HOME

TheInfoList




Hydroamination is the addition of an N-H bond of an
amine In organic chemistry Organic chemistry is a branch of chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, ...

amine
across a carbon-carbon multiple bond of an
alkene In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo dur ...

alkene
,
alkyne In organic chemistry Organic chemistry is a branch of that studies the structure, properties and reactions of s, which contain in .Clayden, J.; Greeves, N. and Warren, S. (2012) ''Organic Chemistry''. Oxford University Press. pp. 1–15. . ...

alkyne
,
diene In organic chemistry Organic chemistry is a branch of that studies the structure, properties and reactions of s, which contain in .Clayden, J.; Greeves, N. and Warren, S. (2012) ''Organic Chemistry''. Oxford University Press. pp. 1–15. . ...

diene
, or
allene Allenes are organic compounds In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and ...

allene
. In the ideal case, hydroamination is
atom economical
atom economical
and
green Green is the color between blue and yellow on the visible spectrum. It is evoked by light which has a dominant wavelength of roughly 495570 Nanometre, nm. In subtractive color systems, used in painting and color printing, it is created by ...
. Amines are common in fine-chemical, pharmaceutical, and agricultural industries. Hydroamination can be used intramolecularly to create heterocycles or intermolecularly with a separate amine and unsaturated compound. The development of
catalyst Catalysis () is the process of increasing the rate of a chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substance A chemical substance is a form of matter In cla ...

catalyst
s for hydroamination remains an active area, especially for alkenes. Although practical hydroamination reactions can be effected for dienes and electrophilic alkenes, the term hydroamination often implies reactions metal-catalyzed processes.


History

Hydroamination is well-established technology for generating fragrances from
myrcene Myrcene, or β-myrcene, is an alkene In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, beh ...

myrcene
. In this conversion, diethylamine adds across the diene substituent, the reaction being catalyzed by lithium diethylamide. Intramolecular hydroaminations were reported by Tobin J. Marks in 1989 using
metallocene A metallocene is a compound typically consisting of two cyclopentadienyl anions (, abbreviated Cp) bound to a metallic element, metal center (M) in the oxidation state II, with the resulting general formula Closely related to the metallocenes are ...
derived from
rare-earth metals The rare-earth elements (REE), also called the rare-earth metals or (in context) rare-earth oxides, or the lanthanides (though yttrium and scandium are usually included as rare-earths) are a set of 17 nearly-indistinguishable lustrous silvery- ...
such as
lanthanum Lanthanum is a chemical element In chemistry, an element is a pure Chemical substance, substance consisting only of atoms that all have the same numbers of protons in their atomic nucleus, nuclei. Unlike chemical compounds, chemical elemen ...

lanthanum
,
lutetium Lutetium is a chemical element In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavio ...

lutetium
, and
samarium Samarium is a chemical element In chemistry, an element is a pure Chemical substance, substance consisting only of atoms that all have the same numbers of protons in their atomic nucleus, nuclei. Unlike chemical compounds, chemical element ...

samarium
. Catalytic rates correlated inversely with the
ionic radius Ionic radius, ''r''ion, is the radius of a monatomic ion An ion () is an atom An atom is the smallest unit of ordinary matter In classical physics and general chemistry, matter is any substance that has mass and takes up space by h ...
of the metal, perhaps as a consequence of steric interference from the ligands. In 1992, Marks developed the first
chiral Chirality is a property of asymmetry Asymmetry is the absence of, or a violation of, symmetry (the property of an object being invariant to a transformation, such as reflection). Symmetry is an important property of both physical and abstrac ...
hydroamination catalysts by using a chiral auxiliary, which were the first hydroamination catalysts to favor only one specific
stereoisomer In stereochemistry s. Stereochemistry focuses on stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but ...
. Chiral auxiliaries on the metallocene ligands were used to dictate the stereochemistry of the product. The first non-metallocene chiral catalysts were reported in 2003, and used bisarylamido and aminophenolate ligands to give higher
enantioselectivity In chemistry, an enantiomer ( ; ) (also named optical isomer, antipode, or optical antipode) is one of two stereoisomers that are mirror images of each other that are non-superposable (not identical), much as one's left and right Chirality (chemi ...
.


