What is the Grignard reaction?
The Grignard reaction is the addition of an organomagnesium halide (Grignard reagent) to an electrophilic substrate, typically a ketone or aldehyde to form a tertiary or secondary alcohol, respectively. The reaction with formaldehyde leads to a primary alcohol.
The Grignard reaction was discovered in 1900 by the French chemist Victor Grignard, when he treated an alkyl halide with magnesium metal in diethyl ether. A cloudy solution was formed, which reacted with aldehydes or ketones to form secondary or tertiary alcohols, respectively. We now know that the magnesium inserted into the carbon–halogen bond, forming a nucleophilic organomagnesium species, with these organomagnesium reagents commonly known as ‘Grignard reagents’ [1].
Scheme 1: General overview of a Grignard reaction
Although Grignard reagents will be the primary focus of this page, it should be noted that other organometallic species can be prepared from organic halides including organolithiums, organoaluminiums and organozincs, which also harbour similar challenges around reactivity and moisture sensitivity in both storage and batch reactions [2].
Challenges for Grignard preparation in flow
While the use of Grignard reagents within batch processes has been well-established for over a century, within continuous flow processing there were several challenges that needed to be overcome before widespread adoption could occur. For example, the pumps and hardware (tubing, mixer chips etc) needed to accommodate potentially exothermic processes, the reaction environment needed to be water- and oxygen-free, and precipitation of solid material should be avoided, as this could cause blockages. In the event, these challenges were not as significant and originally thought, and once it was realised that organomagnesium species could be used without concern, adoption by the flow chemistry community was rapid and innovation soared [3].
Benefits of continuous flow chemistry for organometallic reactions
The benefits of continuous flow chemistry in relation to use of organometallic species are numerous, with flow enabling efficient heat transfer and excellent control of reaction temperature, which is of particular importance when working with highly exothermic reactions.
Initial experiments either relied upon generation of a Grignard reagent in batch mode or use of commercially-available material, which were then reacted with an electrophile in flow mode. For example, in 2010 Rencurosi and co-workers [4] used pre-prepared organomagnesium species to access a range of secondary and tertiary alcohols in good yields, as well as the analgesic Tramadol (Scheme 2a), and in 2014 the Leadbeater group used this approach when developing a continuous flow approach to 3,3,3-trifluormethylpropenes (Scheme 2b)[5].
Scheme 2: (a) Rencurosi and co-workers used pre-prepared Grignard species to prepare a range of secondary and tertiary alcohols in good yields, as well as the analgesic Tramadol [4]; (b) the Leadbeater group used organomagnesium reagents to prepare 3,3,3-trifluormethylpropenes [5]. Image adapted from original paper.
The use of ‘turbo-Grignards’ in flow
The use of iPrMgCl•LiCl, also known as ‘turbo-Grignard’, was exploited by Knochel and Ley in 2012, when they disclosed one of the first procedures for generation and use of non-commercially available Grignard reagents in flow [6] using a Vapourtec R-Series system. In this work, aryl iodides and aryl bromides were first reacted with ‘turbo-Grignard’ to generate the requisite aryl-Grignard species, which was then quenched through addition of an electrophile, such as an aldehyde. A range of products were then prepared, in excellent yield.
This led to considerable further work in the field, and recent advances in ‘plug-and-play’ cartridges have enabled simple formation of ‘traditional’ Grignard reagents, as well as ‘turbo-Grignards’ (i.e. Grignards coordinated to LiCl), on large scale under flow conditions [7, 8]. Although ‘turbo-Grignards’ are a relatively recent innovation, they have potential to further transform the field due to advantages offered through the speed at which transmetallation can occur and the opportunity to use ‘non-traditional’ solvents, such as toluene, without the requirement for HMPA or an ethereal solvent to break up aggregates [9].
For completeness, it should be noted that as well as Grignards, other organometallic compounds have been prepared and used in flow including organolithiums, organozincs and organoaluminiums [10]. In some cases, their use in flow has proven superior to batch, due to the ability to accurately control temperature and tune the flow rates such that unstable species are used quickly, before they can degrade.
References
[1] The Grignard Reagents (D. Seyferth, Organometallics, 2009, 28, 6, 1598 – 1605) https://doi.org/10.1021/om900088z
[2] Preparation of Functionalized Lithium, Magnesium, Aluminum, Zinc, Manganese, and Indium Organometallics from Functionalized Organic Halides (G. Dagousset , C. François , T. Leόn , R. Blanc , E. Sansiaume-Dagousset and P. Knochel, Synthesis, 2014, 46, 23, 3133 – 3171) https://doi.org/10.1055/s-0034-1378672
[3] A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries (G. Gambacorta, J. S. Sharley and I. R. Baxendale, Belstein J. Org. Chem., 2021, 17, 1181 – 1312) https://doi.org/10.3762/bjoc.17.90
[4] Reaction of Grignard reagents with carbonyl compounds under continuous flow conditions (E. Riva, S. Gagliardi, M. Martinelli, D. Passarella, D. Vigo and A. Rencurosi, Tetrahedron, 2010, 66, 3242 – 3247) https://doi.org/10.1016/j.tet.2010.02.078
[5] A Continuous-Flow Approach to 3,3,3-Trifluoromethylpropenes: Bringing Together Grignard Addition, Peterson Elimination, Inline Extraction, and Solvent Switching (T. A. Hamlin, G. M. L. Lazarus, C. B. Kelly and N. E. Leadbeater, Org. Proc. Res. Dev., 2014, 18, 10, 1253 – 1258) https://doi.org/10.1021/op500190j
[6] Continuous Preparation of Arylmagnesium Reagents in Flow with Inline IR Monitoring (T. Brodmann, P. Koos, A. Metzger, P. Knochel, and S. V. Ley, Org. Proc. Res. Dev., 2012, 16, 1102 – 1113) https://doi.org/10.1021/op200275d
[7] Disposable cartridge concept for the on-demand synthesis of turbo Grignards, Knochel–Hauser amides, and magnesium alkoxides (M. Berton, K. Sheehan, A. Adamo and D. T. McQuade, Belstein. J. Org. Chem., 2020, 16, 1343 – 1356). https://doi.org/10.3762/bjoc.16.115
[8] Progress and developments in the turbo Grignard reagent i-PrMgCl•LiCl: a ten-year journey (R. L.-Y. Bao, R. Zhao and L. Shi, Chem. Commun., 2015, 51, 6884 – 6900) https://doi.org/10.1039/C4CC10194D
[9] Improving the Halogen-Magnesium Exchange by using New Turbo-Grignard Reagents (D. S. Ziegler, B. S. Wei and P. Knochel, Chem. Eur. J., 2019, 25, 11, 2695 – 2703) https://doi.org/10.1002/chem.201803904
[10] Synthesis of organometallic compounds in flow (T. Zhao, L. Micouin and R. Piccardi, Helv. Chim. Acta, 2019, 102, 11, e1900172) https://doi.org/10.1002/hlca.201900172
