Methanimine: a C-N building block realised
Lead Research Organisation:
University of Bath
Department Name: Chemistry
Abstract
We have developed an Iron pre-catalyst which is easily synthesised on a multigram scale using reagent grade
ethanol, Fe(OAc)2 and a salen ligand. It was recently ascertained that the Iron pre-catalyst can undertake a range of
transformations using HBpin as a key additive. A transformation that was of particular interest was the reduction of
nitromethane to methanimine within minutes at room
temperature to form a methanimine adduct.
Methanimine is an incredibly unstable molecule only detected in the interstellar medium; previously when prepared in
the lab it instantly oligomerises. We believe this simplest of organic building blocks is isolable because it forms as the
borane-protected adduct. The Adduct is indefinitely stable in dry solvent. Due to the instability of methanimine its
reactivity in organic synthesis is unexplored: this is the basis / aim of this project.
The catalytic transformation is so fast and methanimine is so reactive that, in order to achieve good yield of the
methanimine adduct, careful addition of reagents is important as is order of addition. There are huge limitations when
using batch chemistry for such a process and this is where developing flow techniques for synthesis will help to
overcome issues related to reagent handling, reaction control and reaction scale. This will help us to prove that this
unique molecule is viable beyond the academic chemistry lab. From there a stability study will be undertaken to
investigate whether this molecule can be used or prepared commercially. We will investigate solution, moisture,
heating and light stability of the methanimine adduct by exposing the compound to a range of different conditions.
To the best of our knowledge, there is no current mild method for the synthesis of methanimine. Development of this
methodology could create an opportunity for the use of methanimine as a synthon in both an industrial and academic
setting. From this starting point we have the potential to synthesise a range o f novel organic motifs.
The second supervisor Mike Nunn is based at AstraZeneca and will supervise me during my 3 month industrial
placement at AstraZeneca.
The third supervisor Antoine Buchard has expertise in both [Fe] catalysis and DFT studies. He will therefore act as a
point of call for issues in this area and specifically if the project requires it will show me how to conduct DFT studies
further down the line.
This project involves a diverse mix of synthetic organic chemistry, flow and scale-up synthesis. There are
opportunities for the student to become involved in more fundamental studies related to the mechanistic aspects of
methanimine formation including, kinetics (in situ/flow NMR monitoring using Bath's DReaM facility, ReactIR in RW's
lab) and EPR (through a collaboration with experts at Cardiff University).
If the stability studies prove fruitful, we would like to explore the possibility of IP protection with AZ and the
commercialisation team at the University of Bath (of both the synthetic route to the methanimine synthon and the
method of imine stabilisation). Ideally the work on synthesis in flow and some selected initial organic transformations
will make a major contribution to our initial disclosure of this iron catalysed process. The uniqueness of this
transformation of nitromethane is such that we hope this submission will be to a top-tier journal such as Science,
Nature or Nature Chemistry.
ethanol, Fe(OAc)2 and a salen ligand. It was recently ascertained that the Iron pre-catalyst can undertake a range of
transformations using HBpin as a key additive. A transformation that was of particular interest was the reduction of
nitromethane to methanimine within minutes at room
temperature to form a methanimine adduct.
Methanimine is an incredibly unstable molecule only detected in the interstellar medium; previously when prepared in
the lab it instantly oligomerises. We believe this simplest of organic building blocks is isolable because it forms as the
borane-protected adduct. The Adduct is indefinitely stable in dry solvent. Due to the instability of methanimine its
reactivity in organic synthesis is unexplored: this is the basis / aim of this project.
The catalytic transformation is so fast and methanimine is so reactive that, in order to achieve good yield of the
methanimine adduct, careful addition of reagents is important as is order of addition. There are huge limitations when
using batch chemistry for such a process and this is where developing flow techniques for synthesis will help to
overcome issues related to reagent handling, reaction control and reaction scale. This will help us to prove that this
unique molecule is viable beyond the academic chemistry lab. From there a stability study will be undertaken to
investigate whether this molecule can be used or prepared commercially. We will investigate solution, moisture,
heating and light stability of the methanimine adduct by exposing the compound to a range of different conditions.
