Are transition metals necessary in borrowing-hydrogen chemistry?

Abstract

Both C-N and C-C bond formation reactions are fundamental part of synthetic chemistry and have been widely studied for the past several decades and will most likely continue to do so in the future. In this project, I report a base catalyzed transition metal-free C-N and C-C bond formation reactions from abundant and green substrates with sustainable chemistry in mind. Previous methods uses either halides, transition metal or series of oxidation and reduction steps to produce similar C-N and C-C bonds. These methods except excluding transition metal-based catalyst are both atom inefficient, toxic or produces a lot of wastes. The transition metal-based catalyst method was later developed to overcome these drawbacks and utilizes hydrogen borrowing methodology. The borrowing-hydrogen methodology is much more atom efficient and less toxic as it only produces water as byproduct. The only drawback with this method is the usage of transition metal catalyst as well as to synthesize these catalysts which could be costly and toxic.

In this work, the reactions are less toxic, usage of abundant and greener substrates, more sustainable/greener with water as only byproduct, atom efficient and transition metal-catalyst free. The reaction for N-alkylation (C-N bond formation) was carried out with primary amine such as aniline and primary alcohol as benzyl alcohol with catalytic amount of KOtBu as base with toluene as solvent in closed air at 140ᵒC for 18h. For β-alkylation (C-C bond formation) the reaction was carried out with benzyl alcohol as primary alcohol and 1-phenyl ethanol as secondary alcohol with catalytic amount of KOH as base with toluene as solvent in closed air at 120ᵒC for 18 h shown in scheme 1. The methodologies utilize hydrogen transfer and the product from these reactions were successfully synthesized in 98% yield with only water as a byproduct. The reaction methods were then explored with various derivatives of the standard reaction substrates to investigate the scope of these reactions. The reactions were shown to be successful with various derivative of products which makes the reactions excellent atom efficient, cost effective, greener, and more sustainable methods for C-N and C-C bond formations.

Popular Abstract

The importance of carbon-carbon (C-C) and carbon-nitrogen (C-N) bond formation in pharmaceutical industry as well in general synthetic chemistry is fundamental and essential in many everyday products. Many drug that we take from time to time and for some, every day, in order to keep ourselves healthy are based on these methods for development of various drugs shown in Figure 1.

The bond formation methods are not just to make a bond between two atoms but also a tool to introduce various molecule groups to another molecule. These methods expand the complexity of the molecule which produces different products with desired effects such as the drug molecules mentioned.
Knowing the importance of the C-N and C-C bonds formation, many methods have been developed for the past decades and are still in focus to further improve the efficiency but also with sustainability in mind. Traditionally, making a C-N bond, it was common to use halides (Br, Cl, F) as part of the production process to form the desired C-N bond. Although it is a useful method, this method unfortunately has some large disadvantages where one of them is by generating a lot of waste in form of byproducts. The reactions also involve the use of toxic chemicals (Br, Cl, F) which is far from ideal when striving for greener and more sustainable methods. The N-alkylation (C-N bond formation) was then further improved by using transition metal-based catalyst which resulted in less toxic chemicals being used as well as greatly reducing the amount of byproducts with only water instead, making the reaction much more efficient and sustainable. The previously toxic chemicals (halides) are instead replaced with alcohols and amines which is much less toxic and more sustainable, although the reaction requires higher temperature (often 100ᵒC and higher) it is still considered better alternative. The reaction method was then even further improved by replacing the transition metal-catalyst with other organic chemicals such as nitrile and pyridine as a catalyst or activation molecule with the only drawback being, more waste generated than with transition metal-catalyst.
The situation is similar with β-alkylation (C-C bond formation) as it was traditionally produced by multi step synthesis. These series of reaction steps are less efficient due to the formation of byproducts in each step and generated a lot of waste. The reaction was then also improved by introducing transition metal-based catalysts to the reaction which utilizes a strategy called borrowing-hydrogen (BH) similar to N-alkylation, where the role of the metal was to catalyze the transferring of the hydrogens from the starting material into the product. The reaction uses primary and secondary alcohols which is a great improvement in green and sustainable chemistry as they are abundant and less toxic.
The methods are both atom efficient and less toxic compared to the previous mentioned method as it also only releases water as byproduct. As good as the reaction methods are, the reactions have a drawback which is the usage of transition metal-catalyst as it can be toxic and costly. This was later overcome by having the reaction run without the transition metal but using larger amount of base (stoichiometric) compared to catalytic amount of base with transition metal catalyst.
The aim of this project is therefor, to further improve and push the boundaries of C-N and C-C bond formation methodologies with sustainability and green chemistry in mind. This is done by developing and optimizing transition metal-catalyst free reactions but retaining most of advantages. In this project the methods are aimed to further reduce the amount of waste generated while still using less toxic and abundant chemicals. The reactions methods in this project do not require any activation agents or other chemicals to catalyze but the base itself. The reactions are thus less sensitive to air because of the absence of transition metal-catalyst but instead essential for the reaction to work. The reactions are also explored with various chemicals to synthesize different products to study the scope of the reaction methods.

• author: Tan, Mattias
• supervisor: Nitish Kumar Garg
• organization: Department of Chemistry
• course: KEMP30 20222
• year: 2023
• type: H2 - Master's Degree (Two Years)
• subject: Chemistry
• keywords: C-N bond formation, C-C bond formation, Transition metal-catalyst free, Base catalysed, Sustainability, Green chemistry, Borrowing hydrogen, Analytical chemistry
• language: English
• id: 9114571
• date added to LUP: 2023-05-22 10:46:34
• date last changed: 2023-05-22 10:46:34