Reaction scope

Hydroamination has been examined with a variety of amines, unsaturated substrates, and vastly different catalysts. Amines that have been investigated span a wide scope including primary, secondary, cyclic, acyclic, and
aniline Aniline is an organic compound In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior an ...

aniline
s with diverse
steric Steric effects are nonbonding interactions that influence the shape (conformation Conformation generally means structural arrangement and may refer to: * Conformational isomerism, a form of stereoisomerism in chemistry ** Carbohydrate conformat ...
and
electronic Electronic may refer to: *Electronics Electronics comprises the physics, engineering, technology and applications that deal with the emission, flow and control of electrons in vacuum and matter. It uses active devices to control electron flow b ...
substituents. The unsaturated substrates that have been investigated include alkenes, dienes, alkynes, and allenes. For intramolecular hydroamination, various aminoalkenes have been examined.


Products

Addition across the unsaturated carbon-carbon bond can be
Markovnikov Markovnikov (russian: Марковников) is a Russian masculine surname, which originates from ''морковь'' (''carrot''); its feminine counterpart is Markovnikova. It may refer to * Nikolai Markovnikov (1869–1942), Russian architect and ...

Markovnikov
or depending on the catalyst. When considering the possibly of R/S chirality, four products can be obtained: Markovnikov with R or S and anti-Markovnikov addition with R or S. Although there have been many reports of catalytic hydroamination with a wide range of metals, there are far fewer describing
enantioselective In chemistry, an enantiomer ( ; ) (also named optical isomer, antipode, or optical antipode) is one of two stereoisomers that are mirror images of each other that are non-superposable (not identical), much as one's left and right Chirality (chemi ...
catalysis to selectively make one of the four possible products. Recently, there have been reports of selectively making the thermodynamic or kinetic product, which can be related to the racemic Markovnikov or anti-Markovnikov structures (see Thermodynamic and Kinetic Product below).


Catalysts and catalytic cycle

Hydroamination reactions are atom-efficient processes that generally use readily available and cheap starting materials, therefore a general catalytic strategy is highly desirable. Also, direct catalytic hydroamination strategies have in principle significant benefits over more classical methods to prepare amine containing compounds, including the reduction in the number of synthetic steps required. However, hydroamination reactions pose some tough challenges for catalysis: Strong electron repulsion of the nitrogen atom
lone pair In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts A fact is an occurrence in the ...
and the electron rich carbon-carbon multiple bond, coupled with hydroamination reactions being entropically disfavoured (particularly the intermolecular version), results in a large reaction barrier.
RegioselectivityIn chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemical compound, compounds composed of atoms, molecules and ions: their composition, structure, properties, behavior and the changes they undergo ...
issues also hamper the synthetic utility of the resulting products, with Markovnikov addition of the amine being the most common outcome over the less favoured anti-Markovnikov addition (see figure). As a result, there are now numerous catalysts that can be utilised in the hydroamination of alkene, allene and alkyne substrates, including various metal based heterogeneous catalysts, early-transition metal complexes (e.g. titanium and zirconium), late-transition metal complexes (e.g. ruthenium and palladium), lanthanide and actinide complexes (e.g. samarium and lanthanium), as well as Brønsted acids and bases.


Catalysts

Many metal-ligand combinations have been reported to catalyze hydroamination, including main group elements including alkali metals such as
lithium Lithium (from el, λίθος, lithos, lit=stone) is a chemical element In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: the ...

lithium
, group 2 metals such as
calcium Calcium is a chemical element In chemistry, an element is a pure Chemical substance, substance consisting only of atoms that all have the same numbers of protons in their atomic nucleus, nuclei. Unlike chemical compounds, chemical elem ...

calcium
, as well as group 3 metals such as
aluminum Aluminium (aluminum in American American(s) may refer to: * American, something of, from, or related to the United States of America, commonly known as the United States The United States of America (USA), commonly known as the Uni ...

aluminum
,
indium Indium is a chemical element In chemistry, an element is a pure Chemical substance, substance consisting only of atoms that all have the same numbers of protons in their atomic nucleus, nuclei. Unlike chemical compounds, chemical element ...

indium
, and
bismuth Bismuth is a chemical element upright=1.0, 500px, The chemical elements ordered by link=Periodic table In chemistry Chemistry is the science, scientific study of the properties and behavior of matter. It is a natural science that c ...

bismuth
. In addition to these main group examples, extensive research has been conducted on the transition metals with reports of early, mid, and late metals, as well as first, second, and third row elements. Finally the lanthanides have been thoroughly investigated.
Zeolites Zeolites are microporous, aluminosilicate Aluminosilicate mineral In geology Geology (from the Ancient Greek γῆ, ''gē'' ("earth") and -λoγία, ''-logia'', ("study of", "discourse")) is an Earth science concerned with the solid Ear ...
have also shown utility in hydroamination.


