Date: 23 July 2026 | Category: Headline News, News
Authors: Sebastián Pinzón-López, Dominik Ebert, Matthias Kraume, Peter H. Seeberger, José Danglad-Flores
Peter Seeberger, José Danglad-Flores and co-workers from Technische Universität Berlin have investigated the solvent-dependent swelling of the cross-linked polymer resins that are widely used as solid supports within solid-phase synthesis (SPS).[1] More specifically, the swelling behaviour of spherical polystyrene–divinylbenzene (PS–DVB, 1% cross-linked) resins in both dichloromethane (DCM) and dimethylformamide (DMF) was analysed from both a thermodynamic and a kinetic perspective. Key differences in swelling behaviour were observed depending on the biomolecule attached to the resin. Glycans increased the polymer–solvent affinity in DCM, leading to greater swelling, whereas peptides reduced the affinity and therefore the extent of swelling.
Solid phase synthesis in modern organic chemistry
Solid phase synthesis (SPS) is an enabling technology that allows molecules to be assembled on a polymer resin. A key feature of this approach is that the substrate is tethered to functional groups throughout the polymer resin and then functionalised step by step. Reagents are usually used in excess to drive reactions to completion quickly. A significant advantage is that by-products can, largely, be washed away by rinsing the resin with solvents, meaning that upon cleavage the final product has high purity. This approach is often used in solid phase peptide synthesis (SPPS), and can be readily scaled, enabling rapid synthesis of complex peptide sequences.[2]
However, polymer resins are prone to swelling – in fact, the swelling is an essential feature of their reactivity because it allows reagents to access the functional sites throughout the resin, not just on the surface. The amount of swelling is often reported as the ‘swelling factor’ or ‘swelling degree’, S, which is the volume (or mass) of solvent absorbed per gram (or millilitre) of dry resin at equilibrium. Traditionally, measurement of S requires prolonged equilibration of the resin with solvent—often many hours—and can show considerable batch-to-batch variability. [3]
SPS and resin swelling: an important relationship
Understanding resin swelling is important because most automated SPS systems employ closed reactors, such as packed-bed reactors (PBRs) or cartridges, in which resin expansion directly influences reactor operation. Despite its importance, the underlying physical behaviour is still poorly understood and much of the existing knowledge remains qualitative. To investigate this, the researchers packed a glass column with resin to create a packed-bed reactor, and allowed it to equilibrate to the desired temperature. After this time, the solvent was passed through the packed reactor and the change in height of the packed bed (Δh) was measured. Overall, it was found that the swelling of the resin was related to both the type of substrate bonded to the resin and the loading.
To study resin swelling under realistic synthesis conditions, the researchers employed a Variable Bed Flow Reactor (VBFR), a reactor concept previously developed by the authors with technical support from Vapourtec. The VBFR maintains a constant pressure across the resin bed using a movable plunger, allowing changes in resin volume to be measured directly as the resin swells or contracts. Using this approach, the authors showed that resin swelling reached equilibrium in approximately three minutes within a packed-bed reactor—substantially faster than the 20–60 minute swelling periods commonly employed in SPS protocols. Beyond improving understanding of resin behaviour, the work demonstrates how resin swelling can be used as a practical in-process monitoring tool, providing a foundation for future closed-loop monitoring and control of automated solid-phase synthesis.
Finally, the study showed that temperature has relatively little effect on the equilibrium swelling of Merrifield resin in either DCM or DMF. In contrast, the swelling kinetics were strongly temperature dependent, with relaxation times increasing significantly at lower temperatures.
References:
[1] Swelling Thermodynamics and Kinetics of Crosslinked Polystyrene Resin in Solid-Phase Synthesis (S. Pinzón-López, D. Ebert, M. Kraume, P. H. Seeberger, J. Danglad-Flores, Macromol. Chem. Phys., 2026, 277, e70283). https://doi.org/10.1002/macp.70283
[2] Continuous-Flow Solid-Phase Peptide Synthesis to Enable Rapid, Multigram Deliveries of Peptides (K. E. Ruhl, M. J. Di Maso, H. B. Rose, D. M. Schultz, F. Lévesque, S. T. Grosser, S. M. Silverman, S. Li, N. Sciammetta, U. F. Mansoor, Org. Proc. Res. Dev., 2024, 28, 2896). https://doi.org/10.1021/acs.oprd.4c00165
[3] (a) Thermodynamics of High Polymer Solutions (P. J. Flory, J. Rehner, J. Chem. Phys., 1942, 10, 51) https://doi.org/10.1063/1.1723621; (b) Statistical Mechanics of Cross-Linked Polymer Networks I. Rubberlike Elasticity (P. J. Flory, J. Rehner, J. Chem. Phys., 1943, 11, 512). https://doi.org/10.1063/1.1723791