# Hydroamination

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{{short description|1=Addition of an N–H group across a C=C or C≡C bond}}
In [organic chemistry](/source/organic_chemistry), '''hydroamination''' is the formal [addition](/source/Addition_reaction) of an {{chem2|N\sH}} bond of an [amine](/source/amine) across a [carbon-carbon multiple bond](/source/Carbon%E2%80%93carbon_bond) of an [alkene](/source/alkene), [alkyne](/source/alkyne), [diene](/source/diene), or [allene](/source/allene).<ref name="Togni-2001"/> In the ideal case, hydroamination is [atom economical](/source/Atom_economy) and [green](/source/Green_chemistry);<ref name="Beller-2004"/> and the products could see extensive use in fine-chemical, pharmaceutical, and agricultural industries.<ref name=HAsym/><ref name=Hartwig/><ref name="Pohlki-2003"/>  Hydroamination reactions occur spontaneously only for electrophilic alkenes and some dienes, but these are known by other names (e.g. [Michael addition reaction](/source/Michael_addition_reaction)); "hydroamination" is generally reserved for situations where the reaction requires a catalyst. Hydroamination is however of little value industrially.

Hydroamination can be used [intramolecularly](/source/Intramolecular_reaction) to create [heterocycles](/source/Heterocyclic_compounds) or intermolecularly with a separate amine and [unsaturated compound](/source/unsaturated_compound). <gallery heights=270 mode=packed>
File:Examples of intermolecular hydroamination.png|alt=Prototypical intermolecular hydroamination reactions.|Prototypical intermolecular hydroamination reactions.
File:Examples of intramolecular hydroamination (2).png|alt=Examples of intramolecular hydroamination.|Examples of intramolecular hydroamination.
</gallery>

== Formal hydroamination ==
The addition of hydrogen and an amino group (NR<sub>2</sub>) using reagents other than the amine HNR<sub>2</sub> 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<ref name="Miki-2013"/> and nitroarenes<ref name="Gui-2015"/> have been reported as nitrogen sources.
==History==
Hydroamination was first developed for generating fragrances from [myrcene](/source/myrcene).{{Cn|date=June 2025}} In this conversion, diethylamine adds across the diene substituent, the reaction being catalyzed by lithium diethylamide.<ref name="Takabe-1989"/> Intramolecular hydroaminations were reported by [Tobin J. Marks](/source/Tobin_J._Marks) in 1989 using [metallocene](/source/metallocene) derived from [rare-earth metals](/source/rare-earth_metals) such as [lanthanum](/source/lanthanum), [lutetium](/source/lutetium), and [samarium](/source/samarium). [Catalytic rates](/source/Reaction_rate) correlated inversely with the [ionic radius](/source/ionic_radius) of the metal, perhaps as a consequence of [steric interference](/source/Steric_effects) from the ligands.<ref name="Gagne-1989"/> In 1992, Marks developed the first [chiral](/source/Chirality_(chemistry)) hydroamination catalysts by using a chiral auxiliary, which were the first hydroamination catalysts to favor only one specific [stereoisomer](/source/Stereoisomerism). Chiral auxiliaries on the metallocene ligands were used to dictate the stereochemistry of the product.<ref name="Gagne-1992"/> The first non-metallocene chiral catalysts were reported in 2003, and used bisarylamido and aminophenolate ligands to give higher [enantioselectivity](/source/Enantioselective_synthesis).<ref name="OShaughnessy-2003"/>
center|thumb|Notable hydroamination catalysts by year of publication

== Reaction scope ==
Hydroamination does not occur spontaneously, but requires catalysis.<ref name="jain"/><ref name="Muller-1998"/>  It is, however, approximately thermochemically neutral.  The reaction has a large barrier: the nitrogen atom [lone pair](/source/lone_pair) and the electron-rich carbon-carbon multiple bond repel each other, and (except in the intramolecular case) [addition reaction](/source/addition_reaction)s are inherently [entropically disfavoured](/source/entropically_disfavoured).<ref name="Brunet-1989"/><ref name="Johns-2006"/>  Radical amination is not a [chain reaction](/source/chain_reaction), because hydrogen abstraction from the amine to a carbon atom is thermodynamically disfavored.<ref name="Muller-2008"/>  

