Thiourea organocatalysis
Encyclopedia
urea organocatalysis describes the utilization of properly designed derivatives of urea
and - preferably - thiourea
to accelerate and stereochemically alter organic transformations through predominantly double hydrogen-bonding interactions with the respective substrate(s) (non-covalent organocatalysis
). The scope of these small-molecule H-bond donors termed (thio)urea organocatalysts covers both non-stereoselective and stereoselective applications in organic synthesis
(asymmetric organocatalysis).
In nature non-covalent interactions such as hydrogen bonding ("partial protonation
") play a crucial role in enzyme
catalysis
that is characterized by selective substrate recognition (molecular recognition), substrate activation, and enormous acceleration and stereocontrol of organic transformations.
Based on the pioneering examinations by Kelly, Etter, Jorgensen, Hine, Curran, Göbel, and De Mendoza (see review articles cited below) on hydrogen bonding interactions of small, metal-free compounds with electron-rich binding sites Schreiner and co-workers performed series of theoretical and experimental systematic investigations towards the hydrogen-bonding ability of various thiourea
derivatives.
These purely organic compounds were found to reveal significant rate enhancements of simple Diels-Alder reaction
, act like weak Lewis acid
catalysts, but operate through explicit double hydrogen bonding instead of covalent (strong) binding known from traditional metal
-ion mediated catalysis and BrØnsted-acid catalysis
.
thiourea derivative and combines all typical structural features for double H-bonding mediated organocatalysis:
Advantages of thiourea organocatalysts:
To date various organic transformations are organocatalyzed through double hydrogen-bonding N,N-bis[3,5-bis(trifluoromethyl)]phenyl thiourea at low catalyst loadings and in good to excellent product yields. This electron-poor thiourea derivative enjoys the status of being a privileged catalyst and represents the benchmark for the design of a broad variety of explicit double hydrogen-bonding (thio)urea organocatalysts - achiral, and chiral as well as monofunctional and bifunctional representatives:
Urea
Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....
and - preferably - thiourea
Thiourea
Thiourea is an organosulfur compound of with the formula SC2 . It is structurally similar to urea, except that the oxygen atom is replaced by a sulfur atom, but the properties of urea and thiourea differ significantly. Thiourea is a reagent in organic synthesis. "Thioureas" refers to a broad...
to accelerate and stereochemically alter organic transformations through predominantly double hydrogen-bonding interactions with the respective substrate(s) (non-covalent organocatalysis
Organocatalysis
In organic chemistry, the term Organocatalysis refers to a form of catalysis, whereby the rate of a chemical reaction is increased by an organic catalyst referred to as an "organocatalyst" consisting of carbon, hydrogen, sulfur and other nonmetal elements found in organic compounds...
). The scope of these small-molecule H-bond donors termed (thio)urea organocatalysts covers both non-stereoselective and stereoselective applications in organic synthesis
Organic synthesis
Organic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules can often contain a higher level of complexity compared to purely inorganic compounds, so the synthesis of organic compounds has...
(asymmetric organocatalysis).
In nature non-covalent interactions such as hydrogen bonding ("partial protonation
Protonation
In chemistry, protonation is the addition of a proton to an atom, molecule, or ion. Some classic examples include*the protonation of water by sulfuric acid:*the protonation of isobutene in the formation of a carbocation:2C=CH2 + HBF4 → 3C+ + BF4−*the protonation of ammonia in the...
") play a crucial role in enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
catalysis
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
that is characterized by selective substrate recognition (molecular recognition), substrate activation, and enormous acceleration and stereocontrol of organic transformations.
Based on the pioneering examinations by Kelly, Etter, Jorgensen, Hine, Curran, Göbel, and De Mendoza (see review articles cited below) on hydrogen bonding interactions of small, metal-free compounds with electron-rich binding sites Schreiner and co-workers performed series of theoretical and experimental systematic investigations towards the hydrogen-bonding ability of various thiourea
Thiourea
Thiourea is an organosulfur compound of with the formula SC2 . It is structurally similar to urea, except that the oxygen atom is replaced by a sulfur atom, but the properties of urea and thiourea differ significantly. Thiourea is a reagent in organic synthesis. "Thioureas" refers to a broad...
derivatives.
These purely organic compounds were found to reveal significant rate enhancements of simple Diels-Alder reaction
Diels-Alder reaction
The Diels–Alder reaction is an organic chemical reaction between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene system. The reaction can proceed even if some of the atoms in the newly formed ring are not carbon...
, act like weak Lewis acid
Lewis acid
]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...
catalysts, but operate through explicit double hydrogen bonding instead of covalent (strong) binding known from traditional metal
Metal
A metal , is an element, compound, or alloy that is a good conductor of both electricity and heat. Metals are usually malleable and shiny, that is they reflect most of incident light...
-ion mediated catalysis and BrØnsted-acid catalysis
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
.
Overview
Schreiner and co-workers identified and introduced electron-poor thiourea derivatives as hydrogen-bonding organocatalysts. N,N-bis,5-bis(trifluormethyl)phenyl thiourea is to date the most effective achiralChirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....
thiourea derivative and combines all typical structural features for double H-bonding mediated organocatalysis:
- electron-poor
- rigid structure
- non-coordinating, electron withdrawing substituents in 3,4, and/or 5 position of a phenyl ring
- the 3,5-bis(trifluoromethyl)phenyl-group is the preferred substituentSubstituentIn organic chemistry and biochemistry, a substituent is an atom or group of atoms substituted in place of a hydrogen atom on the parent chain of a hydrocarbon...
Advantages of thiourea organocatalysts:
- no product inhibition due to weak enthalpicEnthalpyEnthalpy is a measure of the total energy of a thermodynamic system. It includes the internal energy, which is the energy required to create a system, and the amount of energy required to make room for it by displacing its environment and establishing its volume and pressure.Enthalpy is a...
binding, but specific binding-“recognition“ - low catalyst-loading (down to 0.001 mol%)
- high TOF (Turn-Over-Frequency) values (up to 5,700 h−1)
- simple and inexpensive synthesis from primary amine functionalized (chiral-pool) starting materials and isothiocyanates
- easily to modulate and to handle (bench-stable), no inert gas atmosphere requireable
- immobilization on a solid phase (polymer-bound organocatalysts), catalyst recovery and reusability
- catalysis under almost neutral conditions (pka thiourea 21.0) and mild conditions, acid-sensitive substrates are tolerated
- metal-free, not toxic (compare traditional metal-containing Lewis-acid catalysts)
- water-tolerant, even catalytically effective in water or aqueous media
- environmentally benign ("Green ChemistryGreen ChemistryGreen Chemistry is a peer-reviewed scientific journal covering any aspect of green chemistry. It is published monthly by the Royal Society of Chemistry and was established in 1999 by James Clark . Articles have to be conceptually accessible to a wide audience...
"), sustainable catalysts
To date various organic transformations are organocatalyzed through double hydrogen-bonding N,N-bis[3,5-bis(trifluoromethyl)]phenyl thiourea at low catalyst loadings and in good to excellent product yields. This electron-poor thiourea derivative enjoys the status of being a privileged catalyst and represents the benchmark for the design of a broad variety of explicit double hydrogen-bonding (thio)urea organocatalysts - achiral, and chiral as well as monofunctional and bifunctional representatives: