Pivotal Role of the Basic Character of Organic and Salt Catalysts in C-N Bond Forming Reactions of Amines with CO2

Organocatalysts promote a range of C-N bond forming reactions of amines with CO2. Herein, we review these reactions and attempt to identify the unifying features of the catalysts that allows them to promote a multitude of seemingly unrelated reactions. Analysis of the literature shows that these reactions predominantly proceed by carbamate salt formation in the form [BaseH][RR ' NCOO]. The anion of the carbamate salt acts as a nucleophile in hydrosilane reductions of CO2, internal cyclization reactions or after dehydration as an electrophile in the synthesis of urea derivatives. The reactions are enhanced by polar aprotic solvents and can be either promoted or hindered by H-bonding interactions. The predominant role of all types of organic and salt catalysts (including ionic liquids, ILs) is the stabilization of the carbamate salt, mostly by acting as a base. Catalytic enhancement depends on the combination of the amine, the base strength, the solvent, steric factors, ion pairing and H-bonding. A linear relationship between the base strength and the reaction yield has been demonstrated with IL catalysts in the synthesis of formamides and quinazoline-2,4-diones. The role of organocatalysts in the reactions indicates that all bases of sufficient strength should be able to catalyze the reactions. However, a physical limit to the extent of a purely base catalyzed reaction mechanism should exist, which needs to be identified, understood and overcome by synergistic or alternative methods.

Organocatalysts in C-N Bond Forming Reactions of Amines with CO2

Martin Hulla

The thesis describes a simple approach for N-formylation of amines with CO2 and hydrosilane reducing agents, the use of organic salts as N-formylation catalysts, their physical properties required for high catalytic activity and their role in the catalytic cycle. The investigation is then extended to the synthesis of quinazoline-2,4(1H,3H)-dione from 2-aminobenzonitrile and CO2 as well as other C-N bond forming reactions. Basicity, as measured by pKb, is identified as the key property required for high catalytic activity of organic salt catalysts. Minor variations in catalytic activity among salts of equal basicity are assigned to the ion pairing energy, hydrogen bonding ability and steric factors. The N-formylation reaction catalysed by organic salts proceeds by the activation of the hydrosilane reducing agent. Although, the catalytic activity was originally assigned to the nucleophilicity of the anion, a detailed investigation of the reaction mechanism and physical parameters of numerous salt catalysts revealed that they are more active as bases. Extensive substituent exchange around the hydrosilane silicon centre confirms its activation and supports the proposed reaction mechanism, where in-situ formed carbamate salt acts as the reaction nucleophile. Accounting for small detrimental effect of ion paring, a linear relationship between the pKa of the salt and catalytic activity is observed. The onset of the base catalysed reaction mechanism is substrate dependent with further variations for amines of high basicity. Nevertheless, highly basic salt catalysts, such as tetra-n-butylammonium fluoride ([TBA]F), promote rapid N-formylation of all types of amines under extremely mild conditions. A linear relationship between the basicity of salt catalysts and their catalytic activity was also observed in the synthesis of quinazoline-2,4(1H,3H)-dione. Similarly, the reaction proceeds by in-situ formation of a carbamate salt, which requires a base catalyst. However, here the reaction mechanism is limited by the acidity of the quinazoline-2,4(1H,3H)-dione product. Quinazoline-2,4(1H,3H)-dione is deprotonated by more basic catalysts (pKa of conjugate acid > 14.7 in DMSO) leading to the neutralization of the base catalyst and the formation of the quinazolide anion, which then acts as the reaction catalyst. Analysis of the reported literature reveals that the findings are directly applicable to the vast majority of C-N bond forming reactions of amines with CO2 and to almost all types of organocatalysts. The reactions proceed by carbamate salt formation in the form [BaseH][RR'NCOO]. The anion of the carbamate salt then acts as a nucleophile in hydrosilane reductions of CO2 towards formamides, N-methylamines and aminals or internal cyclization reactions to quinazoline-2,4-diones, oxazolidinones and oxazin-2-ons or after dehydration as an electrophile in the synthesis of urea derivatives. The role of organocatalysts in the reactions indicates that all bases of sufficient strength should be able to catalyse the reactions.

EPFL2019

Novel Applications of Nitrous Oxide and Transition Metals for C-C and C-N Bond Formation

Gregor Kiefer

This thesis describes novel methods for and investigations into C–C and C–N bond formation reactions. Chapter 1 gives a very brief overview of established strategies for the formation of new C–C bonds in organic synthesis. In chapter 2, a multi‐step one‐pot synthesis is described. Arylalkynes and ethylene are converted to 2‐arylbutadienes by ruthenium catalyzed enyne metathesis. Upon addition of polyhalogenated substrates, the butadienes react in a 1,4‐atom transfer radical addition (ATRA) to yield 1,5‐dichloropen‐2‐enes. These form substituted vinylcyclopropanes via reductive 1,5 dechlorination with magnesium or manganese. Chapter 3 describes a study about two complex organometallic structures that form by reaction of rhodium(III) chloride with tert‐butylacetylene. The reaction products demonstrate the ability of rhodium to mediate various reactions of alkynes such as [2+2+1] cycloadditions, oxidative cleavages and others. Cobalt‐catalyzed reactions for C–C bond formation are reported in chapter 4. In the first part, the focus lies on the putative pre‐catalysts [CoX2(dppe)] (X = Cl, Br, I; dppe = diphenylphosphinoethane), which are used together with a reducing agent (e. g. zinc) in a wide range of C–C bond formation reactions. It is shown that they are, in reality, complex salts of the formula [CoX(dppe)2]2[X3Co(dppe)CoX3]. The second part describes the synthesis and characterization of the complexes [CoX(dppe)(PPh3)] and [CoX(dppe)(η4‐isoprene)]. Without addition of a reducing agent, these cobalt(I) complexes catalyze reactions that are usually accomplished with the catalyst system Co(II)/dppe/Zn. These results provide evidence that the active species in these reactions are indeed Co(I) complexes as supposed. In the fifth chapter, two methods for the use of nitrous oxide (N2O, laughing gas) in organic reactions are described. The challenge of using N2O in synthetic chemistry is to overcome its kinetic inertness. In the oxidative homo‐ and cross‐coupling of Grignard reagents, N2O takes the role of an oxidizing agent. The reactions proceed under mild conditions with copper, iron and cobalt salts as catalysts and exhibit high turnover numbers. The utilization of N2O has advantages compared to established methods with other oxidation agents such as oxygen. Furthermore, a procedure for the synthesis of triazenes from lithium dialkylamides, N2O and Grignard reagents is described. This method enables the synthesis of aryl and alkyl triazenes, but also alkenyl and alkynyl triazenes that are difficult to access via established procedures. Some alkynyl triazenes are selectively cytotoxic against certain cancer cell lines.

EPFL2015

Organic molecules as mediators and catalysts for photocatalytic and electrocatalytic CO2 reduction

Xile Hu, Yeonji Oh

Reduction of CO2 by electrochemical and photoelectrochemical methods to produce carbon-rich fuels is a heavily pursued research theme. Most of the current efforts are focused on the development of transition-metal-based catalysts. In this tutorial review, we present an overview of the development of organic molecules as mediators and catalysts for CO2 reduction. Four classes of organic molecules are discussed: tetraalkylammonium salts, aromatic esters and nitriles, ionic liquids, and pyridinium derivatives. It is shown that reactions mediated or catalyzed by these organic molecules can be competitive compared to their metal-catalyzed counterparts, both in terms of product selectivity and energy efficiency.