Within the area of

organocatalysis In organic chemistry, organocatalysis is a form of catalysis in which the rate of a chemical reaction is increased by an organic catalyst. This "organocatalyst" consists of carbon, hydrogen, sulfur and other nonmetal elements found in organic com ...

, squaramide catalysis describes the use of

squaramide Squaramide is the organic compound with the formula O2C4(NH2)2. Not an amide in the usual sense, it is a derivative of squaric acid wherein the two OH groups are replaced by NH2 groups. Squaramides refer to a large class of derivatives wherein s ...

s to accelerate and stereochemically alter organic transformations. The effects arise through

hydrogen-bonding In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently ...

interactions between the substrate and the squaramide, unlike classic catalysts, and is thus a type of hydrogen-bond catalyst. The scope of these small-molecule H-bond donors termed squaramide organocatalysis covers both non-stereoselective and stereoselective applications.

Structure

A squaramide organocatalyst typically contains the

group and a hydrogen bond donor which is usually a

tertiary amine In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

group. The 3,5-bis(trifluoromethyl)phenyl-group is commonly used for the R group. For

enantioselective In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non- stereospecific creation of a new stereocenter or during a non-stereospecific transformation o ...

squaramide catalysis, chirality is induced via the tertiary amine group. There are cases where both sides of the squaramide are tertiary amines.

Catalyst-substrate interactions

Squaramide catalyst substrate interaction

The interaction between the substrate and the catalyst can be seen in the image above, with the

electrophile In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively Electric charge, charged, have an ...

being bound to the squaramide part and the protonated

nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...

to the amine part (which increases nucleophilicity). However, it must be noted that the position of the nucleophile and electrophile switch when the electrophile can only form one hydrogen bond, as in the case of most

imine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bon ...

Advantages of squaramide organocatalysts

Squaramide catalysts are easily prepared from starting materials like methyl squarate, possess high activities under low catalyst loadings. Squaramide catalysis can be a replacement for

thiourea organocatalysis Within the area of organocatalysis, (thio)urea organocatalysis describes the use of ureas and thioureas to accelerate and stereochemically alter organic transformations. The effects arise through hydrogen-bonding interactions between the substrat ...

in some scenarios. Squaramides have higher affinity for halide ions than thiourea.

Aqueous An aqueous solution is a solution in which the solvent is water. It is mostly shown in chemical equations by appending (aq) to the relevant chemical formula. For example, a solution of table salt, also known as sodium chloride (NaCl), in wat ...

mediums can be used.

Scope

H-bond accepting substrates include

carbonyl In organic chemistry, a carbonyl group is a functional group with the formula , composed of a carbon atom double bond, double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such a ...

compounds imines, Michael acceptors, and

epoxide In organic chemistry, an epoxide is a cyclic ether, where the ether forms a three-atom ring: two atoms of carbon and one atom of oxygen. This triangular structure has substantial ring strain, making epoxides highly reactive, more so than other ...

s. The nucleophile can be nitroalkanes,

enolate In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl () compounds. Rarely isolated, they are widely used as reagents in the Organic synthesis, synthesis of organic compounds. Bonding and structure Enolate ...

s, and even

phenols In organic chemistry, phenols, sometimes called phenolics, are a class of chemical compounds consisting of one or more hydroxyl groups (− O H) bonded directly to an aromatic hydrocarbon group. The simplest is phenol, . Phenolic compounds ar ...

(resulting in

electrophilic aromatic substitution Electrophilic aromatic substitution (SEAr) is an organic reaction in which an atom that is attached to an aromatic ring, aromatic system (usually hydrogen) is replaced by an electrophile. Some of the most important electrophilic aromatic substitut ...

). Subsequent

cascade reaction A cascade reaction, also known as a domino reaction or tandem reaction, is a chemical process that comprises at least two consecutive reactions such that each subsequent reaction occurs only in virtue of the chemical functionality formed in the p ...

s are possible.

History

Squaramides have been synthesized in 1966. Squaramide catalysts are developed in 2008 by Jeremiah P. Malerich, Koji Hagihara, and Viresh H. Rawal.

Catalysts

From the general structure of squaramide catalysts, a number of catalysts have been developed, most with the aim to enable chiral catalysis.

References

{{Reflist Catalysis Organic chemistry