Hydroamination reactions have seen extensive academic research, because they are [atom-efficient](/source/Atom_efficiency) and use common, cheap starting materials.  Also, direct hydroamination strategies can in principle substantially shorten many synthesis protocols.<ref name="Salvatore-2001"/>  As a result, many different situations now admit hydroamination with the appropriate catalyst.  Amines that have been investigated include primary, secondary, cyclic, acyclic, and [anilinic](/source/Aniline) amines with diverse [steric](/source/Steric_effects) and [electronic](/source/Electronic_effect) substituents. Unsaturated substrates include alkenes, dienes, alkynes, and allenes. Reactions occur both intra- and intermolecularly.<ref name="Muller-1998" />  [Markovnikov addition](/source/Markovnikov_addition) is generally favored, but some tools exist to control the regioselectivity of the addition.<ref name="Beller-AngewChemIntEd-2004"/>
center

== Catalysts ==
Many metal-ligand combinations have been reported to catalyze hydroamination, and can be roughly divided into three categories.

=== pH extremes ===
In the simplest case, strong [Brønsted acids and bases](/source/Br%C3%B8nsted%E2%80%93Lowry_acid%E2%80%93base_theory) catalyze hydroamination.<ref name="Muller-2008"/><ref name="Aillaud-2007"/>  One example is the [ethylation](/source/Ethyl_group) of [piperidine](/source/piperidine) using [ethene](/source/ethene):<ref name="Wollensak-1973"/>
[[File:C2H4+piperidine.png|center|thumb|Hydroamination of ethene with [piperidine](/source/piperidine) proceeds with no transition metal catalyst, but requires a strong base.]]
Such pH-extremal reactions proceed well with ethene but higher alkenes are less reactive.

=== Weakly-coordinating metals ===
Alternatively, weakly-coordinating [Lewis acids](/source/Lewis_acids_and_bases) also catalyze the reaction.  These include salts of the [alkali](/source/Alkali_metal),<ref name="Muller-1998"/> [alkaline-earth](/source/Alkaline_earth_metal),<ref name="Crimmin-2005"/> [rare-earth](/source/Rare_earth_metals),<ref name="Crabtree-2005"/> and low-valent early transition metals (e.g. [titanium and zirconium](/source/Titanium_group)),<ref name="jain"/> as well as [bismuth](/source/bismuth)<ref name="Komeyama-2011"/> and probably certain [actinide](/source/actinide) complexes.  [Zeolites](/source/Zeolites) have also shown utility in hydroamination.<ref name="Muller-1998" />  

The [mechanism](/source/Reaction_mechanism) of these hydroaminations has been well studied.<ref name="Muller-1998"/>  First, the catalyst is activated by amide exchange, generating the active catalyst (i). Next, the alkene inserts into the Ln-N bond (ii).<ref name="Crabtree-2005" />   Finally, protonolysis occurs generating the cyclized product while also regenerating the active catalyst (iii).<ref name="Hong-2004"/>
center|frameless

=== Late transition-metal complexes ===
The complexes of late transition metals (e.g. ruthenium and palladium)<ref name="Muller-2008"/><ref name="Alonso-2004"/><ref name="Aillaud-2007"/> and group 13 metals such as [aluminum](/source/aluminum)<ref name="Koller-2010"/> and [indium](/source/indium)<ref name="Sarma-2011"/> offer a great deal of control over the regio- and stereoselectivity of the reaction.  
For example, a rare and more synthetically valuable [kinetic](/source/Thermodynamic_versus_kinetic_reaction_control) [allyl](/source/allyl)amine product was reported when hydroaminating an [allene](/source/allenes). One system utilized temperatures of 80&nbsp;°C with a [rhodium](/source/rhodium) catalyst and [aniline](/source/aniline) derivatives as the amine.<ref name="Cooke-2012"/> The other reported system utilized a [palladium](/source/palladium) catalyst at room temperature with a wide range of primary and secondary cyclic and acyclic amines.<ref name="Beck-2003"/> Both systems produced the desired allyl amines in high yield:
center|frameless|500x500pxIn general, hydroamination with late transition-metal complexes has multiple pathways depending on the regioselective determining step. The four main categories are (1) [nucleophilic attack](/source/Nucleophile) on an alkene alkyne, or allyl ligand and (2) insertion of the alkene into the metal-amide bond.<ref name="Muller-1998"/> Generic catalytic cycles appear below.
center|frameless|751x751px