Catalytic cycles

The
mechanism Mechanism may refer to: *Mechanism (engineering) In engineering, a mechanism is a Machine, device that transforms input forces and movement into a desired set of output forces and movement. Mechanisms generally consist of moving components which m ...

mechanism
of metal-catalyzed hydroamination has been well studied. Particularly well studied is the organolanthanide catalyzed intramolecular hydroamination of alkenes. First, the catalyst is activated by amide exchange, generating the active catalyst (i). Next, the alkene inserts into the Ln-N bond (ii). Finally, protonolysis occurs generating the cyclized product while also regenerating the active catalyst (iii). Although this mechanism depicts the use of a lanthanide catalyst, it is the basis for rare-earth,
actinide The actinoid (IUPAC nomenclature The International Union of Pure and Applied Chemistry The International Union of Pure and Applied Chemistry (IUPAC ) is an international federation of National Adhering Organizations that represents chemis ...
, and
alkali metal The alkali metals consist of the chemical element In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structur ...
based catalysts. Late transition metal hydroamination catalysts have multiple models based on the regioselective determining step. The four main categories are (1)
nucleophilic attack In chemistry, a nucleophile is a chemical species that forms bonds with Electrophile, electrophiles 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 nucleophi ...

nucleophilic attack
on an alkene alkyne, or allyl ligand and (2) insertion of the alkene into the metal-amide bond. Generic catalytic cycles appear below. Mechanisms are supported by rate studies,
isotopic labeling Isotopic labeling (or isotopic labelling) is a technique used to track the passage of an isotope Isotopes are two or more types of atoms that have the same atomic number 300px, The Rutherford–Bohr model of the hydrogen atom () or a hydro ...
, and
trapping Animal trapping, or simply trapping, is the use of a device to remotely catch an animal. Animals may be trapped for a variety of purposes, including food, the fur trade The fur trade is a worldwide industry dealing in the acquisition a ...
of the proposed intermediates.


Thermodynamics and kinetics

The hydroamination reaction is approximately thermochemically neutral. The reaction however suffers from a high , perhaps owing to the repulsion of the electron-rich
substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached **Substrate (locomotion), the surface over which an organism loco ...
and the amine
nucleophile In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo during a ...

nucleophile
. The intermolecular reaction also is accompanied by highly negative changing
entropy Entropy is a scientific concept as well as a measurable physical property that is most commonly associated with a state of disorder, randomness, or uncertainty. The term and the concept are used in diverse fields, from classical thermodynamic ...

entropy
, making it at higher temperatures. Consequently, catalysts are necessary for this reaction to proceed. As usual in chemistry, intramolecular processes occur at faster rates than intermolecular versions.


Thermodynamic vs kinetic product

In general, most hydroamination catalysts require elevated temperatures to function efficiently, and as such, only the thermodynamic product is observed. The isolation and characterization of the rarer and more synthetically valuable kinetic
allyl An allyl group is a substituent A substituent is one or a group of atom An atom is the smallest unit of ordinary matter In classical physics and general chemistry, matter is any substance that has mass and takes up space by having vo ...

allyl
amine product was reported when
allenes Allenes are organic compounds In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and ...
was used at the unsaturated substrate. One system utilized temperatures of 80 °C with a
rhodium Rhodium is a chemical element with the Symbol (chemistry), symbol Rh and atomic number 45. It is a very rare, silvery-white, hard, corrosion, corrosion-resistant, and chemically inert transition metal. It is a noble metal and a member of the pla ...

rhodium
catalyst and
aniline Aniline is an organic compound In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior an ...

aniline
derivatives as the amine. The other reported system utilized a
palladium Palladium is a chemical element In chemistry, an element is a pure Chemical substance, substance consisting only of atoms that all have the same numbers of protons in their atomic nucleus, nuclei. Unlike chemical compounds, chemical elem ...

palladium
catalyst at room temperature with a wide range of primary and secondary cyclic and acyclic amines. Both systems produced the desired allyl amines in high yield, which contain an alkene that can be further functionalized through traditional organic reactions.


