Reactions with Singlet Oxygen and Supercritical Fluids

该提案旨在开发一种更绿色的方法，利用高压CO2（scCO 2）的几种不同性质，将高活性形式的氧（单线态氧，1 O2）用于涉及制药和低吨位精细化学品工业感兴趣的化合物的反应，以解决和克服现有1 O2方法中的问题。该提案是在工业合作伙伴阿斯利康和托马斯天鹅有限公司的积极参与下制定的，这两家公司都与我们的研究小组有着有效的合作记录。1 O2具有清洁化学合成的历史，早在20世纪90年代绿色化学诞生之前，例如，德国化学家申克战后合成了药用化合物蛔虫素，据说是用菠菜叶作为光敏剂！从绿色的角度来看，1 O2有几个吸引人的地方：（i）1 O2有可能促进化学上有用的转化，（ii）1 O2可以光化学产生，有时甚至使用阳光，只需要可见光，而不是紫外线，从而避免无意中产生臭氧的问题。(iii)从安全性和原子效率两方面考虑，光化学生成1 O2优于目前的热方法。1 O2对于制药工艺化学也是有吸引力的，制药工艺化学迫切需要将联合收割机减少废物与复杂化学相结合的转化。特别是，我们的提案针对绿色化学的两个方面，烯丙醇的形成和在非氯化溶剂中安全使用O2，最近强调对制药行业具有特别重要的意义。此外，在大多数制药工艺中的低吨位意味着所需的放大程度小于化学工业的许多部门。我们的目标是证明1 O2在用CO2膨胀的溶剂中连续光化学反应的可行性，所谓的气体膨胀液体，GXL。关键是利用GXL的两相性质，不仅使反应本身的效率最大化，而且使产物和光敏剂的分离效率最大化。我们的策略是建立一个相对较小的高压降膜反应器，FFR，其中液体向下流动的板，从而提供更精确的控制反应条件。选择该设计是为了在反应器的配置方式上给予我们灵活性（例如，并流或逆流等）。将这种灵活性与诺丁汉现有高压设备的模块化特性相结合，将使我们能够根据实验结果迅速修改我们的方法。该设计的一个特别优点是，在大多数情况下，它允许我们在没有CO2的情况下进行对照实验，以便我们可以确定CO2对给定反应的精确影响。我们的化学计划侧重于与我们的合作伙伴协商选择的四类反应，特别是它们与制药工艺化学的相关性。

This Proposal aims to develop a greener approach to the use of a highly reactive form of oxygen (singlet oxygen, 1O2) for reactions involving compounds of interest to the pharmaceutical and low-tonnage fine chemicals industries by exploiting several different properties of high pressure CO2 (scCO2) to address and overcome problems in existing 1O2 methodologies. The Proposal has been developed with the active participation of industrial partners, AstraZeneca and Thomas Swan & Co Ltd, both of whom have a record of effective collaboration with our research group.1O2 has a history of cleaner chemical synthesis which long predates the birth of Green Chemistry in the 1990s for example, with the German chemist Schenck's post-war synthesis of the medicinal compound ascaridole, reputedly with spinach leaves as the photosensitizer! From a green standpoint 1O2 has several attractions: (i) 1O2 has the potential to promote chemically useful transformations and (ii) 1O2 can be generated photochemically, sometimes even using sunlight, and only requires visible light rather than UV, thus avoiding problems of inadvertent generation of ozone. (iii) On grounds of both safety and atom efficiency, the photochemical generation of 1O2 is preferable to current thermal routes. 1O2 is additionally attractive for pharmaceutical process chemistry which has a pressing need for transformations that combine reduction in waste with complex chemistry. In particular, our Proposal targets two aspects of Green chemistry, formation of allylic alcohols, and safe use of O2 in non-chlorinated solvents, recently highlighted as being of specific importance to the pharmaceutical industry. Furthermore, the low tonnages in most pharmaceutical processes mean that the degree of scale-up required is less than in many sectors of the chemical industry.Our aim is to demonstrate the feasibility of continuous photochemical reactions of 1O2 in solvents expanded with CO2, so-called Gas-Expanded liquids, GXLs. The key will be to exploit the biphasic nature of the GXLs to maximize the efficiency not only of the reaction itself but also of the separation of the product and photosensitizer. Our strategy is to build a relatively small high pressure falling-film reactor, FFR, where the liquid flows down a plate thereby giving more precise control over reaction conditions. The design has been chosen to give us flexibility in the way that the reactor is configured (e.g. concurrent or counter-current flow, etc). Combining this flexibility with the modular nature of the high-pressure equipment available in Nottingham will allow us to modify our approach rapidly in response to our experimental results. A particular advantage of the design is that, in most cases, it will allow us to carry out control experiments in the absence of CO2 so that we can establish the precise effect of CO2 on a given reaction. Our chemical programme focuses on four classes of reactions chosen in consultation with our partners, specifically for their relevance to pharmaceutical process chemistry.