==Applications==
No industrial applications of hydroamination are known, but hydroamination syntheses of industrial products have been performed in academia.  

Hydroamination has been utilized to synthesize the anti-[nausea](/source/nausea) medication [cinnarizine](/source/cinnarizine) in quantitative yield.<ref name=Beck-2003 />
thumb|center|500px|Synthesis of cinnarizine via hydroamination.
Hydroamination is also promising for the synthesis of [alkaloid](/source/alkaloid)s as, in the total synthesis of (-)-epimyrtine.<ref name=Trinh-2013/>
thumb|center|700px|Gold-catalyzed hydroamination used for the total synthesis of (-)-epimyrtine.<ref name=Trinh-2013/>

== See also ==
* [Ammoxidation](/source/Ammoxidation) - reaction of ammonia with alkenes to give [nitriles](/source/nitriles)
* [Electrophilic amination](/source/Electrophilic_amination)&nbsp;&mdash; polarity-reversed reaction
* [Hydroboration](/source/Hydroboration)
* [Hydrosilylation](/source/Hydrosilylation)
* (Olefin) [Hydration](/source/Hydration_reaction)
* [Hydrofunctionalization](/source/Hydrofunctionalization)

==References==
{{CC-notice|cc=by2.5|url=https://ora.ox.ac.uk/objects/uuid:18e7c533-3789-4800-9813-1d5c7bb4e4ea|author= David Michael Barber}}

