In
organosulfur chemistry
Organosulfur compounds are organic compounds that contain sulfur. They are often associated with foul odors, but many of the sweetest compounds known are organosulfur derivatives, e.g., saccharin. Nature abounds with organosulfur compounds—sulfur ...
, the thiol-ene reaction (also alkene hydrothiolation) is an
organic reaction
Organic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, Mechanistic Organ ...
between a
thiol
In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...
() and an
alkene
In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond.
Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
() to form a
thioether
In organic chemistry, an organic sulfide (British English sulphide) or thioether is an organosulfur functional group with the connectivity as shown on right. Like many other sulfur-containing compounds, volatile sulfides have foul odors. A sul ...
(). This reaction was first reported in 1905,
but it gained prominence in the late 1990s and early 2000s for its feasibility and wide range of applications.
This reaction is accepted as a
click chemistry
In chemical synthesis, click chemistry is a class of biocompatible small molecule reactions commonly used in bioconjugation, allowing the joining of substrates of choice with specific biomolecules. Click chemistry is not a single specific reaction ...
reaction given the reactions’ high
yield,
stereoselectivity
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 of ...
, high
rate, and thermodynamic driving force.
![Basic schematic of thiol-ene addition reaction](https://upload.wikimedia.org/wikipedia/commons/6/6e/Basic_schematic_of_thiol-ene_addition_reaction.png)
The reaction results in an
anti-Markovnikov addition
In organic chemistry, Markovnikov's rule or Markownikoff's rule describes the outcome of some addition reactions. The rule was formulated by Russian chemist Vladimir Markovnikov in 1870.
Explanation
The rule states that with the addition of a ...
of a thiol compound to an alkene. Given the stereoselectivity, high rate and yields, this synthetically useful reaction may underpin future applications in material and biomedical sciences.
Mechanisms
Radical addition
Thiol-ene additions are known to proceed through two mechanisms: free-radical addition
In organic chemistry, free-radical addition is an addition reaction which involves free radicals. The addition may occur between a radical and a non-radical, or between two radicals.
The basic steps with examples of the free-radical addition (al ...
s and catalyzed Michael additions. Free-radical additions can be initiated by light, heat or radical initiators, which form a thiyl radical In chemistry, a thiyl radical has the formula RS, sometimes written RS• to emphasize that they are free radicals. R is typically an alkyl or aryl substituent. Because S–H bonds are about 20% weaker than C–H bonds, thiyl radicals are relativ ...
species. The radical then propagates with an ene functional group via an anti-Markovnikov addition
In organic chemistry, Markovnikov's rule or Markownikoff's rule describes the outcome of some addition reactions. The rule was formulated by Russian chemist Vladimir Markovnikov in 1870.
Explanation
The rule states that with the addition of a ...
to form a carbon-centered radical. A chain-transfer step removes a hydrogen radical from a thiol, which can subsequently participate in multiple propagation steps.[
Thiol-ene radical additions are advantageous for chemical synthesis because the step growth (propagation and chain-transfer steps) and chain growth (homopolymerization) processes can be effectively used to form homogeneous polymer networks. Photopolymerization is a useful radical-based reaction for applications within the nanotechnology, biomaterial, and material sciences, but these reactions are hindered by the inhibitory capabilities of ]oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
. The thiol-ene radical addition combines the benefits of photopolymerization
In polymer chemistry, polymerization (American English), or polymerisation (British English), is a process of reacting monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are many fo ...
reactions with the aforementioned advantages of click chemistry
In chemical synthesis, click chemistry is a class of biocompatible small molecule reactions commonly used in bioconjugation, allowing the joining of substrates of choice with specific biomolecules. Click chemistry is not a single specific reaction ...
reactions. This reaction is useful to the field of radical-based photopolymerization because it quantitatively and rapidly proceeds through a simple mechanism under ambient atmospheric conditions.[ The carbon-centered radical can undergo chain-growth polymerization depending on the thiol and ene functional groups. This free-radical polymerization can be useful in the synthesis of uniform polymer networks.]
Michael addition
Thiol-ene reactions are known to proceed through a Michael addition
In organic chemistry, the Michael reaction or Michael addition is a reaction between a Michael donor (an enolate or other nucleophile) and a Michael acceptor (usually an α,β-unsaturated carbonyl) to produce a Michael adduct by creating a carbon ...
pathway. These reactions are catalyzed by either a base or a nucleophile, resulting in a similar anti-Markovnikov addition
In organic chemistry, Markovnikov's rule or Markownikoff's rule describes the outcome of some addition reactions. The rule was formulated by Russian chemist Vladimir Markovnikov in 1870.
