Thermodynamics of N‑Isopropylacrylamide in Water: Insight from Experiments, Simulations, and Kirkwood–Buff Analysis Teamwork

The behavior of thermoresponsive polymer poly­(N-isopropylacrylamide) (PNiPAM), an essential building block in the design of smart soft materials, in aqueous solutions has attracted much interest, which contrasts with our knowledge of N-isopropylacrylamide (NiPAM) monomer. Strikingly, the physicochemical properties of aqueous NiPAM are similarly rich, and their understanding is far from being complete. This stems from the lack of accurate thermodynamic data and quantitative model for atomistic simulations. In this joint study, we have probed the thermodynamic behavior of aqueous NiPAM by experimental methods, molecular dynamics (MD) simulations, and Kirkwood–Buff (KB) analysis at ambient conditions. From the partial molar volumes and simultaneously correlated osmotic coefficients, with excess partial molar enthalpies of NiPAM in water, the concentration and temperature dependence of KB integrals was determined. For the purpose of this work, we have developed and employed a novel NiPAM force field, which not only reproduces KB integrals (Gij) and adequately captures macroscopic thermodynamic quantities but also provides more accurate structural insight than the original force fields. We revealed in the vicinity of NiPAM the competing effect of amide hydration with interaction between nonpolar regions. This microscopic picture is reflected in the experimentally observed NiPAM–NiPAM association, which is present from highly dilute conditions up to the solubility limit and is evidenced by G22. From intermediate concentrations, it is accompanied by the existence of apparent dense-water regions, as indicated by positive G11 values. The here-employed KB-based framework provided a mutually consistent thermodynamic and microscopic insight into the NiPAM solution and may be further extended for ion-specific effects. Moreover, our findings contribute to the understanding of thermodynamic grounds behind PNiPAM collapse transition.温敏聚合物聚(N-异丙基丙烯酰胺)(poly(N-isopropylacrylamide), PNiPAM)是智能软材料设计中的核心构筑基元，其在水溶液中的行为受到广泛关注，这与学界对N-异丙基丙烯酰胺(N-isopropylacrylamide, NiPAM)单体的认知形成鲜明反差。令人瞩目的是，水溶液中NiPAM的理化性质同样丰富多样，而学界对其的理解仍远未完善，这一现状源于原子级模拟领域缺乏准确的热力学数据与定量模型。在本联合研究中，我们通过实验方法、分子动力学(molecular dynamics, MD)模拟以及柯克伍德-布拉夫(Kirkwood–Buff, KB)分析，在常温常压条件下探究了水溶液中NiPAM的热力学行为。结合偏摩尔体积以及与水中NiPAM超额偏摩尔焓同步关联的渗透系数，我们测定了KB积分的浓度与温度依赖性。为完成本研究，我们开发并使用了一种新型NiPAM分子力场，该力场不仅能够复现KB积分(Gij)并准确捕捉宏观热力学量，还能比原始力场提供更精准的结构视角。我们揭示了在NiPAM附近区域，酰胺水合作用与非极性区域间的相互作用存在竞争效应，这一微观图景与实验观测到的NiPAM-NiPAM缔合作用相契合：该缔合作用从极高稀释条件下便已存在，直至溶解度极限，并可通过G22得到验证。当中等浓度时，这一现象还伴随有表观致密水区域的存在，这一点可由正的G11值得到佐证。本研究采用的基于KB的分析框架为NiPAM溶液提供了自洽一致的热力学与微观视角，且可进一步拓展用于离子特异性效应的研究。此外，我们的研究结果有助于理解PNiPAM塌缩转变背后的热力学基础。