To the best of our knowledge, there is no current mild method for the synthesis of methanimine. Development of this
methodology could create an opportunity for the use of methanimine as a synthon in both an industrial and academic
setting. From this starting point we have the potential to synthesise a range o f novel organic motifs.
The second supervisor Mike Nunn is based at AstraZeneca and will supervise me during my 3 month industrial
placement at AstraZeneca.
The third supervisor Antoine Buchard has expertise in both [Fe] catalysis and DFT studies. He will therefore act as a
point of call for issues in this area and specifically if the project requires it will show me how to conduct DFT studies
further down the line.
This project involves a diverse mix of synthetic organic chemistry, flow and scale-up synthesis. There are
opportunities for the student to become involved in more fundamental studies related to the mechanistic aspects of
methanimine formation including, kinetics (in situ/flow NMR monitoring using Bath's DReaM facility, ReactIR in RW's
lab) and EPR (through a collaboration with experts at Cardiff University).
If the stability studies prove fruitful, we would like to explore the possibility of IP protection with AZ and the
commercialisation team at the University of Bath (of both the synthetic route to the methanimine synthon and the
method of imine stabilisation). Ideally the work on synthesis in flow and some selected initial organic transformations
will make a major contribution to our initial disclosure of this iron catalysed process. The uniqueness of this
transformation of nitromethane is such that we hope this submission will be to a top-tier journal such as Science,
Nature or Nature Chemistry.
People |
ORCID iD |
| Ruth Webster (Primary Supervisor) | |
| Emily POCOCK (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/V519637/1 | 01/10/2020 | 30/09/2025 | |||
| 2436870 | Studentship | EP/V519637/1 | 01/10/2020 | 30/09/2024 | Emily POCOCK |
| Description | Iron catalysis offers an attractive alternative to the more commonly-used precious metals due to its high abundance and low cost, along with the additional benefits of being a non-toxic and environmentally-benign metal. A large number of transition metal salen complexes have been reported and are capable of mediating lots of organic transformations. Complexes containing these ligands are highly versatile due to the ligand's modular nature and synthesis scalability. Inspired by this the Webster group successfully demonstrated the ability of iron supported by the 'most simple' salen (salen = N,N'-bis(salicylidene)ethane-1,2-diamine) ligand to catalyse both hydrophosphination reactions and more recently, the trimerizations of alkynes and hydroboration of carbonyls. While iron catalysis is becoming prevalent in a range of organic transformations the iron-catalysed reduction of nitro-groups is relatively underdeveloped. With current methods often requiring longer reaction times and high catalyst loadings and temperatures. The reduction of nitro-compounds has been a transformation of great synthetic interest throughout the years due to the wide variety of resulting products that can be accessed. In particular, the complete reduction of the nitro moiety to the corresponding amine is of great importance owing to the fact amines are known to be versatile organic building blocks. Amines are prevalent in a range of different industries such as chemical, pharmaceutical, and material. Throughout the literature a variety of different methods have been reported for the synthesis of amines including but not limited to the alkylation of ammonia, reduction of nitriles, reduction of amides and reductive amination of carbonyls. The limitations associated with these methods mean that the reduction of nitro-compounds offers an alternative and convenient method for accessing functionalised amines. In light of this, herein we report the use of the Fe-salen catalyst alongside a reducing agent for the selective one-step reduction of various nitro-compounds to yield synthetically-important products under mild reaction conditions in short reaction times. Based on our understanding of how the mechanism for pre-activation of the catalyst proceeds and comparison to current literature, we successfully extended the reactivity to one-pot hydroaminations and other highly desirable organic transformations. (Due to the ongoing work being in the process of being published at this stage specific details cannot be given). |
| Exploitation Route | The hope is to further investigate the scope and limitations of this catalytic system to synthesise additional synthetically useful products. |
| Sectors | Chemicals,Pharmaceuticals and Medical Biotechnology |