View source for Suzuki reaction

{{Short description|Cross-coupling reaction between boronic acid & an organohalide}}
{{Reactionbox
| Name = Suzuki reaction
| Type = Coupling reaction
| NamedAfter = [[Akira Suzuki (chemist)|Akira Suzuki]]
| Section3 = {{Reactionbox Identifiers
| OrganicChemistryNamed = suzuki-coupling
| RSC_ontology_id = 0000140
}}
}}
The '''Suzuki reaction''' or '''Suzuki coupling''' is an [[organic reaction]] that uses a [[palladium]] complex catalyst to [[cross-coupling reaction|cross-couple]] a [[boronic acid]] to an [[organohalide]].<ref>{{cite journal| last1 = Miyaura |first1 = Norio |last2=Yamada |first2=Kinji |last3= Suzuki |first3=Akira| year= 1979| title = A new stereospecific cross-coupling by the palladium-catalyzed reaction of 1-alkenylboranes with 1-alkenyl or 1-alkynyl halides| journal= Tetrahedron Letters| volume = 20| issue = 36| pages = 3437–3440 | doi =10.1016/S0040-4039(01)95429-2| url = http://eprints.lib.hokudai.ac.jp/dspace/handle/2115/44006|hdl = 2115/44006 | hdl-access = free}}</ref><ref>{{cite journal| last1 = Miyaura |first1=Norio |last2=Suzuki |first2=Akira| year= 1979| title = Stereoselective synthesis of arylated (E)-alkenes by the reaction of alk-1-enylboranes with aryl halides in the presence of palladium catalyst| journal= Chem. Comm. | issue = 19| pages = 866–867| doi =10.1039/C39790000866}}</ref><ref>{{cite journal|author1-link=Norio Miyaura | last1=Miyaura |first1=Norio |last2=Suzuki |first2=Akira| year= 1995| title = Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds| journal= Chemical Reviews| volume = 95| issue = 7| pages = 2457–2483| doi =10.1021/cr00039a007|citeseerx=10.1.1.735.7660 | s2cid=53050782 }}</ref> It was first published in 1979 by [[Akira Suzuki (chemist)|Akira Suzuki]], and he shared the 2010 [[Nobel Prize in Chemistry]] with [[Richard F. Heck]] and [[Ei-ichi Negishi]] for their contribution to the discovery and development of [[palladium-catalysed cross coupling|noble metal catalysis in organic synthesis]].<ref>{{cite web|last=Nobelprize.org|title=The Nobel Prize in Chemistry 2010|url=https://www.nobelprize.org/nobel_prizes/chemistry/laureates/2010/|publisher=Nobel Prize Foundation|access-date=2013-10-25}}</ref> This reaction is sometimes [[telescoping (chemistry)|telescoped]] with the related [[Miyaura borylation]]; the combination is the '''Suzuki–Miyaura reaction'''. It is widely used to [[organic synthesis|synthesize]] poly[[olefin]]s, [[styrene]]s, and substituted [[biphenyl]]s. 

The general scheme for the Suzuki reaction is shown below, where a [[carbon–carbon single bond]] is formed by coupling a [[halide]] (R<sup>1</sup>-X) with an [[organoboron]] species (R<sup>2</sup>-BY<sub>2</sub>) using a [[palladium]] catalyst and a [[base (chemistry)|base]]. The [[organoboron]] species is usually synthesized by [[hydroboration]] or [[carboboration]], allowing for rapid generation of molecular complexity. 
{{Image frame|align=center|content=<math chem>\begin{array}{c} \\ {\color{Red}\ce{R^1}}\ce{-X} + {\color{Blue}\ce{R^2-BY2}} \ \ce{->[\text{[Pd] cat., base}]}\ {\color{Red}\ce{R^1}}\ce{-}{\color{Blue}\ce{R^2}} \\ \end{array}</math>|caption=General scheme of Suzuki reaction}}
Several reviews have been published describing advancements and the development of the Suzuki reaction.<ref>{{cite journal|last=Suzuki|first=Akira|title=Synthetic Studies via the cross-coupling reaction of organoboron derivatives with organic halides|journal=Pure Appl. Chem.|year=1991|volume=63|issue=3|pages=419–422|doi=10.1351/pac199163030419|doi-access=free}}</ref><ref>{{cite journal| last1=Miyaura |first1=Norio |last2=Suzuki |first2=Akira| year= 1979| title = Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds | journal= Chemical Reviews| volume = 95| issue = 7| pages = 2457–2483| doi = 10.1021/cr00039a007| url =http://eprints.lib.hokudai.ac.jp/dspace/handle/2115/44007|citeseerx=10.1.1.735.7660|s2cid=53050782 }}(Review)</ref><ref>{{cite journal|doi=10.1016/S0022-328X(98)01055-9|title=Recent advances in the cross-coupling reactions of organoboron derivatives with organic electrophiles, 1995–1998|year=1999|last1=Suzuki|first1=Akira|journal=Journal of Organometallic Chemistry|volume=576|issue=1–2|pages=147–168|doi-access=free}}</ref>