Explanation
The rule states that with the addition of a ...
product as the thiol-ene radical addition.
Kinetics
Click chemistry reactions are known to be high efficiency and have fast reaction rates, yet there is considerable variability in the overall reaction rate depending on the functionality of the alkene. To better understand the kinetics
Kinetics ( grc, κίνησις, , kinesis, ''movement'' or ''to move'') may refer to:
Science and medicine
* Kinetics (physics), the study of motion and its causes
** Rigid body kinetics, the study of the motion of rigid bodies
* Chemical ki ...
of thiol-ene reactions, calculations and experiments of transition-state and reaction enthalpies were conducted for a number of alkenes and their radical intermediates. It was shown that the reactivity and structure of the alkene determines whether the reaction will follow a step-growth or chain-growth pathway. It was also shown that the thiol-ene polymerization can be tuned by enhancing intermolecular interactions between the thiol and alkene functional groups. A currently accepted trend is that electron-rich alkenes (such as vinyl ether or allyl
In organic chemistry, an allyl group is a substituent with the structural formula , where R is the rest of the molecule. It consists of a methylene bridge () attached to a vinyl group (). The name is derived from the scientific name for garlic, ...
ether) and norbornene are highly reactive compared to conjugated and electron-poor alkenes (butadiene
1,3-Butadiene () is the organic compound with the formula (CH2=CH)2. It is a colorless gas that is easily condensed to a liquid. It is important industrially as a precursor to synthetic rubber. The molecule can be viewed as the union of two viny ...
and methoxyethene). In the case of norbornene and vinyl ether only step-growth is observed, no homopolymerization occurs after the formation of the carbon centered radical.[
]
Due to the complex kinetics of this two-step cyclic reaction, the rate-determining step
In chemical kinetics, the overall rate of a reaction is often approximately determined by the slowest step, known as the rate-determining step (RDS or RD-step or r/d step) or rate-limiting step. For a given reaction mechanism, the prediction of the ...
was difficult to delineate. Given that the rates of both steps must be equal, the concentration of the radical species is determined by the rate constant of the slower of the reaction steps. Thus the overall reaction rate (''R''P) can be modeled by the ratio of the propagation rate (''k''P) to the chain-transfer rate (''k''CT).The behavior of the reaction rate is outlined by the relationship below. In all cases the reaction is first order, when ''k''P ≫ ''k''CT q. 1the reaction rate is determined by the thiol concentration and the rate limiting step is chain-transfer, when ''k''P ≪ ''k''CT q. 2the reaction rate is determined by the alkene concentration and the rate limiting step is the propagation, and finally when ''k''P ≈ ''k''CT q. 3the reaction is half order with respect to both the alkene and thiol concentrations.
The functional groups on the thiol and alkene compounds can affect the reactivity of the radical species and their respective rate constants. The structure of the alkene determines whether the reaction will be propagation or chain-transfer limited, and therefore first order with respect to alkene or thiol concentration respectively. In the case of reactive alkenes, such as allyl ether, chain-transfer is the rate-limiting step, while in the case of less reactive alkenes, such as vinyl silazanes, propagation is the rate-limiting step. The thiol’s hydrogen affinity also affects the rate-limiting step. Alkyl thiols have less abstractable protons and therefore the chain-transfer step has a lower reaction rate than the propagation step.[
]
Most time the quasi-first-order reaction yields a kinetic rate equation
In chemistry, the rate law or rate equation for a reaction is an equation that links the initial or forward reaction rate with the concentrations or pressures of the reactants and constant parameters (normally rate coefficients and partial reacti ...
following the exponential decay
A quantity is subject to exponential decay if it decreases at a rate proportional to its current value. Symbolically, this process can be expressed by the following differential equation, where is the quantity and (lambda) is a positive rate ...
function for the reactants and products.
: ormalized thiol-ene product=
where ''k'' is an effective rate constant and ''t'' is time.
However, when the radical generation becomes the rate-limiting step, an induction period is often observed at the early stage of the reaction, for example, for photoinitiated reaction under weak light condition. The kinetic curve deviates from the exponential decay function for a common first-order reaction by having a slow growth period. The kinetic model has to include the radical generation step to explain this induction period (right figure). The final expression has a Gaussian-like shape.
: ormalized thiol-ene product=
where ''k'' is an effective rate constant and ''t'' is time.
