Using Carbon Dioxide as a Building Block in Continuous Flow Synthesis The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Seo, Hyowon et al. "Using Carbon Dioxide as a Building Block in Continuous Flow Synthesis." Advanced Synthesis & Catalysis 361, 2 (November 2018): 247-264 © 2019 Wiley As Published http://dx.doi.org/10.1002/adsc.201801228 Publisher Wiley Version Author's final manuscript Citable link https://hdl.handle.net/1721.1/128013 Terms of Use Creative Commons Attribution-Noncommercial-Share Alike Detailed Terms http://creativecommons.org/licenses/by-nc-sa/4.0/ REVIEW DOI: 10.1002/adsc.201((will be filled in by the editorial staff)) Using Carbon Dioxide as a Building Block in Continuous Flow Synthesis Hyowon Seo,a Long V. Nguyen,a and Timothy F. Jamisona* a Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States Fax: (+1) 617-324-0253 ;Phone: (+1) 617-253-2135; e-mail: [email protected] Received: ((will be filled in by the editorial staff)) Abstract. Carbon dioxide, CO2, is an attractive building block 1. Introduction for organic synthesis that is environmentally friendly. 2. C–heteroatom bond formation with CO2 Continuous flow technologies have enabled C–O and C–C 2.1 C–O bond formation bond forming reactions with CO2 that previously were either 2.2 C–N bond formation low-yielding or impossible in batch to afford value-added 3. C–C bond formation with CO2 chemicals. This review describes recent advances in 3.1. Carboxylations in noncatalytic systems continuous flow as an enabling strategy in utilizing CO2 as a 3.1.1. Carboxylations of organolithium/magnesium C1 building block in chemical synthesis. compounds 3.1.2. Electrochemical carboxylations 3.2. Carboxylations in catalytic systems 3.2.1. Enzyme catalyzed carboxylation 3.2.2. Photoredox catalyzed carboxylation 4. Conclusions Keywords: C1 building blocks; Flow chemistry; Carboxylation; Green chemistry; Gas-liquid reactions; Carbon dioxide (e.g., high-pressure reactors). New technologies have 1. Introduction been the focus of research for the practical setup of gas-liquid reactions in lab scale has increased Carbon dioxide (CO2) is one of the most concurrently with the emerging attention on important chemical feedstocks because it is nontoxic, continuous flow chemistry in the recent decade. In non-flammable, abundant, economical, and particular, flow chemistry has emerged as an [1,2] intrinsically renewable. CO2 as a single carbon important tool in organic synthesis by enabling source has received considerable attention from the chemical transformations that were either low- chemical community the last several decades since it yielding or otherwise considered impossible under could potentially replace toxic single carbon sources traditional batch conditions.[9–11] In particular, such as phosgene and derivatives. Particularly, continuous flow has demonstrated great improvements incorporation of CO2 into complex organic for multiphasic systems; for example, gas-liquid compounds has become an important topic in organic biphasic reactions become more efficient due to an [3,4] synthesis. CO2 has traditionally been used as a enhanced surface area to volume ratio, rapid mixing, single carbon electrophile reacting with strong and straightforward application of high pressure in nucleophiles such as Grignard reagents. However, in laboratory scale.[12] the last decade, several invaluable catalytic Furthermore, safety concerns are reduced in [5– transformations utilizing CO2 have been developed. continuous flow systems by processing small 7] quantities of material at continuous rates, allowing for The challenge in utilizing CO2 lies in its high inline generation and rapid consumption of highly thermodynamic stability and low kinetic reactivity.[8] reactive chemical species. In addition, telescoped Thus, reaction with CO2 often requires forcing processes obviating unnecessary purifications and conditions such as high pressure, elevated temperature, isolations in multistep sequences in continuous flow and highly reactive reaction partners. Because of these has been greatly advanced in recent years.