==Reaction mechanism==
The [[reaction mechanism|mechanism]] of the Suzuki reaction is best viewed from the perspective of the palladium catalyst. The catalytic cycle is initiated by the formation of an active Pd<sup>0</sup> catalytic species, '''A'''. This participates in the [[oxidative addition]] of palladium to the [[halide]] reagent '''1''' to form the [[organopalladium]] intermediate '''B'''.  Reaction ([[Salt metathesis reaction|metathesis]]) with base gives [[Reaction intermediate|intermediate]] '''C''', which via [[transmetalation]]<ref>{{cite journal | last1 = Matos | first1 = K. | last2 = Soderquist | first2 = J. A. | year = 1998 | title =  Alkylboranes in the Suzuki−Miyaura Coupling: Stereochemical and Mechanistic Studies| journal =[[J. Org. Chem.]] | volume = 63 | issue = 3| pages = 461–470 | doi = 10.1021/jo971681s | pmid = 11672034}}</ref> with the boron-[[ate complex]] '''D'''  (produced by reaction of the boronic acid reagent '''2''' with base) forms the transient [[organopalladium]] species '''E'''.  [[Reductive elimination]] step leads to the formation of the desired product '''3''' and restores the original palladium catalyst '''A''' which completes the [[catalytic cycle]].

[[File:Reaciton Mechanism of Suzuki reaction.png|center|500px]]

The Suzuki coupling takes place in the presence of a base and for a long time the role of the base was not fully understood. The base was first believed to form a trialkyl borate (R<sub>3</sub>B-OR), in the case of a reaction of a trialkylborane (BR<sub>3</sub>) and [[alkoxide]] (<sup>−</sup>OR); this species could be considered as being more [[nucleophilic]] and then more reactive towards the palladium complex present in the transmetalation step.<ref name="Duc - Kinetics" /><ref name="Kinetics 2">{{cite journal|last=Smith|first=George B.|author2=Dezeny, George C. |author3=Hughes, David L. |author4=King, Anthony O. |author5= Verhoeven, Thomas R. |title=Mechanistic Studies of the Suzuki Cross-Coupling Reaction|journal=The Journal of Organic Chemistry|date=1 December 1994|volume=59|issue=26|pages=8151–8156|doi=10.1021/jo00105a036}}</ref><ref name="Kinetics 3">{{cite journal|last=Matos|first=Karl|author2=Soderquist, John A. |title=Alkylboranes in the Suzuki−Miyaura Coupling: Stereochemical and Mechanistic Studies|journal=The Journal of Organic Chemistry|date=1 February 1998|volume=63|issue=3|pages=461–470|doi=10.1021/jo971681s|pmid=11672034}}</ref> Duc and coworkers investigated the role of the base in the reaction mechanism for the Suzuki coupling and they found that the base has three roles: Formation of the palladium complex [ArPd(OR)L<sub>2</sub>], formation of the trialkyl borate and the acceleration of the reductive elimination step by reaction of the alkoxide with the palladium complex.<ref name="Duc - Kinetics">{{cite journal|last1=Amatore|first1=Christian|last2=Jutand |first2=Anny |last3=Le Duc |first3=Gaëtan|title=Kinetic Data for the Transmetalation/Reductive Elimination in Palladium-Catalyzed Suzuki-Miyaura Reactions: Unexpected Triple Role of Hydroxide Ions Used as Base|journal=Chemistry: A European Journal|date=18 February 2011|volume=17|issue=8|pages=2492–2503|doi=10.1002/chem.201001911|pmid=21319240}}</ref>

===Oxidative addition===
{{main article|Oxidative addition}}
In most cases the oxidative addition is the [[rate determining step]] of the catalytic cycle.<ref name="Kurti and Czako">{{cite book|last=Kurti|first=Laszlo|title=Strategic Applications of Named Reactions in Organic Synthesis|year=2005|publisher=Elsevier Academic Press|isbn=978-0124297852}}</ref> During this step, the palladium catalyst is [[oxidized]] from palladium(0) to palladium(II). The catalytically active palladium species '''A''' is coupled with the aryl halide substrate '''1''' to yield an organopalladium complex '''B'''. As seen in the diagram below, the oxidative addition step breaks the [[carbon]]-[[halogen]] bond where the [[palladium]] is now bound to both the halogen (X) as well as the R<sup>1</sup> group.

[[File:Suzuki Coupling Oxidative Addition.png|center|200px|Oxidative addition step in Suzuki coupling.]]