Synthetically useful thiol-ene reactions
Initiation of cascade cyclization
The thiol-ene reaction (and analogous thiol-yne reaction) have extensively been used in generating reactive intermediates for the cyclization of unsaturated substrates. Radical hydrothiolation of an unsaturated functional group indirectly generates a carbon-centered radical, which can then cyclize intramolecularly onto alkenes, oxime ethers, isocyanide
An isocyanide (also called isonitrile or carbylamine) is an organic compound with the functional group –. It is the isomer of the related nitrile (–C≡N), hence the prefix is ''isocyano''.IUPAC Goldboo''isocyanides''/ref> The organic fragme ...
s, cyano groups, and aromatic rings. The use of thiyl radicals as initiators of cyclization has been employed in the synthesis of a number of natural products, including aplysins, α-kainic acid
Kainic acid, or kainate, is an acid that naturally occurs in some seaweed. Kainic acid is a potent neuroexcitatory amino acid agonist that acts by activating receptors for glutamate, the principal excitatory neurotransmitter in the central nervo ...
, asperparalines, and alkaloid
Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...
s such as narciclasine and lycoricidine.
Intramolecular thiol-ene reactions
Intramolecular thiol-ene reactions provide a means to create sulphur-containing heterocycles. The radical-initiated thiol-ene reaction has enabled the synthesis of four- to eight-membered rings, as well as macrocycles. While the radical thiol-ene reaction favors the anti-Markovnikov product, the regiochemistry
In chemistry, regioselectivity is the preference of chemical bonding or breaking in one direction over all other possible directions. It can often apply to which of many possible positions a reagent will affect, such as which proton a strong base ...
of the cycloaddition
In organic chemistry, a cycloaddition is a chemical reaction in which "two or more Unsaturated hydrocarbon, unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of th ...
depends on substituent effects and reaction conditions, which serve to direct the cyclization towards the thermodynamically or kinetically favored product respectively. This section examines intramolecular thiol-ene cyclization reactions, which yields a mixture of 5-''exo'' and 6-''endo'' products in order to facilitate a discussion of the factors, which may affect the regioselectivity of the intramolecular addition. This reaction has relevance for the synthesis of ''C''-linked thiosugars. Both the furanose and pyranose thiosugars can be prepared from the same thiyl radical precursor; 5-''exo'' and 6-''endo'' cyclizations of this precursor form the respective desired compound. The conditions under which these cyclization reactions occur follow Baldwin's rules
Baldwin's rules in organic chemistry are a series of guidelines outlining the relative favorabilities of ring closure reactions in alicyclic compounds. They were first proposed by Jack Baldwin in 1976.
Baldwin's rules discuss the relative rates ...
for ring closure.
''Cis''–''trans'' conversion of alkenes
Given the reversibility of the thiol-ene radical addition, the reaction can be used to facilitate ''cis''–''trans'' isomerizations. The thiyl radical propagates with the alkene to form a carbon-centered radical, the previous double bond now allows free rotation around the single sigma bond
In chemistry, sigma bonds (σ bonds) are the strongest type of covalent chemical bond. They are formed by head-on overlapping between atomic orbitals. Sigma bonding is most simply defined for diatomic molecules using the language and tools of s ...
. When the reverse reaction occurs, the orientation of the hydrogen addition on the carbon radical determines whether the isomerization product will be ''cis'' or ''trans''. Therefore, composition of the products depends on the conformational stability of the carbon-centered radical intermediate.
Potential applications
Dendrimer synthesis
Dendrimer
Dendrimers are highly ordered, branched polymeric molecules. Synonymous terms for dendrimer include arborols and cascade molecules. Typically, dendrimers are symmetric about the core, and often adopt a spherical three-dimensional morphology. The ...
s are promising in medicine, biomaterials, and nanoengineering
Nanoengineering is the practice of engineering on the nanoscale. It derives its name from the nanometre, a unit of measurement equalling one billionth of a meter.
Nanoengineering is largely a synonym for nanotechnology, but emphasizes the engine ...
. These polymers can functions as targeting components, detecting agents, and pharmaceutically-active compounds. Thiol-ene additions are useful in the divergent synthesis of dendrimers due to the characteristics of click chemistry such as the mild reaction conditions (benign solvents), regioselectivity
In chemistry, regioselectivity is the preference of chemical bonding or breaking in one direction over all other possible directions. It can often apply to which of many possible positions a reagent will affect, such as which proton a strong base ...
, high efficiency, high conversion and quantitative yield. Because this reaction is photo-initiated, it does not require copper
Copper is a chemical element with the symbol Cu (from la, cuprum) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkis ...
catalysis
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
, unlike other common reactions used in dendrimer preparation; this is advantageous for the synthesis of functional biomaterials given the inhibitory characteristic of copper on biological systems. Thiol-ene reactions have been used alongside anhydride, esterification
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...
