Click chemistry
Encyclopedia
Click chemistry is a chemical philosophy introduced by K. Barry Sharpless
of The Scripps Research Institute, in 2001 and describes chemistry
tailored to generate substances quickly and reliably by joining small units together. This is inspired by the fact that nature
also generates substances by joining small modular units.
Click chemistry is not a specific reaction; it is a concept that mimicks nature.
The reactions in Click chemistry must (or would be desirable):
The process must (or would be desirable):
, protein
s are made from repeating amino acid
units and sugars are made from repeating monosaccharide
units. The connecting units are based on carbon - hetero atom bonds C-X-C rather than carbon - carbon bonds. In addition, enzyme
s ensure that chemical processes can overcome large enthalpy
hurdles by a series of reactions each requiring only a small energy step. Mimicking nature in organic synthesis is essential in the discovery of new pharmaceuticals given the large number of possible structures.
In 1996, Guida calculated the size of the pool of drug candidates at 1063, based on the presumption that a candidate consists of less than 30 non-hydrogen atoms, weighs less than 500 daltons, is made up of atoms of hydrogen
, carbon
, nitrogen
, oxygen
, phosphorus
, sulfur
, chlorine
and bromine
, and is stable at room temperature
and stable towards oxygen and water. Click chemistry in combination with combinatorial chemistry
, high-throughput screening
and building chemical libraries
speeds up new drug discoveries by making each reaction in a multistep synthesis fast, efficient and predictable.
Many of the Click chemistry criteria are subjective; and even if measurable and objective criteria could be agreed upon, it's unlikely that any reaction will be perfect for every situation and application. However, several reactions have been identified which fit the concept better than others:
using a Copper
(Cu) catalyst at room temperature
. It was discovered concurrently and independently by the groups of Valery V. Fokin and K. Barry Sharpless
at the Scripps Research Institute in California
and Morten Meldal in the Carlsberg Laboratory
, Denmark. Although the Cu(I)-catalyzed variant was first reported by Meldal and co-workers for the synthesis of peptidotriazoles on solid support, these authors did not recognize the potential of the reaction and did not make a connection with the click chemistry concept. Fokin and Sharpless independently described it as a reliable catalytic process offering "an unprecedented level of selectivity, reliability, and scope for those organic synthesis endeavors which depend on the creation of covalent links between diverse building blocks", firmly placing it among the most reliable processes fitting the click criteria.
Copper and ruthenium
are the commonly used catalysts in the reaction. The use of copper as a catalyst results in the formation of 1,4-regioisomer whereas ruthenium results in formation of the 1,5- regioisomer. A disadvantage of the Cu catalysed click reaction is that it does not work on internal alkynes. A mechanism for this reaction was originally proposed based on theoretical calculations.
Click chemistry also has been used for selectively labeling biomolecules within biological system. A click reaction that is to be performed in a living system needs to meet an even more rigorous set of criteria; it must be bioorthogonal, meaning the reagents used may not interact with the biological system in any way, nor may they be toxic. The reaction must also be carried out at neutral pH and at or around body temperature. Most click reactions have a high energy content which make the reactions irreversible and involve carbon-hetero atom bonding processes. An example of this is the Staudinger ligation
of azides.
, a privately held, Seattle based biotechnology company. The agreement with The Scripps Research Institute provides Allozyne
with a license to apply Click chemistry for exclusive development in key therapeutic fields in addition to a non-exclusive license for diagnostic applications.
K. Barry Sharpless
Karl Barry Sharpless is an American chemist known for his work on stereoselective reactions.-Early years:Sharpless was born in Philadelphia. He graduated from Friends' Central School in 1959. He continued his studies at Dartmouth College and earned his Ph.D from Stanford University in 1968...
of The Scripps Research Institute, in 2001 and describes chemistry
Chemistry
Chemistry is the science of matter, especially its chemical reactions, but also its composition, structure and properties. Chemistry is concerned with atoms and their interactions with other atoms, and particularly with the properties of chemical bonds....
tailored to generate substances quickly and reliably by joining small units together. This is inspired by the fact that nature
Nature
Nature, in the broadest sense, is equivalent to the natural world, physical world, or material world. "Nature" refers to the phenomena of the physical world, and also to life in general...
also generates substances by joining small modular units.