Oxidative addition proceeds with retention of [[stereochemistry]] with [[vinyl halide]]s, while giving [[Walden inversion|inversion]] of stereochemistry with [[allylic]] and [[benzylic]] halides.<ref>{{cite journal|doi=10.1021/ar50120a002|title=Mechanisms of oxidative addition of organic halides to Group 8 transition-metal complexes|year=1977|last1=Stille|first1=John K.|last2=Lau|first2=Kreisler S. Y.|journal=Accounts of Chemical Research|volume=10|issue=12|pages=434–442}}</ref> The oxidative addition initially forms the [[cis isomer|cis]]–palladium complex, which rapidly [[isomerization|isomerizes]] to the trans-complex.<ref>{{cite journal|doi=10.1021/om9709502|title=On the Configuration Resulting from Oxidative Addition of RX to Pd(PPh3)4and the Mechanism of the cis-to-transIsomerization of \PdRX(PPh3)2] Complexes (R = aryl, X = halide)†|year=1998|last1=Casado|first1=Arturo L.|last2=Espinet|first2=Pablo|journal=Organometallics|volume=17|issue=5|pages=954–959}}</ref>

[[File:Pd cis-trans equilibrium.png|center|300px|''Cis''-''trans'' isomerization of Pd oxidative addition product]]

The Suzuki coupling occurs with retention of configuration on the double bonds for both the organoboron reagent or the halide.<ref name="Carey and Sundberg" /> However, the configuration of that double bond, [[sterochemistry|''cis'']] or ''trans'' is determined by the ''cis''-to-''trans'' isomerization of the palladium complex in the oxidative addition step where the trans palladium complex is the predominant form. When the organoboron is attached to a double bond and it is coupled to an alkenyl halide the product is a diene as shown below.

[[File:Suzuki Double Bond Three.png|center|500px]]

===Transmetalation===
{{main article|Transmetalation}}
Transmetalation is an [[organometallic]] reaction where [[ligands]] are transferred from one species to another. In the case of the Suzuki coupling the ligands are transferred from the organoboron species '''D''' to the palladium(II) complex '''C''' where the base that was added in the prior step is exchanged with the R<sub>2</sub> substituent on the organoboron species to give the new palladium(II) complex '''E'''. The exact mechanism of transmetalation for the Suzuki coupling  remains to be discovered. The organoboron compounds do not undergo transmetalation in the absence of base and it is therefore widely believed that the role of the base is to activate the organoboron compound as well as facilitate the formation of R<sup>1</sup>-Pd<sup>ll</sup>-O''<sup>t</sup>''Bu intermediate ('''C''') from oxidative addition product R<sup>1</sup>-Pd<sup>ll</sup>-X ('''B''').<ref name="Kurti and Czako" />

[[File:Transmetallation in Suzuki reaction.png|center|350px|Transmetallation in Suzuki reaction.]]

===Reductive elimination===
{{main article|Reductive elimination}}
The final step  is the reductive elimination step where the palladium(II) complex ('''E''') eliminates the product ('''3''') and regenerates the palladium(0) catalyst ('''A'''). Using [[deuterium labelling]], Ridgway ''et al.'' have shown the reductive elimination proceeds with retention of stereochemistry.<ref>{{cite journal|doi=10.1021/jo970803d|title=Transmetalation of Alkylboranes to Palladium in the Suzuki Coupling Reaction Proceeds with Retention of Stereochemistry|year=1998|last1=Ridgway|first1=Brian H.|last2=Woerpel|first2=K. A.|journal=The Journal of Organic Chemistry|volume=63|issue=3|pages=458–460|pmid=11672033}}</ref>

[[File:Suzuki Coupling Reductive Elimination.png|center|200px|Reductive elimination step in the catalytic cycle of Suzuki reaction.]]

The ligand plays an important role in the Suzuki reaction. Typically, the phosphine ligand is used in the Suzuki reaction. Phosphine ligand increases the electron density at the metal center of the complex and therefore helps in the oxidative addition step. In addition, the bulkiness of substitution of the phosphine ligand helps in the reductive elimination step. However, ''N''-heterocyclic carbene ligands have recently been used in this cross coupling, due to the instability of the phosphine ligand under Suzuki reaction conditions.<ref>{{Cite web|title=Science of Synthesis: Best methods. Best results – Thieme Chemistry|url=https://science-of-synthesis.thieme.com/app/text/|access-date=2021-04-14|website=science-of-synthesis.thieme.com}}</ref> ''N''-Heterocyclic carbenes are more electron rich and bulky than the phosphine ligand. Therefore, both the steric and electronic factors of the ''N''-heterocyclic carbene ligand help to stabilize active Pd(0) catalyst.<ref>{{Cite journal|last1=Hopkinson|first1=Matthew N.|last2=Richter|first2=Christian|last3=Schedler|first3=Michael|last4=Glorius|first4=Frank|date=June 2014|title=An overview of N-heterocyclic carbenes|url=https://www.nature.com/articles/nature13384|journal=Nature|language=en|volume=510|issue=7506|pages=485–496|doi=10.1038/nature13384|pmid=24965649|bibcode=2014Natur.510..485H|s2cid=672379|issn=1476-4687}}</ref>

