连续流动化学: Diphenyldiazomethane 与p硝基苯甲酸的反应
Summary
流动化学通过利用优异的混合、传热和成本效益来实现环境和经济优势。在此, 我们提供了一个蓝图, 从分批转移到流程模式的化学过程。采用间歇和流动的方法对 diphenyldiazomethane 的反应进行了研究, 选择了以批和流为依据的p硝基苯甲酸。
Abstract
连续流技术被确定为它的环境和经济优势的工具, 利用优越的混合, 传热和成本节约通过 “扩展” 战略, 而不是传统的 “扩大”。在此, 我们报告的反应 diphenyldiazomethane 与p硝基苯甲酸在批和流模式。为了有效地将反应从批处理转移到流模式, 必须在批处理过程中首先进行反应。因此, diphenyldiazomethane 的反应首先作为温度、反应时间和浓度的函数来研究, 以获得动力学信息和工艺参数。描述了玻璃流反应器的结构, 并将两类反应模块结合为 “混合” 和 “线性” 显微组织。最后, 在流动反应器中成功地进行了 diphenyldiazomethane 与p硝基苯甲酸的反应, 在11分钟内, diphenyldiazomethane 的转化率高达95%。这一概念反应的证明旨在为科学家们提供洞察力, 以考虑流动技术的竞争力、可持续性和在其研究中的通用性。
Introduction
绿色化学与工程正在为工业的未来方向创造文化变革1,2,3,4。通过 “扩展” 策略, 而不是传统的 “向上扩展”5 , 连续流技术已被确定为利用优异的混合、传热和成本节约的环境和经济优势的工具。,6,7,8,9,10。
虽然制药行业等高价值产品的行业长期青睐批量加工, 但由于经济竞争和商业生产效益的不断增加, 流动技术的优势已变得十分诱人11. 例如, 当扩展批处理过程时, 必须建立和操作先导刻度单位, 以确定精确的热传导和传质机制。这是几乎不可持续的并且从产品的适销对路的专利生活极大地减去。相比之下, 连续流程处理允许扩展的优势, 消除了与生产规模相关的先导工厂阶段和工程-一项重大的财务激励。除了经济影响之外, 连续的技术还能使原子能和能源效率的过程。例如, 增强的混合改善了双相系统的传质, 从而提高了产量、催化剂回收策略和随后的回收计划。此外, 准确地管理反应温度的能力导致反应动力学的精确控制和产品分布12。强化过程控制、产品质量 (产品选择性) 和重现性都对环境和财务观点都有影响力。
流动反应器是可利用的商业与各种各样的大小和设计。此外, 可以很容易地实现对反应器的定制以满足工艺需要。在此, 我们报告在玻璃连续流反应器中进行的实验 (图 1)。由玻璃制成的微结构 (161 毫米 x 131 mm x 8 mm) 的组装与多种化学品和溶剂相兼容, 并且在广泛的温度范围内 (-25–200° c) 和压力 (高达 18 bar) 具有耐腐蚀性。设计了 multi-injection、高性能混合、弹性停留时间、精确传热的显微组织及其布置。所有的显微组织都装有两个射流层 (-25–200° c, 高达 3 bar), 用于在反应层的两侧进行热交换。传热速率与传热面面积成正比, 与体积成反比。因此, 这些微结构促进了最佳的表面积比以改善传热。有两种类型的微结构 (即模块): “混合” 模块和 “线性” 模块 (图 2)。心形 “混合” 模块的设计, 以诱导湍流和最大的混合。相反, 线性模块提供额外的居留时间。
作为概念的证明, 我们选择了羧酸 diphenyldiazomethane 的描述反应13,14,15,16,17。反应方案显示在图 3中。质子从羧酸到 diphenyldiazomethane 的初始转移是缓慢的, 是速率决定的步骤。第二步是快速, 产生反应产物和氮。初步研究了有机羧酸的相对酸度 (质子和质子) 的反应。反应是第一顺序在 diphenyldiazomethane 和一阶在羧酸。
实验中, 这种反应是在大量过量的羧酸 (10 摩尔当量) 的存在下进行的。因此, 这一比率是伪的第一个订单就 diphenyldiazomethane。通过将实验所得的伪一阶速率常数除以羧酸的初始浓度, 即可得到二阶速率常数。初步研究了 diphenyldiazomethane 与苯甲酸 (pKa = 4.2) 的反应。在间歇期, 反应似乎相对缓慢, 在96分钟内达到约90% 的转换。由于反应速率与羧酸的酸度成正比, 我们选择作为反应伙伴的酸性羧酸、 p硝基苯甲酸 (pKa = 3.4) 来缩短反应时间。因此, 在间歇和流中对 diphenyldiazomethane 在无水乙醇中的反应进行了研究 ( 图 4)。下一节将详细介绍结果。
当反应在乙醇中进行时, 可以形成三产品: (i) benzhydryl-4-nitrobenzoate, 这是由p硝基苯甲酸与甲烷氮中间体的反应产生的;(二) 从溶剂、乙醇和甲烷氮反应得到的 benzhydryl 乙醚;和 (iii) 氮。产品分布没有研究, 因为它在文献中有很好的记载;相反, 我们关注的是批量反应的技术转移到连续流13,14,15。实验 diphenyldiazomethane 的消失被监测。反应进行生动的颜色变化, 可以直观地观察到紫外-可见光谱。这是由于 diphenyldiazomethane 是一种强烈的紫色化合物, 而所有其他的反应产物都是无色的。因此, 这种反应可以在定性的基础上进行目视监测, 并定量地遵循紫外光谱 (即 525 nm 的二苯基甲烷吸收消失)。本文首先报告了 diphenyldiazomethane 和p硝基苯甲酸在间歇性乙醇中的反应, 作为时间的函数。然后将反应成功地转移到玻璃流反应器中进行。利用紫外光谱 (分批和流态) 监测 diphenyldiazomethane 的消失, 确定了反应的进展。
Protocol
Representative Results
Discussion
最近, 在化学 (29%) 和工程学 (25%) 的研究领域中, 平均每年大约有1500份关于这个主题的出版物引起了流动化学的关注。许多成功的流程都是在流程中进行的。在许多情况动化学被证明表现出优异的性能 , 以批处理很多应用 , 如准备药学活性成分30,31, 自然产品32, 以及专业, 高价值的化学品, 如高性能的聚合物33,<s…
Disclosures
The authors have nothing to disclose.
Acknowledgements
我们要感谢康宁玻璃流反应器的礼物。
Materials
| Thermometer | HB-USA/ Enviro-safe | Any other instrument scientific company provider works | |