Click chemistry is not a specific reaction; it is a concept that mimicks nature.
The reactions in Click chemistry must (or would be desirable):
- be modular
- be wide in scope
- give very high chemical yields
- generate only inoffensive byproducts
- be stereospecific
- be physiologically stable
- exhibit a large thermodynamic driving force > 84 kJ/molMole (unit)The mole is a unit of measurement used in chemistry to express amounts of a chemical substance, defined as an amount of a substance that contains as many elementary entities as there are atoms in 12 grams of pure carbon-12 , the isotope of carbon with atomic weight 12. This corresponds to a value...
to favor a reaction with a single reaction product. A distinct exothermic reaction makes a reactant "spring-loaded". - have high atom economyAtom economyAtom economy describes the conversion efficiency of a chemical process in terms of all atoms involved . In an ideal chemical process, the amount of starting materials or reactants equals the amount of all products generated and no atom is wasted...
.
The process must (or would be desirable):
- have simple reaction conditions
- use readily available starting materials and reagents
- use no solvent or use a solvent that is benign or easily removed (preferably water)
- provide simple product isolation by non-chromatographic methods (crystallisation or distillationDistillationDistillation is a method of separating mixtures based on differences in volatilities of components in a boiling liquid mixture. Distillation is a unit operation, or a physical separation process, and not a chemical reaction....
)
Explanation
In biological systems and biochemistryBiochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
, protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s are made from repeating amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
units and sugars are made from repeating monosaccharide
Monosaccharide
Monosaccharides are the most basic units of biologically important carbohydrates. They are the simplest form of sugar and are usually colorless, water-soluble, crystalline solids. Some monosaccharides have a sweet taste. Examples of monosaccharides include glucose , fructose , galactose, xylose...
units. The connecting units are based on carbon - hetero atom bonds C-X-C rather than carbon - carbon bonds. In addition, 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...
s ensure that chemical processes can overcome large enthalpy
Enthalpy
Enthalpy 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...
hurdles by a series of reactions each requiring only a small energy step. Mimicking nature in organic synthesis is essential in the discovery of new pharmaceuticals given the large number of possible structures.
In 1996, Guida calculated the size of the pool of drug candidates at 1063, based on the presumption that a candidate consists of less than 30 non-hydrogen atoms, weighs less than 500 daltons, is made up of atoms of hydrogen
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
, carbon
Carbon
Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...
, nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
, oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
, phosphorus
Phosphorus
Phosphorus is the chemical element that has the symbol P and atomic number 15. A multivalent nonmetal of the nitrogen group, phosphorus as a mineral is almost always present in its maximally oxidized state, as inorganic phosphate rocks...
, sulfur
Sulfur
Sulfur or sulphur is the chemical element with atomic number 16. In the periodic table it is represented by the symbol S. It is an abundant, multivalent non-metal. Under normal conditions, sulfur atoms form cyclic octatomic molecules with chemical formula S8. Elemental sulfur is a bright yellow...
, chlorine
Chlorine
Chlorine is the chemical element with atomic number 17 and symbol Cl. It is the second lightest halogen, found in the periodic table in group 17. The element forms diatomic molecules under standard conditions, called dichlorine...
and bromine
Bromine
Bromine ") is a chemical element with the symbol Br, an atomic number of 35, and an atomic mass of 79.904. It is in the halogen element group. The element was isolated independently by two chemists, Carl Jacob Löwig and Antoine Jerome Balard, in 1825–1826...