==Advantages==
The advantages of Suzuki coupling over other similar reactions include availability of common boronic acids, mild reaction conditions, and its less toxic nature. [[Boronic acids]] are less toxic and safer for the environment than [[organotin]] and [[organozinc compound]]s. It is easy to remove the inorganic by-products from the reaction mixture. Further, this reaction is preferable because it uses relatively cheap and easily prepared reagents. Being able to use water as a [[solvent]]<ref name=water/> makes this reaction more economical, eco-friendly, and practical to use with a variety of water-soluble reagents. A wide variety of reagents can be used for the Suzuki coupling, e.g., aryl or vinyl boronic acids and [[Aryl halide|aryl]] or [[Vinyl halide|vinyl]] halides. Work has also extended the scope of the reaction to incorporate alkyl bromides.<ref>{{cite journal|doi=10.1021/ja0283899|title=Boronic Acids: New Coupling Partners in Room-Temperature Suzuki Reactions of Alkyl Bromides. Crystallographic Characterization of an Oxidative-Addition Adduct Generated under Remarkably Mild Conditions|year=2002|last1=Kirchhoff|first1=Jan H.|last2=Netherton|first2=Matthew R.|last3=Hills|first3=Ivory D.|last4=Fu|first4=Gregory C.|journal=Journal of the American Chemical Society|volume=124|issue=46|pages=13662–3|pmid=12431081}}</ref> In addition to many different type of halides being possible for the Suzuki coupling reaction, the reaction also works with [[pseudohalide]]s such as [[triflate]]s (OTf), as replacements for [[halides]]. The relative reactivity for the coupling partner with the halide or pseudohalide is: R<sub>2</sub>–I > R<sub>2</sub>–OTf > R<sub>2</sub>–Br ≫ R<sub>2</sub>–Cl. [[Boronic ester]]s and [[organotrifluoroborate|organotrifluoroborate salts]] may be used instead of boronic acids. The catalyst can also be a palladium [[nanomaterial-based catalyst]].<ref>{{cite journal| author = Ohtaka, Atsushi| year= 2013| title = Recyclable Polymer-Supported Nanometal Catalysts in Water| journal= The Chemical Record| volume = 13| issue = 3| pages = 274–285 | doi = 10.1002/tcr.201300001| pmid= 23568378}}</ref> With a novel [[organophosphine]] [[ligand]] ([[SPhos]]), a catalyst loading of down to 0.001&nbsp;mol% has been reported.<ref>{{cite journal | last1 = Martin | first1 = R. | last2 = Buchwald | first2 = S. L. | year = 2008 | title = Palladium-Catalyzed Suzuki−Miyaura Cross-Coupling Reactions Employing Dialkylbiaryl Phosphine Ligands | journal = Accounts of Chemical Research | volume = 41 | issue = 11| pages = 1461–1473 | doi = 10.1021/ar800036s | pmid = 18620434 | pmc = 2645945 }}</ref> These advances and the overall flexibility of the process have made the Suzuki coupling widely accepted for chemical synthesis.

==Applications==
===Industrial applications===
The Suzuki coupling reaction is scalable and cost-effective for use in the synthesis of intermediates for [[pharmaceuticals]] or [[fine chemicals]].<ref name="Rouhi - Industry">{{cite news|last=Rouhi|first=A. Maureen|title=Fine Chemicals|newspaper=C&EN|date=6 September 2004}}</ref> The Suzuki reaction was once limited by high levels of catalyst and the limited availability of [[boronic acid]]s. Replacements for halides were also found, increasing the number of coupling partners for the halide or pseudohalide as well. Scaled up reactions have been carried out in the synthesis of a number of important biological compounds such as CI-1034 which used [[triflate]] and [[boronic acid]] coupling partners which was run on an 80 kilogram scale with a 95% yield.<ref name=AOC-231>{{cite journal|last1=Jacks|first1=Thomas E.|last2=Belmont |first2=Daniel T. |last3=Briggs |first3=Christopher A. |last4=Horne |first4= Nicole M. |last5=Kanter |first5=Gerald D. |last6=Karrick |first6=Greg L. |last7=Krikke |first7=James J. |last8=McCabe |first8=Richard J. |last9=Mustakis |first0=Jason G. |last10=Nanninga |first10=Thomas N. |title=Development of a Scalable Process for CI-1034, an Endothelin Antagonist|journal=Organic Process Research & Development|date=1 March 2004|volume=8|issue=2|pages=201–212|doi=10.1021/op034104g}}</ref>

Another example is the coupling of 3-pyridylborane and 1-bromo-3-(methylsulfonyl)benzene that formed an intermediate that was used in the synthesis of a potential central nervous system agent. The coupling reaction to form the intermediate produced 278 kilograms in a 92.5% yield.<ref name="Carey and Sundberg">{{cite book|title=Advanced Organic Chemistry|url=https://archive.org/details/advancedorganicc00care_636|url-access=limited|year=2007|publisher=Springer|pages=[https://archive.org/details/advancedorganicc00care_636/page/n762 739]–747}}</ref><ref name="Rouhi - Industry" />

[[File:CNS Intermediate Synthesis Suzuki.png|center|600px]]