| Benzophenone hydrazone | Sigma-Aldrich | Store at 2-8 °C, 96% purity | |
| Activated MnO2 | Fluka | ≥ 90% purity, harmful if inhaled or swallowed. Refer to MSDS for more safety precautions | |
| Dibasic KH2PO4 | Sigma-Aldrich | Serious eye damage, respiratory irritant. Refer to MSDS for more safety precautions | |
| Dichloromethane (DCM) | Alfa Aesar | ≥ 99.7% purity, argon packed | |
| Rotovap | Büchi | accessory parts include Welch self-cleaning dry vacuum model 2027, and Neuberger KNP dry ice trap | |
| Bump trap | Chemglass | Any other instrument scientific company provider works | |
| Neutral Silica Gel (50-200 mM) | Acros Organic/ Sorbent Technology | Respiratory irritant if inhaled, refer to MSDS for more safety precautions | |
| Inert Argon Gas | Airgas | Always ensure proper regulator is in place before using | |
| Medium Porosity Sintered Funnel Glass Filter | Sigma-Aldrich | Any other instrument scientific company provider works | |
| Aluminum Foil | Reynolds Wrap | Any other company works. Used to prevent photolytic damage towards DDM | |
| Para-NO2 benzoic acid | Sigma-Aldrich | Skin contact irritant, eye irritant, respiratory irritant. Refer to MSDS for more safety precautions | |
| Pure ethyl alcohol (200 proof) | Sigma-Aldrich | ≥ 99.5% purity, anhydrous. Highly flammable | |
| Toluene | Sigma-Aldrich | ≥ 99.8% purity, anhydrous. Skin permeator, flammable | |
| Ortho-xylene | Sigma-Aldrich | 99% purity, anhydrous. Toxic to organs and CNS. Adhere to specifications dictated within MSDS | |
| Diphenyl diazo methane | Produced in-house | Respiratory irritant, refer to MSDS for more safety precautions | |
| Corning reactor | Corning Proprietary | Manufactured in 2009. model number MR 09-083-1A | |
| Stop watch | Traceable Calibration Control Company | Any other company that provides monitoring with laboratory grade accredidation works | |
| Analytical balance | Denver Instruments | Model M-2201, or any analytical balance that has sub-milligram capabilities | |
| Dram vials | VWR | 2 dram, 4 dram, and 6 dram vials | |
| Micropipettes | Eppendorf | 2-20 μL and 100-1000 μL micropipettes work | |
| Glass pipettes | VWR | Any other instrument scientific company provider works | |
| GC-MS | Shimadzu GC | Software associated: GC Real Time Analysis | |
| GC vials | VWR | Any other providing company works | |
| Beakers | Pyrex | 500 mL beakers | |
| Syringe pumps | Sigma Aldrich | Teledyne Isco Model 500D | |
| Relief valve | Swagelok | Spring loaded relieve valve | |
| One-way valves | Nupro | 10 psi grade | |
| Two-way straight valves | HiP | 15,000 psi grade |
References
- Jimenez-Gonzalez, C., et al. Engineering Research Areas for Sustainable Manufacturing: A Perspective from Pharmaceutical and Fine Chemicals Manufacturers. Org Process Res Dev. 15 (4), 900-911 (2011).