{{reflist|30em|refs=<!--Roughly alphabetical by last name-->
<ref name="Aillaud-2007">{{cite journal |last1=Aillaud |first1=I. |last2=Collin |first2=J. |last3=Hannedouche |first3=J. |last4=Schulz |first4=E. |year=2007 |title=Asymmetric hydroamination of non-activated carbon–carbon multiple bonds |journal=[Dalton Trans.](/source/Dalton_Trans.) |issue=44 |pages=5105–5118 |doi=10.1039/b711126f |issn=1477-9226 |pmid=17985016}}</ref>
<ref name="Alonso-2004">{{cite journal |last1=Alonso |first1=F. |last2=Beletskaya |first2=I.P. |last3=Yus |first3=M. |year=2004 |title=Transition-Metal-Catalyzed Addition of Heteroatom−Hydrogen Bonds to Alkynes |journal=[Chem. Rev.](/source/Chem._Rev.) |volume=104 |issue=6 |pages=3079–3160 |doi=10.1021/cr0201068 |issn=0009-2665 |pmid=15186189}}</ref>
<ref name="Beck-2003">{{cite journal |last=Beck |first=J.F. |author2=Samblanet, D.C. |author3=Schmidt, J.A.R. |year=2013 |title=Palladium catalyzed intermolecular hydroamination of 1-substituted allenes: an atom-economical method for the synthesis of N-allylamines |journal=[RSC Adv.](/source/RSC_Adv.) |volume=3 |issue=43 |pages=20708–20718 |bibcode=2013RSCAd...320708B |doi=10.1039/c3ra43870h}}</ref>
<ref name="Beller-2004">{{cite book |last1=Beller |first1=M. |title=Transition metals for organic synthesis : building blocks and fine chemicals |last2=Bolm |first2=C. |publisher=Wiley-VCH |year=2004 |isbn=9783527306138 |edition=2nd |location=Weinheim |doi=10.1002/9783527619405}}</ref>
<ref name="Beller-AngewChemIntEd-2004">{{cite journal |author1=Beller, M. |author2=Seayad, J. |author3=Tillack, A. |author4=Jiao, H. |year=2004 |title=Catalytic Markovnikov and anti-Markovnikov Functionalization of Alkenes and Alkynes: Recent Developments and Trends |journal=[Angew. Chem. Int. Ed.](/source/Angew._Chem._Int._Ed.) |volume=43 |issue=26 |pages=3368–3398 |doi=10.1002/anie.200300616 |pmid=15221826}}</ref>
<ref name="Brunet-1989">{{cite journal |last1=Brunet |first1=J.-J. |author2=Neibecker, D. |author3=Niedercorn, F. |year=1989 |title=Functionalisation of alkenes: catalytic amination of monoolefins |journal=[J. Mol. Catal.](/source/J._Mol._Catal.) |volume=49 |issue=3 |pages=235–259 |doi=10.1016/0304-5102(89)85015-1}}</ref>
<ref name="Cooke-2012">{{cite journal |last=Cooke |first=M.L. |author2=Xu, K. |author3=Breit, B. |year=2012 |title=Enantioselective Rhodium-Catalyzed Synthesis of Branched Allylic Amines by Intermolecular Hydroamination of Terminal Allenes |journal=[Angew. Chem. Int. Ed.](/source/Angew._Chem._Int._Ed.) |volume=51 |issue=43 |pages=10876–10879 |doi=10.1002/anie.201206594 |pmid=23011801}}</ref>
<ref name="Crabtree-2005">{{cite book |last=Crabtree |first=Robert H. |url=https://archive.org/details/The_Organometallic_Chemistry_Of_Transition_Metals |title=The organometallic chemistry of the transition metals |publisher=John Wiley |year=2005 |isbn=978-0-471-66256-3 |edition=4th |location=Hoboken, N.J.}}</ref>
<ref name="Crimmin-2005">{{cite journal |last=Crimmin |first=M.R. |author2=Casely, I.J. |author3=Hill, M.S. |year=2005 |title=Calcium-Mediated Intramolecular Hydroamination Catalysis |journal=[J. Am. Chem. Soc.](/source/J._Am._Chem._Soc.) |volume=127 |issue=7 |pages=2042–2043 |bibcode=2005JAChS.127.2042C |doi=10.1021/ja043576n |pmid=15713071}}</ref>
<ref name="Gagne-1992">{{cite journal |last1=Gagné |first1=M.R. |last2=Brard |first2=L. |last3=Conticello |first3=V.P. |last4=Giardello |first4=M.A. |last5=Marks |first5=T.J. |last6=Stern |first6=C.L. |year=1992 |title=Stereoselection effects in the catalytic hydroamination/cyclization of amino olefins at chiral organolanthanide centers |journal=[Organometallics](/source/Organometallics) |volume=11 |issue=6 |page=2003 |doi=10.1021/om00042a012}}</ref>