, Grignard, and Michael reactions to functionalize chain ends and build polymer backbones in the synthesis of branched molecules such as glycodendrons, polythioether dendrimers and organosilicon thioether dendrimers.
A general strategy for the divergent synthesis of a dendrimer
Dendrimers are highly ordered, branched polymeric molecules. Synonymous terms for dendrimer include arborols and cascade molecules. Typically, dendrimers are symmetric about the core, and often adopt a spherical three-dimensional morphology. The ...
begins with a core; commonly-used cores include 2,4,6-triallyloxy-1,3,5-triazine, triallyl isocyanurate and tetravinylsilane. In a well cited report, 2,4,6-triallyloxy-1,3,5-triazine was mixed with 1-thioglycerol in the absence of solvent, the thiol-ene reaction was initiated by the radical initiator
In chemistry, radical initiators are substances that can produce radical species under mild conditions and promote radical reactions. These substances generally possess weak bonds—bonds that have small bond dissociation energies. Radical i ...
2,2-dimethoxy-2-phenylacetophenone and UV irradiation. Terminal alkene functional groups were added to the dendrimer via esterification
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...
by pent-4-enoic anhydride in the presence of DMAP and pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with a d ...
. The fourth generation product prepared in a stepwise fashion contains 48 terminal hydroxyl
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
groups[
]
Surface patterning
The thiol-ene functionalization of surface has been widely investigated in material science and biotechnology. The attachment of a molecule with a sterically accessible alkene or thiol group to a solid surface enables the construction of polymers on the surface through subsequent thiol-ene reactions.[ Given that in aqueous solutions thiol-ene reactions can be initiated by UV light (wavelength 365–405 nm) or sunlight, the attachment of a given functional group to the exposed thiol or alkene can be controlled spatially through photomasking.] More specifically, a photomask
A photomask is an opaque plate with holes or transparencies that allow light to shine through in a defined pattern. They are commonly used in photolithography and the production of integrated circuits (ICs or "chips") in particular. Masks are used ...
, enables the selective exposure of a surface to a UV light source, controlling the location of a given thiol-ene reaction, whereas the identity of the attached molecule is determined by the composition of the aqueous phase placed above the surface at the time of UV exposure. Thus, the manipulation of the shape of the photomask and the composition of the aqueous layer results in the creation of heterogeneous surface, whose properties depend on identity of the attached molecule at a given location.[
Thiol-ene functionalization of a surface can be achieved with a high level of spatial specificity, allowing the production of photomasks.][
Organo-triethoxysilane molecules, either thiol or vinyl tailed, have been introduced in surface functionalization. Ethoxysilane and methoxysilane functional groups are commonly used to anchor organic molecules on a variety of oxides surfaces. The thiol-ene coupling can be achieved either in the bulk solution before molecular anchoring ] or step-wise onto a substrate that enables photolithography. The reaction can be done in five minutes under sunlight that has ~4% UV light that is useful for the thiol-ene reaction.
Protein patterning on electron beam resist
Thiol-ene can also be used as an electron beam
Cathode rays or electron beam (e-beam) are streams of electrons observed in discharge tubes. If an evacuated glass tube is equipped with two electrodes and a voltage is applied, glass behind the positive electrode is observed to glow, due to ele ...
resist, resulting in nanostructures that allow direct protein functionalization.
See also
*Click chemistry
In chemical synthesis, click chemistry is a class of biocompatible small molecule reactions commonly used in bioconjugation, allowing the joining of substrates of choice with specific biomolecules. Click chemistry is not a single specific reaction ...
*Thiol-yne reaction The thiol-yne reaction (also known as alkyne hydrothiolation) is an organic reaction between a thiol and an alkyne. The reaction product is an alkenyl sulfide. The reaction was first reported in 1949 with thioacetic acid as reagent and rediscovere ...
*Off-stoichiometry thiol-ene polymer
An off-stoichiometry thiol-ene polymer is a polymer platform comprising off-stoichiometry thiol-enes (OSTE) and off-stoichiometry thiol-ene-epoxies (OSTE+).
The OSTE polymers comprise off-stoichiometry blends of thiols and allyls. After complete p ...
*Free-radical addition
In organic chemistry, free-radical addition is an addition reaction which involves free radicals. The addition may occur between a radical and a non-radical, or between two radicals.
The basic steps with examples of the free-radical addition (al ...
References
{{Reflist
Chemical reactions
Alkenes
Thiols