- Constable, D. J. C., et al. Key green chemistry research areas – a perspective from pharmaceutical manufacturers. Green Chem. 9 (5), 411-420 (2007).
- Plutschack, M. B., Pieber, B., Gilmore, K., Seeberger, P. H. The Hitchhiker’s Guide to Flow Chemistry. Chem Rev. , (2017).
- Dallinger, D., Kappe, C. O. Why flow means green – Evaluating the merits of continuous processing in the context of sustainability. Curr Opin Green Sustain Chem. 7, 6-12 (2017).
- Movsisyan, M., et al. Taming hazardous chemistry by continuous flow technology. Chem Soc Rev. 45 (18), 4892-4928 (2016).
- Hessel, V., Ley, S. V. Flow Chemistry in Europe. J Flow Chem. 6 (3), 135-135 (2016).
- Mascia, S., et al. End-to-End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation. Angew Chem Int Edit. 52 (47), 12359-12363 (2013).
- Newman, S. G., Jensen, K. F. The role of flow in green chemistry and engineering. Green Chem. 15 (6), 1456-1472 (2013).
- Watts, P., Haswell, S. J. The application of micro reactors for organic synthesis. Chem Soc Rev. 34 (3), 235-246 (2005).
- Wiles, C., Watts, P. Continuous flow reactors: a perspective. Green Chem. 14 (1), 38-54 (2012).
- Roberge, D. M., et al. Microreactor technology and continuous processes in the fine chemical and pharmaceutical industry: Is the revolution underway. Org Process Res Dev. 12 (5), 905-910 (2008).
- Degennaro, L., Carlucci, C., De Angelis, S., Luisi, R. Flow Technology for Organometallic-Mediated Synthesis. J Flow Chem. 6 (3), 136-166 (2016).
- Roberts, J. D., Watanabe, W. The Kinetics and Mechanism of the Acid-Catalyzed Reaction of Diphenyldiazomethane with Ethyl Alcohol. J Am Chem Soc. 72 (11), 4869-4879 (1950).
- Roberts, J. D., Watanabe, W., Mcmahon, R. E. The Kinetics and Mechanism of the Reaction of Diphenyldiazomethane and Benzoic Acid in Ethanol. J Am Chem Soc. 73 (2), 760-765 (1951).
- Roberts, J. D., Watanabe, W., Mcmahon, R. E. The Kinetics and Mechanism of the Reaction of Diphenyldiazomethane with 2,4-Dinitrophenol in Ethanol. J Am Chem Soc. 73 (6), 2521-2523 (1951).
- Roberts, J. D., Regan, C. M. Kinetics and Some Hydrogen Isotope Effects of the Reaction of Diphenyldiazomethane with Acetic Acid in Ethanol. J Am Chem Soc. 74 (14), 3695-3696 (1952).
- Oferrall, R. A., Kwok, W. K., Miller, S. I. Medium Effects Isotope Rate Factors + Mechanism of Reaction of Diphenyldiazomethane with Carboxylic Acids in Solvents Ethanol + Toluene. J Am Chem Soc. 86 (24), 5553 (1964).