<ref name="Gagne-1989">{{cite journal |last1=Gagné |first1=M.R. |last2=Marks |first2=T.J. |year=1989 |title=Organolanthanide-catalyzed hydroamination. Facile, regiospecific cyclization of unprotected amino olefins |journal=[J. Am. Chem. Soc.](/source/J._Am._Chem._Soc.) |volume=111 |issue=11 |page=4108 |bibcode=1989JAChS.111.4108G |doi=10.1021/ja00193a056}}</ref>
<ref name="Gui-2015">{{cite journal |last1=Gui |first1=J. |last2=Pan |first2=C.-M. |last3=Jin |first3=Y. |last4=Qin |first4=T. |last5=Lo |first5=J.C. |last6=Lee |first6=B.J. |last7=Spergel |first7=S.H. |last8=Mertzman |first8=M.E. |last9=Pitts |first9=W.J. |year=2015 |title=Practical olefin hydroamination with nitroarenes |journal=[Science](/source/Science_(journal)) |volume=348 |issue=6237 |pages=886–891 |bibcode=2015Sci...348..886G |doi=10.1126/science.aab0245 |issn=0036-8075 |pmid=25999503 |doi-access=free}}</ref>
<ref name=Hartwig>{{cite journal |author=Hartwig, J. F. |author-link=John F. Hartwig |year=2004 |title=Development of catalysts for the hydroamination of olefins |url=http://www.iupac.org/publications/pac/2004/pdf/7603x0507.pdf |journal=[Pure Appl. Chem.](/source/Pure_Appl._Chem.) |volume=76 |issue=3 |pages=507–516 |doi=10.1351/pac200476030507 |s2cid=29945266}}</ref>
<ref name="Hong-2004">{{cite journal |last=Hong |first=S. |author2=Marks, T.J. |year=2004 |title=Organolanthanide-Catalyzed Hydroamination |journal=[Acc. Chem. Res.](/source/Acc._Chem._Res.) |volume=37 |issue=9 |pages=673–686 |doi=10.1021/ar040051r |pmid=15379583}}</ref>
<ref name=HAsym>{{cite journal |last=Hultzsch |first=Kai C. |year=2005 |title=Catalytic asymmetric hydroamination of non-activated olefins |journal=[Org. Biomol. Chem.](/source/Org._Biomol._Chem.) |type=Review |volume=3 |issue=10 |pages=1819–1824 |doi=10.1039/b418521h |pmid=15889160}}</ref>
<ref name="Johns-2006">{{cite journal |last=Johns |first=A.M. |author2=Sakai, N. |author3=Ridder, A. |author4=Hartwig, J.F. |year=2006 |title=Direct Measurement of the Thermodynamics of Vinylarene Hydroamination |journal=[J. Am. Chem. Soc.](/source/J._Am._Chem._Soc.) |volume=128 |issue=29 |pages=9306–9307 |bibcode=2006JAChS.128.9306J |doi=10.1021/ja062773e |pmid=16848446}}</ref>
<ref name="Koller-2010">{{cite journal |last=Koller |first=J. |author2=Bergman, R.G. |year=2010 |title=Highly Efficient Aluminum-Catalyzed Hydro-amination/-hydrazination of Carbodiimides |journal=[Organometallics](/source/Organometallics) |volume=29 |issue=22 |pages=5946–5952 |doi=10.1021/om100735q}}</ref>
<ref name="Komeyama-2011">{{cite journal |last1=Komeyama |first1=K. |author2=Kouya, Y. |author3=Ohama, Y. |author4=Takaki, K. |year=2011 |title=Tandem ene-reaction/hydroamination of amino-olefin and -allene compounds catalyzed by Bi(OTf)<sub>3</sub> |journal=[Chem. Commun.](/source/Chem._Commun.) |volume=47 |issue=17 |pages=5031–5033 |doi=10.1039/c0cc05258b |pmid=21423974}}</ref>
<ref name="Miki-2013">{{cite journal |last1=Miki |first1=Y. |last2=Hirano |first2=K. |last3=Satoh |first3=T. |last4=Miura |first4=M. |year=2013 |title=Copper-Catalyzed Intermolecular Regioselective Hydroamination of Styrenes with Polymethylhydrosiloxane and Hydroxylamines |journal=[Angew. Chem. Int. Ed.](/source/Angew._Chem._Int._Ed.) |volume=52 |issue=41 |pages=10830–10834 |doi=10.1002/anie.201304365 |issn=1521-3773 |pmid=24038866}}</ref>
<ref name="Muller-1998">{{cite journal |last=Müller |first=Thomas E. |author2=Beller, Matthias |year=1998 |title=Metal-Initiated Amination of Alkenes and Alkynes |journal=[Chem. Rev.](/source/Chem._Rev.) |volume=98 |issue=2 |pages=675–704 |doi=10.1021/cr960433d |pmid=11848912}}</ref>
