Administrative Supplement for Equipment

Massachusetts Institute Of Technology, Cambridge MA

Investigators

Linked publications, trials & patents

Abstract

NOT-GM-24-021 Parent Grant: R35-GM122483. Metal Catalyzed Methods for Organic Synthesis Research Plan: Our group's research focuses on developing methods for forming carbon-heteroatom and carbon- carbon bonds. Creating highly functionalized molecules in a reliable manner is crucial for organic synthesis, underpinning drug discovery, development, and scale-up. Our techniques are widely adopted in academia and industry for synthesizing complex molecules, serving as important processes for synthetic chemists. By inventing new methods, we not only gain access to important compounds but also the ability to modify them efficiently and selectively, altering their properties and minimizing side effects. Our ongoing projects encompass various areas, including palladium-catalyzed cross coupling methods for generating heterocyclic carbon-nitrogen bonds; copper-catalyzed methods for the construction of carbon-oxygen or carbon-nitrogen bonds; copper-catalyzed methods for the highly regio- diastereo-, and enantioselective synthesis of aliphatic amines; and copper-catalyzed methods for the asymmetric formation of carbon-carbon bonds. Mechanistic studies have helped us to investigate the fundamental aspects of these transformations, guiding us to enhance their efficiency and applicability. The substrates we target are integral structural components found in pharmaceuticals, natural products, agrochemicals and sensors. In our continued efforts in Pd-catalyzed cross coupling reactions we have developed easily accessible precursors for Pd oxidative addition complexes.1 We have also designed new ligands and mild reaction conditions for the C–N cross coupling of five-membered heteroaryl halides with secondary, primary aliphatic amines and anilines.2 Ullmann-type C–N coupling reactions represent an important alternative to well-established palladium-catalyzed approaches due to the differing reactivity, lower cost, and diminished toxicity of copper. Using a combination of experimental and theoretical methods we have established a new class of anionic ligands for Cu-catalyzed C–N coupling of aryl bromides and alkyl amines at room temperature.3 Using our newly developed N1,N2-diarylbenzene-1,2-diamine ligand class, we have also developed a Cu- catalyzed method for the coupling of alcohols and (hetero)aryl bromides.4 We have introduced new copper-hydride methods for the enantioselective olefin hydromethylation,5 alkyne hydroalkylation,6 and the asymmetric formal hydroformylation of vinyl arenes.7 Since the submission of our last renewal in 2022, we have reported 14 publications that were funded by the parent grant R35-122483. We dedicate significant efforts to make our methods user- friendly, practical, and applicable across a broad spectrum of compounds. We systematically optimize the limitations and range of conditions and substrates they can accommodate. Several analytical instruments play important roles in our studies including, nuclear magnetic spectroscopy (NMR) spectroscopy, supercritical fluid chromatography (SFC), automated flash column purification system, high-performance liquid chromatography (HPLC), infrared (IR) spectroscopy, gas chromatography (GC) and mass spectrometry (MS). One of the most heavily relied on tools in our lab is the GCMS. Researchers employ the GCMS to analyze volatile reaction products, identify intermediates and quantify reactants and products. By coupling gas chromatography with mass spectrometry, it can separate and detect compounds based on their mass-to-charge rations. The GCMS helps in the Identification and quantification of reaction components, monitoring reaction progress, elucidation of reaction mechanisms, characterization of intermediates, analysis of catalyst stability and deactivation, and reaction optimization. It is a powerful analytical technique that enables us to explore the intricacies of catalytic systems and its impact. Our current instrument is an Agilent GC model 6850 and MS model 5975 system. It was acquired in 2006 and has undergone numerous repairs to address a range of issues. Just since 2020, we have spent $15,000 in repairs and services. At this point, it is so outdated that Agilent can no longer offer us repair options or service contracts for this system. It is essential to our