, and is stable at room temperature
Room temperature
-Comfort levels:The American Society of Heating, Refrigerating and Air-Conditioning Engineers has listings for suggested temperatures and air flow rates in different types of buildings and different environmental circumstances. For example, a single office in a building has an occupancy ratio per...
and stable towards oxygen and water. Click chemistry in combination with combinatorial chemistry
Combinatorial chemistry
Combinatorial chemistry involves the rapid synthesis or the computer simulation of a large number of different but structurally related molecules or materials...
, high-throughput screening
High-throughput screening
High-throughput screening is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry. Using robotics, data processing and control software, liquid handling devices, and sensitive detectors, High-Throughput Screening allows a...
and building chemical libraries
Chemical library
A chemical library or compound library is a collection of stored chemicals usually used ultimately in high-throughput screening or industrial manufacture. The chemical library can consist in simple terms of a series of stored chemicals...
speeds up new drug discoveries by making each reaction in a multistep synthesis fast, efficient and predictable.
Many of the Click chemistry criteria are subjective; and even if measurable and objective criteria could be agreed upon, it's unlikely that any reaction will be perfect for every situation and application. However, several reactions have been identified which fit the concept better than others:
- [3+2] cycloadditionCycloadditionA cycloaddition is a pericyclic chemical reaction, in which "two or more unsaturated molecules combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity." The resulting reaction is a cyclization reaction.Cycloadditions are usually described by the...
s, such as the Huisgen 1,3-dipolar cycloaddition, in particular the Cu(I)-catalyzed stepwise variant, is often referred to simply as the "click reaction" - thiol-ene click reactions
- Diels-Alder reactionDiels-Alder reactionThe 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...
and inverse electron demand Diels-Alder reactionInverse electron demand Diels-Alder reactionThe Inverse electron demand Diels-Alder reaction, or DAINV is an organic chemical reaction, related to the Diels-Alder reaction. Unlike the Diels-Alder reaction, the DAINV is a cycloaddition between an electron-rich dienophile and an electron-poor diene. During a DAINV reaction, three pi-bonds... - [4+1] cycloadditionCycloadditionA cycloaddition is a pericyclic chemical reaction, in which "two or more unsaturated molecules combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity." The resulting reaction is a cyclization reaction.Cycloadditions are usually described by the...
s between isonitriles (isocyanides) and tetrazines - nucleophilic substitutionNucleophilic substitutionIn organic and inorganic chemistry, nucleophilic substitution is a fundamental class of reactions in which an electron nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms called the leaving group; the positive or partially positive...
especially to small strainedStrain (chemistry)In chemistry, a molecule experiences strain when its chemical structure undergoes some stress which raises its internal energy in comparison to a strain-free reference compound. The internal energy of a molecule consists of all the energy stored within it. A strained molecule has an additional...
rings like epoxyEpoxyEpoxy, also known as polyepoxide, is a thermosetting polymer formed from reaction of an epoxide "resin" with polyamine "hardener". Epoxy has a wide range of applications, including fiber-reinforced plastic materials and general purpose adhesives....
and aziridineAziridineAziridines are organic compounds containing the aziridine functional group, a three-membered heterocycle with one amine group and two methylene groups...
compounds - carbonyl-chemistry-like formation of ureaUreaUrea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....
s but not reactions of the aldolAldol reactionThe aldol reaction is a powerful means of forming carbon–carbon bonds in organic chemistry.Discovered independently by Charles-Adolphe Wurtz and Alexander Porfyrevich Borodin in 1872, the reaction combines two carbonyl compounds to form a new β-hydroxy carbonyl compound...
type due to low thermodynamic driving force. - addition reactionAddition reactionAn addition reaction, in organic chemistry, is in its simplest terms an organic reaction where two or more molecules combine to form a larger one....
s to carbon-carbon double bondDouble bondA double bond in chemistry is a chemical bond between two chemical elements involving four bonding electrons instead of the usual two. The most common double bond, that between two carbon atoms, can be found in alkenes. Many types of double bonds between two different elements exist, for example in...
s like dihydroxylation or the alkynes in the thiol-yne reactionThiol-yne reactionThe Thiol-yne reaction is an organic reaction between a thiol and an alkyne. The reaction product is an alkenyl sulfide...