Significant efforts have been put into the development of heterogeneous catalysts for the Suzuki CC reaction, motivated by the performance gains in the industrial process (eliminating the catalyst separation from the substrate), and recently a Pd single atom heterogeneous catalyst has been shown to outperform the industry default homogeneous [[Tetrakis(triphenylphosphine)palladium(0)|Pd(PPh<sub>3</sub>)<sub>4</sub>]] catalyst.<ref>{{cite journal| author1 = Chen, Zupeng |author2= Vorobyeva, Evgeniya |author3= Mitchell, Sharon |author4= Fako, Edvin |author5= Ortuño, Manuel A. |author6= López, Núria |author-link6=Núria López|author7= Collins, Sean M. |author8= Midgley, Paul A. |author9= Richard, Sylvia |author10= Vilé, Gianvito |author11= Pérez-Ramírez, Javier| year= 2018| title = A heterogeneous single-atom palladium catalyst surpassing homogeneous systems for Suzuki coupling| journal= Nature Nanotechnology| volume = 13| issue = 8| pages = 702–707 | doi =10.1038/s41565-018-0167-2|pmid= 29941887 |bibcode= 2018NatNa..13..702C | hdl= 2072/359786|s2cid= 49415437 |url= http://eprints.whiterose.ac.uk/156636/1/s41565-018-0167-2.pdf }}</ref>

===Synthetic applications===
The Suzuki coupling has been frequently used in syntheses of complex compounds.<ref>{{cite journal| doi =10.1002/anie.199628011| title =Total Synthesis of(–)-Epothilone A| year =1996| last1 =Balog| first1 =Aaron| last2 =Meng| first2 =Dongfang| last3 =Kamenecka| first3 =Ted| last4 =Bertinato| first4 =Peter| last5 =Su| first5 =Dai-Shi| last6 =Sorensen| first6 =Erik J.| last7 =Danishefsky| first7 =Samuel J.| journal =Angewandte Chemie International Edition in English| volume =35| issue =2324| pages =2801–2803}}</ref><ref>{{cite journal| doi =10.1039/C0CC04077K| title =A concise synthesis of the molecular framework of pleuromutilin| year =2011| last1 =Liu| first1 =Junjia| last2 =Lotesta| first2 =Stephen D.| last3 =Sorensen| first3 =Erik J.| journal =Chemical Communications| volume =47| issue =5| pages =1500–2| pmid =21079876|pmc=3156455}}</ref> The Suzuki coupling has been used on a [[citronellal]] derivative for the synthesis of [[caparratriene]], a natural product that is highly active against leukemia:<ref>{{cite journal | author = Vyvyan, J. R. | year = 1999 | title = An expedient total synthesis of (+/−)-caparratriene | journal = Tetrahedron Letters | volume = 40 | issue = 27 | pages = 4947–4949 | doi = 10.1016/S0040-4039(99)00865-5 | first2 = Emily A. | last3 = Stephan | first3 = Mari L.| last2 = Peterson}}</ref>

[[File:Suzuki coupling capparatriene.tif|frameless|center|700x200px]]

==Variations==
===Metal catalyst===
Various catalytic uses of metals other than palladium (especially nickel) have been developed.<ref name="Han - Nickel">{{cite journal|last=Han|first=Fu-She|title=Transition-metal-catalyzed Suzuki–Miyaura cross-coupling reactions: a remarkable advance from palladium to nickel catalysts|journal=Chemical Society Reviews|date=1 January 2013|volume=42|issue=12|pages=5270–98|doi=10.1039/c3cs35521g|pmid=23460083}}</ref> The first nickel catalyzed cross-coupling reaction was reported by Percec and co-workers in 1995 using aryl mesylates and boronic acids.<ref>{{cite journal|last1=Percec|first1=Virgil|first2=Jin-Young |last2=Bae|first3=Dale |last3=Hill|title=Aryl Mesylates in Metal Catalyzed Homocoupling and Cross-Coupling Reactions. 2. Suzuki-Type Nickel-Catalyzed Cross-Coupling of Aryl Arenesulfonates and Aryl Mesylates with Arylboronic Acids|journal=Journal of Organic Chemistry|date=1995|volume=60|issue=4|pages=1060–1065|doi=10.1021/jo00109a044}}</ref> Even though a higher amount of nickel [[catalyst]] was needed for the reaction, around 5&nbsp;mol %, [[nickel]] is not as expensive or as [[precious metal|precious]] a metal as [[palladium]]. The nickel catalyzed Suzuki coupling reaction also allowed a number of compounds that did not work or worked worse for the palladium catalyzed system than the nickel-catalyzed system.<ref name="Han - Nickel"/> The use of nickel catalysts has allowed for electrophiles that proved challenging for the original Suzuki coupling using palladium, including substrates such as phenols, aryl ethers, esters, phosphates, and fluorides.<ref name="Han - Nickel"/>

[[File:Nickel Suzuki 1.png|center|Nickel Suzuki 1]]