<ref name="Muller-2008">{{cite journal |last1=Müller |first1=T.E. |last2=Hultzsch |first2=K.C. |last3=Yus |first3=M. |last4=Foubelo |first4=F. |last5=Tada |first5=M. |year=2008 |title=Hydroamination: Direct Addition of Amines to Alkenes and Alkynes |journal=[Chem. Rev.](/source/Chem._Rev.) |volume=108 |issue=9 |pages=3795–3892 |doi=10.1021/cr0306788 |issn=0009-2665 |pmid=18729420}}</ref>
<ref name="OShaughnessy-2003">{{cite journal |last1=O'Shaughnessy |first1=P.N. |last2=Scott |first2=P. |year=2003 |title=Biaryl amine ligands for lanthanide catalysed enantioselective hydroamination/cyclisation of aminoalkenes |journal=[Tetrahedron Asymmetry](/source/Tetrahedron_Asymmetry) |volume=14 |issue=14 |page=1979 |doi=10.1016/s0957-4166(03)00429-4}}</ref>
<ref name="Pohlki-2003">{{cite journal |author1=Pohlki, F. |author2=Doye, S. |year=2003 |title=The catalytic hydroamination of alkynes |journal=[Chem. Soc. Rev.](/source/Chem._Soc._Rev.) |volume=32 |issue=2 |pages=104–114 |doi=10.1039/b200386b |pmid=12683107}}</ref>
<ref name="jain">{{cite book |last1=Reznichenko |first1=A. L. |title=Hydroamination of Alkenes |last2=Hultszch |first2=K. C. |journal=[Org. React.](/source/Org._React.) |year=2015 |isbn=978-0471264187 |volume=88 |page=1 |doi=10.1002/0471264180.or088.01}}</ref>
<ref name="Salvatore-2001">{{Cite journal |last1=Salvatore |first1=R.N. |last2=Yoon |first2=C.H. |last3=Jung |first3=K.W. |year=2001 |title=Synthesis of secondary amines |journal=[Tetrahedron](/source/Tetrahedron_(journal)) |volume=57 |issue=37 |pages=7785–7811 |doi=10.1016/S0040-4020(01)00722-0}}</ref>
<ref name="Sarma-2011">{{cite journal |last1=Sarma |first1=R. |author2=Prajapati, D. |year=2011 |title=Indium catalyzed tandem hydroamination/hydroalkylation of terminal alkynes |journal=[Chem. Commun.](/source/Chem._Commun.) |volume=47 |issue=33 |pages=9525–7 |doi=10.1039/c1cc13486h |pmid=21776504}}</ref>
<ref name="Takabe-1989">{{cite journal |author1=Takabe, K. |author2=Katahiri, T. |author3=Tanaka, J. |author4=Fujita, T. |author5=Watanabe, S. |author6=Suga, K. |year=1989 |title=Addition Of Dialkylamines To Myrcene: N,N-diethylgeranylamine |journal=[Org. Synth.](/source/Org._Synth.) |volume=67 |page=44 |doi=10.15227/orgsyn.067.0044}}</ref>
<ref name="Togni-2001">{{cite book |last1=Togni |first1=Antionio |title=Catalytic heterofunctionalization: from hydroanimation to hydrozirconation |last2=Grützmacher |first2=Hansjörg |publisher=Wiley-VCH |year=2001 |isbn=978-3527302345 |edition=1. |location=Weinheim |doi=10.1002/3527600159}}</ref>
<ref name=Trinh-2013>{{cite journal |author1=Trinh, T.T.H. |author2=Nguyen, K.H. |author3=Amaral, P. de A. |author4=Gouault, N. |journal=[Beilstein J. Org. Chem.](/source/Beilstein_J._Org._Chem.) |title=Total synthesis of (−)-epimyrtine by a gold-catalyzed hydroamination approach |year=2013 |volume=9 |pages=2042–2047 |doi=10.3762/bjoc.9.242|pmid=24204417 |pmc=3817515 }}</ref>
<ref name="Wollensak-1973">{{cite journal |author1=Wollensak, J. |author2=Closson, R.D. |year=1963 |title=N-Ethylpiperidine |journal=[Org. Synth.](/source/Org._Synth.) |volume=43 |pages=45 |doi=10.15227/orgsyn.043.0045}}</ref>
}}

Category:Addition reactions
Category:Organometallic chemistry
Category:Homogeneous catalysis
Category:Catalysis

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Adapted from the Wikipedia article [Hydroamination](https://en.wikipedia.org/wiki/Hydroamination) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Hydroamination?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.