.
Azide alkyne Huisgen cycloaddition
One of the most popular reactions within the click chemistry concept is the azide alkyne Huisgen cycloadditionAzide alkyne Huisgen cycloaddition
The Azide-Alkyne Huisgen Cycloaddition is a 1,3-dipolar cycloaddition between an azide and a terminal or internal alkyne to give a 1,2,3-triazole. Rolf Huisgen was the first to understand the scope of this organic reaction. American chemist K...
using a Copper
Copper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...
(Cu) catalyst at room temperature
Room temperature
-Comfort levels:The American Society of Heating, Refrigerating and Air-Conditioning Engineers has listings for suggested temperatures and air flow rates in different types of buildings and different environmental circumstances. For example, a single office in a building has an occupancy ratio per...
. It was discovered concurrently and independently by the groups of Valery V. Fokin and K. Barry Sharpless
K. Barry Sharpless
Karl Barry Sharpless is an American chemist known for his work on stereoselective reactions.-Early years:Sharpless was born in Philadelphia. He graduated from Friends' Central School in 1959. He continued his studies at Dartmouth College and earned his Ph.D from Stanford University in 1968...
at the Scripps Research Institute in California
California
California is a state located on the West Coast of the United States. It is by far the most populous U.S. state, and the third-largest by land area...
and Morten Meldal in the Carlsberg Laboratory
Carlsberg Laboratory
The Carlsberg Laboratory in Copenhagen, Denmark was created in 1875 by J. C. Jacobsen, the founder of the Carlsberg brewery, for the sake of advancing biochemical knowledge, especially relating to brewing. It featured a Department of Chemistry and a Department of Physiology...
, Denmark. Although the Cu(I)-catalyzed variant was first reported by Meldal and co-workers for the synthesis of peptidotriazoles on solid support, these authors did not recognize the potential of the reaction and did not make a connection with the click chemistry concept. Fokin and Sharpless independently described it as a reliable catalytic process offering "an unprecedented level of selectivity, reliability, and scope for those organic synthesis endeavors which depend on the creation of covalent links between diverse building blocks", firmly placing it among the most reliable processes fitting the click criteria.
Copper and ruthenium
Ruthenium
Ruthenium is a chemical element with symbol Ru and atomic number 44. It is a rare transition metal belonging to the platinum group of the periodic table. Like the other metals of the platinum group, ruthenium is inert to most chemicals. The Russian scientist Karl Ernst Claus discovered the element...
are the commonly used catalysts in the reaction. The use of copper as a catalyst results in the formation of 1,4-regioisomer whereas ruthenium results in formation of the 1,5- regioisomer. A disadvantage of the Cu catalysed click reaction is that it does not work on internal alkynes. A mechanism for this reaction was originally proposed based on theoretical calculations.
Applications
Click chemistry has widespread applications. Some of them are:- preparative organic synthesis of 1,4-substituted triazoleTriazoleTriazole refers to either one of a pair of isomeric chemical compounds with molecular formula C2H3N3, having a five-membered ring of two carbon atoms and three nitrogen atoms.The two isomers are:*1,2,3-Triazole 100px*1,2,4-Triazole 100px...
s - modification of peptide function with triazoles
- modification of natural products and pharmaceuticals
- drug discovery
- macrocyclizations using Cu(I) catalyzed triazole couplings
- modification of DNADNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
and nucleotideNucleotideNucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
s by triazole ligation - supramolecular chemistrySupramolecular chemistrySupramolecular chemistry refers to the area of chemistry beyond the molecules and focuses on the chemical systems made up of a discrete number of assembled molecular subunits or components...