[13,14] Lastly, limitations, laboratory scale gas-liquid reactions with the inherent scalability of any given process is an CO2 in batch usually require specialized equipment 1 important distinguishing feature of continuous flow systems, this review will focus on the use of CO2 as a systems. building block in continuous flow. Common flow equipment and the corresponding schematic representations particularly for the setup with gas reagents used herein are illustrated in Figure Hyowon Seo was born in Seoul, 1. Pumps (HPLC, syringe, and peristaltic) are used to South Korea. She attended the deliver liquids, whereas mass flow controllers (MFCs) Seoul National University, where she obtained a B.S. and deliver gaseous reagents via a programmed system. M.S. majoring in Pharmacy. Gas control valves are also frequently used to deliver Her M.S. work in the laboratory gas, albeit they are arbitrarily controlled. Reactors are of Prof. Young-Ger Suh focused usually tubular and their length, diameter, and on the total synthesis of materials can be chosen to accommodate various incarvilline. In 2014, she joined reaction conditions. Packed-bed reactors are cartridges the laboratory of Prof. Tim packed with solid reagents or materials to utilize solid Jamison as a graduate student reagents, bases, solid-supported reagents, etc. Mixers at MIT. Her current research focuses on the photoredox activation of CO2 in are used to join separate reagent streams; T-, Y-, and continuous flow. cross-mixers are commonly installed in continuous flow setups. Static mixers are often used to enhance inline mixing. Check valves allowing one-way flow are installed to prevent back-flow of the reaction Long Nguyen grew up in mixtures and back pressure regulators (BPRs) are Southern California and frequently used to keep the system pressurized, obtained a B.S. in Chemistry particularly for gas-liquid biphasic reactions. These from the University of California, Davis in 2012 can be purchased from various commercial suppliers. where he performed Although many transformations employing undergraduate research in the stoichiometric CO2 in batch conditions have been laboratory of Prof. Bruce D. reported recently, the scope of this review article is Hammock. He received his limited to reactions with CO2 in continuous flow PhD in Organic Chemistry in systems. Since the use of supercritical CO2 (scCO2) as 2018 from Boston University [15–18] with Prof. Aaron B. Beeler a reaction medium and transformations of CO2 [19,20] where his graduate studies focused on the total synthesis into other C1 compounds has been expanded in the of daphnane diterpene orthoesters. He is currently a laboratory scale by introducing continuous flow postdoctoral associate at MIT in the laboratory of Prof. Tim Jamison. Tim Jamison was born in San Jose, CA, and grew up in neighboring Los Gatos, CA. He received his undergraduate education at UC Berkeley, where he conducted research in the laboratory of Prof. Henry Rapoport for nearly three years. He was then a Fulbright Scholar with Prof. Steven A. Benner at the ETH Zurich, and thereafter he undertook his PhD studies at Harvard University with Prof. Stuart L. Schreiber. He then moved to the laboratory of Prof. Eric N. Jacobsen at Harvard University, where he was a Damon Runyon- Walter Winchell postdoctoral fellow. In 1999, he began his independent career at MIT, where he currently holds the positions of Professor and Head of the Chemistry Department. Figure 1. Representative images of common flow equipment. 2 2. C–heteroatom bond formation with was insoluble in scCO2 however was soluble in a CO2 binary mixture of scCO2 and EO. Importantly, the catalyst showed equal activity after subjection to the 2.1. C–O bond formation reaction conditions over a 24-hour period. Presently, the development of continuous flow A similar flow system was developed by methodologies for the fixation of carbon dioxide in Sakakura and co-workers utilizing scCO2 in combination with propylene oxide (PO) in 2006 which specifically new carbon–oxygen bonds are [22] formed has been limited to the preparation of organic (Scheme 2). Employing a relatively simple flow carbonates from epoxide precursors. Cyclic carbonates system, both scCO2 and PO were pumped via HPLC are broadly useful synthetic precursors and find pumps into a fixed-bed reactor containing a important applications in the chemical synthesis of heterogeneous cesium-phosphorous-silicon mixed bioactive molecules; raw starting materials in plastics; oxide catalyst. Under optimal conditions (10 g catalyst bed, 200 electrolytes for lithium-ion batteries; and -1 -1 environmentally conscience ‘green’ solvents. °C, 2030 psi, 0.05 mL·min and 0.2 mL·min flow Literature preparations of cyclic carbonates rate for PO and scCO2, respectively) initial yields of employing catalytic batch reactions are extensive and 81% were observed although precipitous drops in yield include both homogeneous and heterogeneous were found to be a result of catalyst leaching under components. However, trending limitations such as continuous operation exceeding 5 h. Interestingly, low conversions, catalyst deactivation, and high gas cesium phosphate (Cs3PO4) was found to be an pressures and temperature regimes pose concerns effective homogeneous catalyst for propylene regarding the general