Base catalyzed hydroamination

Strong bases catalyze hydroamination, an example being the
ethylation Image:Ethyl group V.1.png, 500px, Ethyl group (highlighted blue) as part of a molecule, as the ethyl radical, and in the compounds ethanol, bromoethane, ethyl acetate, and ethyl methyl ether. In chemistry, an ethyl group is an alkyl substituent der ...

ethylation
of
piperidine Piperidine is an organic compound In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior ...
using
ethene Ethylene (IUPAC The International Union of Pure and Applied Chemistry (IUPAC ) is an international federation of National Adhering OrganizationsNational Adhering Organizations in chemistry are the organizations that work as the authoritativ ...
: Such base catalyzed reactions proceed well with ethene but higher alkenes are less reactive.


Hydroamination catalyzed by group (IV) complexes

Certain
titanium Titanium is a chemical element In chemistry, an element is a pure Chemical substance, substance consisting only of atoms that all have the same numbers of protons in their atomic nucleus, nuclei. Unlike chemical compounds, chemical ele ...

titanium
and
zirconium Zirconium is a chemical element In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behav ...

zirconium
complexes catalyze intermolecular hydroamination of alkynes and allenes. Both
stoichiometric Stoichiometry is the calculation of reactants and products in chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical A chemical s ...
and catalytic variants were initially examined with zirconocene bis(amido) complexes. Titanocene amido and sulfonamido complexes catalyze the intra-molecular hydroamination of aminoalkenes via a +2cycloaddition that forms the corresponding azametallacyclobutane, as illustrated in the figure below. Subsequent protonolysis by incoming substrate gives the α-vinyl-pyrrolidine (1) or tetrahydropyridine (2) product. Experimental and theoretical evidence support the proposed imido intermediate and mechanism with neutral group IV catalysts.


Formal hydroamination

The addition of hydrogen and an amino group (NR2) using reagents other than the amine HNR2 is known as a "formal hydroamination" reaction. Although the advantages of atom economy and/or ready available of the nitrogen source are diminished as a result, the greater thermodynamic driving force, as well as ability to tune the aminating reagent are potentially useful. In place of the amine, hydroxylamine esters and nitroarenes have been reported as nitrogen sources.


Applications

Hydroamination could find applications due to the valuable nature of the resulting amine, as well as the greenness of the process. Functionalized
allylamine Allylamine is an organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, cate ...

allylamine
s, which can be produced through hydroamination, have extensive pharmaceutical application, although presently such species are not prepared by hydroamination. Hydroamination has been utilized to synthesize the allylamine
Cinnarizine Cinnarizine is an antihistamine and calcium channel blocker of the diphenylmethylpiperazine group. It is prescribed for nausea and vomiting due to motion sickness Motion sickness occurs due to a difference between actual and expected motion. ...

Cinnarizine
in quantitative yield. Cinnarizine treats both
vertigo Vertigo is a condition where a person has the sensation of movement or of surrounding objects moving when they are not. Often it feels like a spinning or swaying movement. This may be associated with nausea Nausea is a diffuse sensation of ...

vertigo
and
motion sickness Motion sickness occurs due to a difference between actual and expected motion. Symptoms commonly include nausea Nausea is a diffuse sensation of unease and discomfort, often perceived as an urge to vomiting, vomit. While not painful, it can ...
related
nausea Nausea is a diffuse sensation of unease and discomfort, often perceived as an urge to vomiting, vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, upper abdomen, or ...

nausea
. Hydroamination is also promising for the synthesis of
alkaloid Alkaloids are a class of basic BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming language In computer science Computer science deals with the theoretical foundations of ...
s. An example was the hydroamination step used in the total synthesis of (-)-epimyrtine.


See also

*
Ammoxidation In chemistry, ammoxidation is an industrial process for the production of nitriles using ammonia and oxygen. The usual substrates are alkenes. It is sometimes called the Sohio process, acknowledging that ammoxidation was first discovered by Standard ...
- reaction of ammonia with alkenes to give
nitriles A nitrile is any organic compound In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior ...
*
Hydroboration In chemistry, hydroboration refers to the addition of a hydrogen-boron bond to C-C, C-N, and C-O double bonds, as well as C-C triple bonds. This chemical reaction is useful in the organic synthesis of organic compounds. The development of this tech ...

Hydroboration
*
HydrosilylationHydrosilylation, also called catalytic hydrosilation, describes the addition of Si-H bonds across unsaturated bonds."Hydrosilylation A Comprehensive Review on Recent Advances" B. Marciniec (ed.), Advances in Silicon Science, Springer Science, 2009. ...

Hydrosilylation
* (Olefin) Hydration *


References

{{reflist, 30em Addition reactions Organometallic chemistry Homogeneous catalysis Catalysis