: calixareneCalixareneA calixarene is a macrocycle or cyclic oligomer based on a hydroxyalkylation product of a phenol and an aldehyde. The word calixarene is derived from calix or chalice because this type of molecule resembles a vase and from the word arene that refers to the aromatic building block...
s, rotaxaneRotaxaneA rotaxane is a mechanically-interlocked molecular architecture consisting of a "dumbbell shaped molecule" which is threaded through a "macrocycle" . The name is derived from the Latin for wheel and axle...
s, and catenaneCatenaneA catenane is a mechanically-interlocked molecular architecture consisting of two or more interlocked macrocycles. The interlocked rings cannot be separated without breaking the covalent bonds of the macrocycles. Catenane is derived from the Latin catena meaning "chain"...
s - dendrimerDendrimerDendrimers are repetitively branched molecules. The name comes from the Greek word "δένδρον" , which translates to "tree". Synonymous terms for dendrimer include arborols and cascade molecules. However, dendrimer is currently the internationally accepted term. A dendrimer is typically symmetric...
design - carbohydrateCarbohydrateA carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
clusters and carbohydrate conjugation by Cu(1) catalyzed triazole ligation reactions - polymers
- material science
- nanotechnology, and
- Bioconjugation, for example, azidocoumarin.
Click chemistry also has been used for selectively labeling biomolecules within biological system. A click reaction that is to be performed in a living system needs to meet an even more rigorous set of criteria; it must be bioorthogonal, meaning the reagents used may not interact with the biological system in any way, nor may they be toxic. The reaction must also be carried out at neutral pH and at or around body temperature. Most click reactions have a high energy content which make the reactions irreversible and involve carbon-hetero atom bonding processes. An example of this is the Staudinger ligation
Staudinger reaction
The Staudinger reaction or Staudinger reduction is a chemical reaction in which the combination of an azide with a phosphine or phosphite produces an iminophosphorane intermediate. Combined with the hydrolysis of the aza-ylide to produce a phosphine oxide and an amine, this reaction is a mild...
of azides.
Technology License
On July 15, 2010, it was announced that The Scripps Research Institute signed a license agreement with AllozyneAllozyne
Allozyne is a clinical stage biotechnology company headquartered in Seattle’s biotech and high tech innovation corridor. Its lead product AZ01 is a long acting interferon beta for the treatment of the relapsing remitting form of multiple sclerosis, a chronic degenerative disease characterized by...
, a privately held, Seattle based biotechnology company. The agreement with The Scripps Research Institute provides Allozyne
Allozyne
Allozyne is a clinical stage biotechnology company headquartered in Seattle’s biotech and high tech innovation corridor. Its lead product AZ01 is a long acting interferon beta for the treatment of the relapsing remitting form of multiple sclerosis, a chronic degenerative disease characterized by...
with a license to apply Click chemistry for exclusive development in key therapeutic fields in addition to a non-exclusive license for diagnostic applications.
External links
- Professor Karl Barry Sharpless's Research Website including comprehensive list of click chemistry papers.
- Click Chemistry: Short Review and Recent Literature
- National Science Foundation: Feature "Going Live with Click Chemistry."
- Chemical and Engineering News: Feature "In-Situ Click Chemistry."
- Chemical and Engineering News: Feature "Copper-free Click Chemistry"
- Metal-free click chemistry review
- Click Chemistry - a Chem Soc Rev themed issue highlighting the latest applications of click chemistry, guest edited by M G Finn and Valery Fokin. Published by the Royal Society of ChemistryRoyal Society of ChemistryThe Royal Society of Chemistry is a learned society in the United Kingdom with the goal of "advancing the chemical sciences." It was formed in 1980 from the merger of the Chemical Society, the Royal Institute of Chemistry, the Faraday Society and the Society for Analytical Chemistry with a new...