Reactions with Singlet Oxygen and Supercritical Fluids

本提案旨在通过利用高压CO2 （scCO2）的几种不同性质来解决和克服现有的1O2方法中的问题，开发一种更环保的方法，将高活性形式的氧（单线态氧，1O2）用于涉及制药和低吨位精细化工行业感兴趣的化合物的反应。该提案是在工业合作伙伴阿斯利康和托马斯斯旺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有效的合作记录。早在20世纪90年代绿色化学诞生之前，1O2就有更清洁的化学合成历史，例如，德国化学家申克在战后合成了药用化合物阿斯卡利，据说是用菠菜叶作为光敏剂！从绿色的角度来看，1O2有几个吸引人的地方：(i) 1O2有可能促进化学上有用的转化；（ii） 1O2可以光化学方式产生，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）基于安全和原子效率两方面的考虑，光化学法产生氧比目前的热法更可取。对于迫切需要将废物减少与复杂化学相结合的转化的制药过程化学，1O2也具有吸引力。特别是，我们的提案针对绿色化学的两个方面，即烯丙醇的形成和在非氯化溶剂中安全使用O2，这两个方面最近被强调为对制药行业的特别重要性。此外，大多数制药工艺的低吨位意味着所需的放大程度低于化学工业的许多部门。我们的目的是证明1O2在用CO2膨胀的溶剂中连续光化学反应的可行性，即所谓的气体膨胀液体（gxl）。关键在于利用gxl的双相性质，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。我们的策略是建造一个相对较小的高压降膜反应器（FFR），其中液体沿板流下，从而对反应条件进行更精确的控制。选择这种设计是为了使我们在反应器配置方式上具有灵活性（例如，并发或逆流等）。将这种灵活性与诺丁汉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快速修改我们的方法。这种设计的一个特别的优点是，在大多数情况下，它将允许我们在没有二氧化碳的情况下进行控制实验，这样我们就可以确定二氧化碳对给定反应的精确影响。我们的化学课程侧重于与合作伙伴协商选择的四类反应，特别是与制药过程化学相关的反应。

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.