work and used daily by researchers in our lab. The duration of downtime resulting from these repairs has varied, spanning from a day to several weeks, contingent upon the complexity of the issue, technician availability and awaiting replacement parts. During method development, GCMS is used to analyze reaction mixtures, aiding in the identification of starting materials, intermediates, by-products, and final products generated. By comparing the mass spectra and retention times with authentic standards, we can identify and quantify each component which helps us to assess the efficiency and selectivity of the reaction. By analyzing samples at different time points, GCMS allows for the monitoring of reaction progress. We can see the consumption of starting materials and formation of products over time. It can possibly also help to identify side reactions or undesirable decomposition pathways. In this manner, we can adjust the reaction conditions such as temperature, solvent, catalyst loading and reaction times for optimization. In combination with other analytical tools, we can use GCMS data to elucidate reaction mechanisms. Analysis of reaction products, isotopic labeling studies and reaction kinetics would provide insight into plausible mechanistic pathways. Understanding of the fundamental reaction mechanism is essential for the rational design of new ligands and catalyst systems and predicting outcomes in related transformations. A GCMS plays a pivotal role in our research and development of new organometallic-catalyzed methodology by enabling the identification, quantification, monitoring, mechanistic elucidation, and characterization of reaction components, intermediates, and catalysts. Its versatility and sensitivity make it an indispensable tool for advancing our understanding of catalytic processes and facilitating the design of novel catalysts for synthetic applications. A new system would help us optimize the workflow for all the ongoing projects in our lab and provide comprehensive capabilities to identify diverse samples. We plan to cover recurring costs associated with the requested GCMS system through service contracts for regular maintenance and repairs to ensure optimal performance and longevity. We have budgeted in the expendable supplies (i.e., gases, sample vials, syringe needles, and septa) as part of our routine operations and consumables of our parent grant. The initial training will be provided by the manufacturer (Agilent) as part of the installation of the instrument. Additionally, we will designate a person to internally maintain and be responsible for regular upkeep of the GCMS system. This includes in-house protocols for use and providing ongoing training for new users and refresher courses for existing users. By implementing these plans, we aim to ensure long-term reliability, performance, and accessibility of the GCMS system for our research activities. Bibliography: 1. King, R. P.; Krska, S. W.; Buchwald, S. L. A Neophyl Palladacycle as an Air- and Thermally Stable Precursor to Oxidative Addition Complexes. Org. Lett. 2021, 23, 7927-7932. (PMCID: PMC9235910). 2. Reichert, E. C.; Feng, K.; Sather, A. C.; Buchwald, S. L. Pd-Catalyzed Amination of Base-Sensitive Five-Membered Heteroaryl Halides with Aliphatic Amines. J. Am. Chem. Soc. 2023,145, 3323-3329. (PMCID:PMC9988406) 3. Kim, S.-T.; Strauss, M. J.; Cabré, A.; Buchwald, S. L. Room-Temperature Cu-Catalyzed Amination of Aryl Bromides Enabled by DFT-Guided Ligand Design. J. Am. Chem. Soc. 2023, 145, 6966-6975. (PMCID:PMC10415864 4. Strauss, M.; Greaves, M.; Kim, S.-T.; Teijaro, C.; Schmidt, M.; Scola, P.; Buchwald, S. L. Room Temperature Cu-Catalyzed Etherification of Aryl Bromides. Angew. Chem. Int. Ed. 2024, 63, e202400333. (PMCID:PMC11045308) 5. Dong, Y.; Shin, K.; Mai, B. K.; Liu, P.; Buchwalds, S. L. Copper Hydride-Catalyzed Enantioselective Olefin Hydromethylation. J. Am. Chem. Soc. 2022, 144, 16303-16309. (PMCID:PMC9994624) 6. Kutateladze, D. A.; Mai, B. K.; Dong, Y.; Zhang, Y.; Peng, L.; Buchwald, S. L. Stereoselective Synthesis of Trisubstituted Alkenes via Copper Hydride-Catalyzed Alkyne Hydroalkylation. J. Am. Chem. Soc. 2023, 145, 17557-17563. PMCID:PMC10569085 7. Garhwal, S.; Dong, Y.; Mai, B. K.; Liu, P.; Buchwald, S. L. CuH-Catalyzed Regio-and Enantioselective Formal Hydroformylation of Vinyl Arenes. J. Am. Chem. Soc. 2024, ASAP. https://doi.org/10.021/jacs.4c04287 (PMCID in progress).