Investigation into the nickel catalyzed cross-coupling continued and increased the scope of the reaction after these first examples were shown and the research interest grew. Miyaura and Inada reported in 2000 that a cheaper nickel catalyst could be utilized for the [[coupling reaction|cross-coupling]], using [[triphenylphosphine]] (PPh<sub>3</sub>) instead of the more expensive [[ligands]] previously used.<ref>{{cite journal|last=Inada|first=Kaoru|author2=Norio Miyaura |title=Synthesis of Biaryls via Cross-Coupling Reaction of Arylboronic Acids with Aryl Chlorides Catalyzed by NiCl2/Triphenylphosphine Complexes|journal=Tetrahedron|year=2000|volume=56|pages=8657–8660|doi=10.1016/S0040-4020(00)00814-0|issue=44}}</ref> However, the nickel-catalyzed cross-coupling still required high catalyst loadings (3-10%), required excess ligand (1-5 equivalents) and remained sensitive to air and moisture.<ref name="Han - Nickel"/> Advancements by Han and co-workers have tried to address that problem by developing a method using low amounts of nickel catalyst (<1&nbsp;mol%) and no additional equivalents of ligand.<ref name="Han - 38">{{cite journal|last=Zhao|first=Yu-Long|author2=Li, You |author3=Li, Shui-Ming |author4=Zhou, Yi-Guo |author5=Sun, Feng-Yi |author6=Gao, Lian-Xun |author7= Han, Fu-She |title=A Highly Practical and Reliable Nickel Catalyst for Suzuki-Miyaura Coupling of Aryl Halides|journal=Advanced Synthesis & Catalysis|date=1 June 2011|volume=353|issue=9|pages=1543–1550|doi=10.1002/adsc.201100101}}</ref>

[[File:Nickel Suzuki 2.png|center|Nickel Suzuki 2]]

It was also reported by Wu and co-workers in 2011 that a highly active nickel catalyst for the cross-coupling of aryl chlorides could be used that only required 0.01-0.1&nbsp;mol% of nickel catalyst. They also showed that the catalyst could be recycled up to six times with virtually no loss in catalytic activity.<ref>{{cite journal|last=Wu|first=Lei|author2=Ling, Jie |author3=Wu, Zong-Quan |title=A Highly Active and Recyclable Catalyst: Phosphine Dendrimer-Stabilized Nickel Nanoparticles for the Suzuki Coupling Reaction|journal=Advanced Synthesis & Catalysis|date=1 June 2011|volume=353|issue=9|pages=1452–1456|doi=10.1002/adsc.201100134}}</ref> The catalyst was recyclable because it was a phosphine nickel [[nanoparticle]] catalyst  (G<sub>3</sub>DenP-Ni) that was made from [[dendrimer]]s.

[[File:Nickel Suzuki 3.png|center|Nickel Suzuki 3]]

Advantages and disadvantages apply to both the palladium and nickel-catalyzed Suzuki coupling reactions. Apart from Pd and Ni catalyst system, cheap and non-toxic metal sources like iron and copper<ref>{{cite journal|last1=Yang|first1=C.T.|journal=Angew. Chem. Int. Ed.|year=2011|volume=50|pages=3904–3907|doi=10.1002/anie.201008007|pmid=21455914|title=Copper-Catalyzed Cross-Coupling Reaction of Organoboron Compounds with Primary Alkyl Halides and Pseudohalides|first2=Zhen-Qi|last3=Liu|first3=Yu-Chen|last4=Liu|first4=Lei|issue=17|last2=Zhang}}</ref> have been used in Suzuki coupling reaction. The Bedford research group<ref>{{cite journal|last1=Bredford|first1=R.B.|journal=Chem. Commun.|year=2009|pages=6430–6432| doi = 10.1039/B915945B|pmid=19841799|title=Simple mixed Fe–Zn catalysts for the Suzuki couplings of tetraarylborates with benzyl halides and 2-halopyridines|first2=Mark A.|last3=Hodges|first3=George R.|last4=Huwe|first4=Michael|last5=Wilkinson|first5=Mark C.|issue=42 |last2=Hall|s2cid=40428708}}</ref>  and the Nakamura research group<ref>{{cite journal|last1=Nakamura|first1=M|journal=Angew. Chem. Int. Ed.|year=2012|volume=51|pages=8834–883|doi=10.1002/anie.201202797|pmid=22848024|title=Iron-Catalyzed Alkyl-Alkyl Suzuki-Miyaura Coupling|first2=Toru|last3=Kathriarachchi|first3=Kalum K. A. D. S.|last4=Zenmyo|first4=Takeshi|last5=Seike|first5=Hirofumi|last6=Nakamura|first6=Masaharu|issue=35|last2=Hashimoto}}</ref>  have extensively worked on developing the methodology of iron catalyzed Suzuki coupling reaction. Ruthenium is another metal source that has been used in Suzuki coupling reaction.<ref>{{cite journal|last1=Na|first1=Y|journal=J. Am. Chem. Soc.|year=2004|volume=126|pages=250–258|doi=10.1021/ja038742q|title=Ruthenium-Catalyzed Heck-Type Olefination and Suzuki Coupling Reactions: Studies on the Nature of Catalytic Species|first2=Soyoung|last3=Han|first3=Soo Bong|last4=Han|first4=Hoon|last5=Ko|first5=Sangwon|last6=Chang|first6=Sukbok|pmid=14709090|issue=1|last2=Park}}</ref>