- Aldrich, S. . Material Safety Data Sheet: Benzophenone Hydrazone. 4.2, 3-6 (2014).
- Science Lab Chemicals & Laboratory Equipment. . Material Safety Data Sheet: Manganese dioxide MSDS. , (2005).
- Science Lab Chemicals & Laboratory Equipment. . Material Safety Data Sheet: Potassium phosphate dibasic MSDS. , 1-5 (2005).
- Science Lab Chemicals & Laboratory Equipment. . Material Safety Data Sheet: Methylene Chloride MSDS. , 3-5 (2005).
- Smith, L. I., Howard, K. Diphenyldiazomethane. Org. Synth. 3 (351), (1955).
- Capot Chemical Co. . Material Safety Data Sheet, diphenyldiazomethane. 2017, (2010).
- Science Lab. . Material Safety Data Sheet: P-nitrobenzoic acid MSDS. , 3-5 (2005).
- Science Lab Chemicals & Laboratory Equipment. . Material Safety Data Sheet Ethyl Alcohol 200 proof MSDS. , (2005).
- Science Lab Chemicals & Laboratory Equipment. . Material Safety Data Sheet Toluene MSDS. , 4-5 (2005).
- Science Lab Chemicals & Laboratory Equipment. . Material Safety Data Sheet o-Xylene MSDS. , 3-5 (2005).
- Zheng, J., et al. Cross-Coupling between Difluorocarbene and Carbene-Derived Intermediates Generated from Diazocompounds for the Synthesis of gem-Difluoroolefins. Organic Letters. 17, 6150-6153 (2015).
- Reimlinger, H. 1,5-Dipolar cyclizations, I. Definition and contributions to the Imidazide/Tetrazole tautomerism. Chem. Ber. 103, 1900 (1970).
- Baumann, M., Garcia, A. M. R., Baxendale, I. R. Flow synthesis of ethyl isocyanoacetate enabling the telescoped synthesis of 1,2,4-triazoles and pyrrolo-[1,2-c] pyrimidines. Org Biomol Chem. 13 (14), 4231-4239 (2015).
- Baumann, M., Baxendale, I. R. The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry. Beilstein J Org Chem. 11, 1194-1219 (2015).
- Pastre, J. C., Browne, D. L., Ley, S. V. Flow chemistry syntheses of natural products. Chem Soc Rev. 42 (23), 8849-8869 (2013).
- Pirotte, G., et al. Continuous Flow Polymer Synthesis toward Reproducible Large-Scale Production for Efficient Bulk Heterojunction Organic Solar Cells. Chemsuschem. 8 (19), 3228-3233 (2015).
- Kumar, A., et al. Continuous-Flow Synthesis of Regioregular Poly(3-Hexylthiophene): Ultrafast Polymerization with High Throughput and Low Polydispersity Index. J Flow Chem. 4 (4), 206-210 (2014).
- Helgesen, M., et al. Making Ends Meet: Flow Synthesis as the Answer to Reproducible High-Performance Conjugated Polymers on the Scale that Roll-to-Roll Processing Demands. Adv Energy Mater. 5 (9), 1401996 (2015).
- Grenier, F., et al. Electroactive and Photoactive Poly[lsoindigo-alt-EDOT] Synthesized Using Direct (Hetero)Arylation Polymerization in Batch and in Continuous Flow. Chem Mater. 27 (6), 2137-2143 (2015).
- Pollet, P., et al. Production of (S)-1-Benzyl-3-diazo-2-oxopropylcarbamic Acid tert-Butyl Ester, a Diazoketone Pharmaceutical Intermediate, Employing a Small Scale Continuous Reactor. Ind Eng Chem Res. 48 (15), 7032-7036 (2009).
- Flack, K., et al. Al(OtBu)(3) as an Effective Catalyst for the Enhancement of Meerwein-Ponndorf-Verley (MPV) Reductions. Org Process Res Dev. 16 (3), 1301-1306 (2012).
- Aponte-Guzman, J., et al. A Tandem, Bicatalytic Continuous Flow Cyclopropanation-Homo-Nazarov-Type Cyclization. Ind Eng Chem Res. 54 (39), 9550-9558 (2015).
- Liotta, C. L., et al. Synthetic Transformations Employing Continuous Flow. ACS- Fall 2013.Synthetic Transformations Employing Continuous Flow. , (2013).
