To ensure uniformity, the growing oligomer requires purification
from excess building block and reaction debris after each extension. In this strategy, intermediate and
final products en route to the desired poly(ethylene glycol) oligomer are freed from impurities by
diafiltration.
In order to facilitate the removal of impurities during diafiltration, multiple oligomers are synchronously
grown on a soluble, multivalent anchor. The attachment of multiple growing oligomers onto the anchor
leads to a fast-growing product complex with enough size to be well-retained by a membrane. On the
other hand, the separable impurities consisting of much smaller building block and reaction debris can
readily pass through the membrane, resulting in an efficient separation. To enhance discrimination, the
anchor is enlarged, and the size of the functional groups on the building block minimized. Further, the
anchor is designed to be sufficiently distinct and readily detectable by UV.
A two-stage diafiltration process then allowed the synthesis of uniform, mono-methyl Eg60 (mPEG-2700)
with excellent quality (dispersity Đ = 1.0006, oligomer purity = 97 %) from an Eg12 building block in four
chain extension cycles.
It is demonstrated that deprotection and purification may be accomplished jointly via nanofiltration with a
poly(ether ether ketone) membrane that is sufficiently stable towards acidic deprotection conditions and
that spent diafiltration solvent may be partially recovered by membrane-based solvent recovery in a
closed loop.