Catalytic Amidation Guide

We believe that catalytic amidation methods have now reached the stage where they could readily be employed by many researchers in their day-to-day lab work. We would like to see them adopted more widely as a ‘go to’ method for preparing amides that is routinely used in place of common stoichiometric coupling reagents. This could greatly reduce the wsste associated with synthetic chemistry operations, especially given that amidation is one of the most common reactions used in organic chemistry. This is turn would lead to environmental benefits and cost savings in most cases, by avoiding the generation of stoichiometric byproducts. However, we recognise that most people have no experience or knowledge about the various catalytic methods available particularly with regard to reaction setup and the scope of the reactions. The aim of this page is to provide chemists with a ‘user guide’ for catalytic amidaiton reactions that can help with details of reaction setup and catalyst choice. This information will be updated over time with the addition of flowcharts to facilitate catalyst choice and reaction conditions.

Dehydration Methods

The catalytic amidation between a carboxylic acid and an amine only generates a single benign stoichiometric byproduct – water. This enables the process to be extremely efficient in comparison to reactions that employ typical amide coupling reagents, and can make purification of the reaction products very straightforward. However, the accumulation of water in the reaction mixture can often impede catalysis so water removal methods are normally employed to achieve high conversions in catalytic amidation reactions. Although there are many reports in the literature that claim various particular catalytic amidation reactions do not require water removal in our experience this is not generally the case. Whilst small-scale reactions can often be performed without active water removal, on a larger (multigram) scale active water removal is generally essential for high conversions to be obtained. The most common approaches are summarised below:

Dean-Stark water removal: By carrying out the reaction at reflux in a suitable solvent (toluene, tert-amyl methyl ether, tert-butyl acetate, etc), water can be efficiently removed azeotropically using a Dean-Stark apparatus. This is easy to setup, highly efficient and readily scalable, allowing reactions to be performed easily on multigram scales at relatively high concentration. A key disadvantage is that reactions must be performed at reflux, and only a limited range of solvents which form effective azeotropes with water (and are immiscible with water in the liquid phase) can be employed. Higher temperatures may result in significant decomposition of the reactants and/or catalysts. However, this remains the most efficient approach for larger scale reactions. This approach is recommended for your amidation reaction if your reactants are at least partially soluble in a suitable solvent and are stable to the temperatures employed, as it is the only method that does not require the use of a stoichiometric dehydrating agent.

Soxhlet extraction: In a similar approach to the Dean-Stark approach, a Soxhlet apparatus can be used to remove water from the reaction mixture through the use of a dehydrating agent (e.g. molecular sieves) in the Soxhlet thimble. Again, reflux temperature are required for this approach but the reaction is no longer limited to solvents that are immiscible with water in the liquid phase. Azeotropic removal of the water is still required, however. The use of stoichiometric dehydrating agents means the approach is less efficient than a Dean-Stark apparatus but is worth considering if your amidation reaction cannot be performed in a suitable solvent for a Dean-Stark dehydration. This approach benefits from simple separation of the dehydrating agents from the products leading to lower solvent use.

Dehydrating agent in the reaction: In many cases a dehydrating agent (e.g. molecular sieves) can be added directly into the catalytic amidation reaction to remove water from the mixture directly, without the need for reflux temperatures. This approach offers the mildest reaction conditions, and effective catalysis has even been achieved at room temperature although moderate heating is typically used for less reactive substrates. The main disadvantage of this approach is the increased solvent requirements – reactions often need to be considerably more dilute due to the often large quantities of dehydrating agents used; an inert atmosphere and anhydrous solvent is often essential Additional solvent is also required when separating the dehydrating agent from the products as extensive washing may be needed to separate the amide product from the dehydrating agent. However, a wide range of solvents can be employed and the milder temperatures used are more compatible with sensitive substrates. Molecular sieves typically require extensive pre-drying at high temperature before use in order to work well in the reaction.

Solvent Choice

Most catalytic amidation reactions are performed in relatively non-polar solvents including aromatic hydrocarbons (toluene, benzene, fluorobenzene, mesitylene, anisole) or ethers (THF, Et2O, tert-amyl methyl ether) though chlorinated solvents (CH2Cl2), esters (tert-butyl acetate) and nitriles (EtCN) have also been employed. To the best of our knowledge, there are no reports of catalytic amidation reactions in highly polar solvents (DMSO, DMF) or alcohols/water, in contrast to stoichiometric amide coupling reactions. The choice of solvents for your reaction will primarily depend on the solubility of your carboxylic acid/amine (and the salt they may form), although it should be noted that the reactants often only need to be slightly soluble for the catalytic amidation reaction to proceed efficiently. We also recommend consultation of green solvent guides such as the CHEM21 solvent selection guide to take into account safety and sustainability considerations for the various solvents.

Catalyst Choice

A bewildering array of catalysts have been reported for amidation reactions and you can find an extensive list starting to appear on our methods page which provides an overview of the reaction scope of the various catalysts as well as links to the original literature and relevant commercial suppliers. The list of considerations below is designed to help you select the most suitable (and cost effective) catalyst for your reaction that should have the best chance of succeeding.

1. How reactive are your substrates? If your carboxylic acid and amine do not couple well with a standard amide coupling reagent (e.g. EDC, T3P, etc) then they are unlikely to work well in a catalytic amidation reaction. It should be noted however, that catalytic amidation reactions often display higher chemoselectivity for amide formation (e.g. esterification of alcohols is not generally observed; carboxylic acid of unprotected amino acids can undergo selective amidation) so in some cases a catalytic amidation reaction may be higher yielding.

Reactive amines: aliphatic amines, electron-rich or electron neutral anilines, cyclic secondary amines.

Lower reactivity amines: hindered amines, electron-deficient or sterically hindered anilines, acylic secondary amines, amino acid derivatives, electron-deficient aliphatic amines, amines containing polar functional groups.

Reactive carboxylic acids: Unhindered aliphatic/aromatic carboxylic acids, relatively non-polar carboxylic acids.

Lower reactivity carboxlic acids: Strongly acidic carboxylic acids (pKa <4?), sterically hindered carboxylic acids, heteroaromatic carboxylic acids (CO2H bonded to heterocycle), protected/unprotected amino acids, carboxylic acids containing polar functional groups.

As a general guide, the following catalyst selection approach is sensible:

Reactive acid/amine pair: If both reaction partners are reactive, then almost any catalyst should work for the reaction. Consequently, it would be sensible to initially screen the cheapest catalysts such as boric acid, a simple boronic acid [e.g. PhB(OH)2] or Ti(OiPr)4. If your substrates are compatible, then Dean-Stark conditions will provide the most efficient and low-cost approach. If these catalysts are ineffective, then see below….

Reactive amine + unreactive acid or Reactive acid + unreactive amine: Either of these combinations will likely require the use of a more reactive amidation catalyst. Possibilities include B(OCH2CF3)3, functionalised boronic acids, a B-N-B heterocyclic catalyst or a Zr catalyst. In most cases it is likely that a catalytic amidation reaction can be identified that will provide a good yield of amide.

Lower reactivity amine + lower reactivity carboxylic acid: In this situation, only the most reactive catalysts are likely to work and even then the reaction may be low-yielding. Possible catalysts to try initially: B(OCH2CF3)3, B-N-B heterocyclic catalyst.

More content to come……flowcharts, typical reaction procedures, etc

Tel: +44 (0)20 7679 2467 Email:

site by orang-utan productions