=== Amide coupling ===
Nickel catalysis can construct C-C bonds from amides. Despite the inherently inert nature of amides as synthons, the following methodology can be used to prepare C-C bonds. The coupling procedure is mild and tolerant of myriad functional groups, including: amines, ketones, heterocycles, groups with acidic protons. This technique can also be used to prepare bioactive molecules and to unite heterocycles in controlled ways through shrewd sequential cross-couplings. A general review of the reaction scheme is given below.<ref name="Weires 75–79">{{Cite journal|title = Nickel-catalysed Suzuki–Miyaura coupling of amides|journal = Nature Chemistry|pages = 75–79|volume = 8|issue = 1|doi = 10.1038/nchem.2388|pmid = 26673267|first1 = Nicholas A.|last1 = Weires|first2 = Emma L.|last2 = Baker|first3 = Neil K.|last3 = Garg|year = 2015|bibcode = 2016NatCh...8...75W}}</ref>
[[File:Suzuki-Miyaura coupling amides.png|centre|frameless|850px]]

The synthesis of a [[tubulin]]-binding compound ([[Cytostasis|antiproliferative]] agent) was carried out using a trimethoxy[[benzamide]] and an [[Indole|indolyl]] [[pinacol]]<nowiki/>atoboron coupling partner on a gram scale.<ref name="Weires 75–79"/>
[[File:Suzuki-Miyaura synthesis antiproliferative agent.png|centre|700px]]

===Organoboranes===
Aryl [[boronic acid]]s are comparatively cheaper than other organoboranes and a wide variety of aryl [[boronic acid]]s are commercially available. Hence, it has been widely used in Suzuki reaction as an organoborane partner. [[organotrifluoroborate|Aryltrifluoroborate salts]] are another class of organoboranes that are frequently used because they are less prone to [[protodeboronation]] compared to aryl [[boronic acid]]s. They are easy to synthesize and can be easily purified.<ref>{{cite journal|last1=Molander|journal=J. Org. Chem.|year=2003|volume=68|pages=4302–4314|doi=10.1021/jo0342368|title=Palladium-Catalyzed Suzuki−Miyaura Cross-Coupling Reactions of Potassium Aryl- and Heteroaryltrifluoroborates|first1=Gary A.|last2=Biolatto|first2=Betina|issue=11|pmid=12762730}}</ref> Aryltrifluoroborate salts can be formed from [[boronic acids]] by the treatment with [[potassium hydrogen fluoride]] which can then be used in the Suzuki coupling reaction.<ref>{{cite book|last=Bates|first=Roderick|title=Organic Synthesis Using Transition Metals|year=2012|publisher=Wiley|isbn=978-1119978930}}</ref>

{{olist|list-style-type=lower-alpha
|Aryltrifluoroborate synthesis:<br/>
<math display="block" chem>{\color{Blue}\ce{R-B(OH)2} } \ \ce{->[{} \atop \ce{KHF2}]} \ {\color{Blue}\ce{R-BF3^-K+} }</math>
|Aryltrifluoroborates in Suzuki reaction:<br/>
<math display="block" chem>{\color{Red}\ce{Ar-Br} } + {\color{Blue}\ce{R-BF3K} } \ \ce{->[{} \atop \text{[Pd] cat., base}]} \ {\color{Red}\ce{Ar} }\ce{-}{\color{Blue}\ce{R} } </math>
}}

===Solvent variations===
The Suzuki coupling reaction is different from other coupling reactions in that it can be run in biphasic organic-water,<ref name=biphasicsolvent>{{cite journal|last1=Dolliver|first1=Debra|journal=J. Org. Chem.|year=2013|volume=78|issue=8|pages=3676–3687|doi=10.1021/jo400179u|title=Stereospecific Suzuki, Sonogashira, and Negishi Coupling Reactions of N-Alkoxyimidoyl Iodides and Bromides|first2=Bijay T.|last3=Pandey|first3=Arjun|last4=Lanier|first4=Megan L.|last5=Bordelon|first5=Amber S.|last6=Adhikari|first6=Sarju|last7=Dinser|first7=Jordan A.|last8=Flowers|first8=Patrick F.|last9=Wills|first9=Veronica S.|last10=Schneider|first10=Caroline L.|last11=Shaughnessy|first11=Kevin H.|last12=Moore|first12=Jane N.|last13=Raders|first13=Steven M.|last14=Snowden|first14=Timothy S.|last15=McKim|first15=Artie S.|last16=Fronczek|first16=Frank R.|pmid=23534335|last2=Bhattarai}}</ref> water-only,<ref name=water>{{cite journal|last1=Casalnuovo|author2=Calabrese |journal=J. Am. Chem. Soc.|year=1990|volume=112|pages=4324–4330|doi=10.1021/ja00167a032|title=Palladium-catalyzed alkylations in aqueous media|first1=Albert L.|issue=11}}</ref> or no solvent.<ref>{{cite journal|last1=Asachenko|first1=Andrey|last2=Sorochkina|first2=Kristina|last3=Dzhevakov|first3=Pavel|last4=Topchiy|first4=Maxim|last5=Nechaev|first5=Mikhail|title=Suzuki–Miyaura Cross-Coupling under Solvent-Free Conditions|journal=Adv. Synth. Catal.|date=2013|volume=355|issue=18|pages=3553–3557|doi=10.1002/adsc.201300741}}</ref> This increased the scope of coupling reactions, as a variety of water-soluble bases, catalyst systems, and reagents could be used without concern over their solubility in organic solvent. Use of water as a solvent system is also attractive because of the economic and safety advantages. Frequently used in solvent systems for Suzuki coupling are [[toluene]],<ref>{{cite journal|first1=Changduo |last1=Pan|last2=Liu |first2= Zhang |last3= Wu |first3=Huayue |last4=Din |first4=Jinchang |last5= Cheng |first5=Jiang|journal=Catalysis Communications|year=2008|volume=9|pages=321–323|doi=10.1016/j.catcom.2007.06.022|title=Palladium catalyzed ligand-free Suzuki cross-coupling reaction|issue=4}}</ref> [[tetrahydrofuran|THF]],<ref name=solvent>{{cite journal|last1=Littke|author2=Fu |journal=J. Am. Chem. Soc.|year=2000|volume=122|pages=4020–4028|doi=10.1021/ja0002058|title=Versatile Catalysts for the Suzuki Cross-Coupling of Arylboronic Acids with Aryl and Vinyl Halides and Triflates under Mild Conditions|first1=Adam F.|issue=17}}</ref> [[dioxane]],<ref name=solvent/> and [[Dimethylformamide|DMF]].<ref>{{cite journal|first1=Ming-Gang|last1=Hu|last2=Wei |first2=Song |last3=Jian |first3=Ai-Ai|journal=Chinese Journal of Chemistry|year=2007|volume=25|pages=1183–1186|doi=10.1002/cjoc.200790220|title=Highly Efficient Pd/C-Catalyzed Suzuki Coupling Reaction ofp-(un)Substituted Phenyl Halide with (p-Substituted phenyl) Boronic Acid|issue=8}}</ref> The most frequently used bases are [[Potassium Carbonate|K<sub>2</sub>CO<sub>3</sub>]],<ref name=biphasicsolvent/> [[Potassium tert-butoxide|KO''t''Bu]],<ref>{{cite journal|last1=Saito|first1=B|last2=Fu |journal=J. Am. Chem. Soc.|year=2007|volume=129|pages=9602–9603|doi= 10.1021/ja074008l|title=Alkyl−Alkyl Suzuki Cross-Couplings of Unactivated Secondary Alkyl Halides at Room Temperature|issue=31|pmid=17628067|pmc=2569998}}</ref>  [[Caesium carbonate|Cs<sub>2</sub>CO<sub>3</sub>]],<ref>{{cite journal|last1=Kingston|first1=J.V.|journal=J. Org. Chem.|year=2007|volume=72|pages=2816–2822|doi=10.1021/jo062452l|title=Synthesis and Characterization of R2PNP(iBuNCH2CH2)3N: A New Bulky Electron-Rich Phosphine for Efficient Pd-Assisted Suzuki−Miyaura Cross-Coupling Reactions|first2=John G.|issue=8|pmid=17378611|last2=Verkade}}</ref> [[Tripotassium phosphate|K<sub>3</sub>PO<sub>4</sub>]],<ref>{{cite journal|last1=Baillie|first1=C|journal=J. Org. Chem.|year=2004|volume=69|pages=7779–7782|doi=10.1021/jo048963u|title=Ferrocenyl Monophosphine Ligands: Synthesis and Applications in the Suzuki−Miyaura Coupling of Aryl Chlorides|first2=Lixin|last3=Xiao|first3=Jianliang|issue=22|pmid=15498017|last2=Zhang}}</ref> [[NaOH]],<ref>{{cite journal|last1=Han|first1=J|journal=J. Am. Chem. Soc.|year=2009|volume=131|pages=2060–2061|doi=10.1021/ja808935n|pmid=19170490|first2=Y|last3=Guo|first3=R|title=Facile synthesis of highly stable gold nanoparticles and their unexpected excellent catalytic activity for Suzuki-Miyaura cross-coupling reaction in water|issue=6|last2=Liu}}</ref> and [[Triethylamine|NEt<sub>3</sub>]].<ref>{{cite journal|last1=Lipshutz|first1=B.H.|journal=Org. Lett.|year=2008|volume=10|pages=1333–1336 |doi=10.1021/ol702714y|title=Room-Temperature Suzuki−Miyaura Couplings in Water Facilitated by Nonionic Amphiphiles†|first2=Tue B.|last3=Abela|first3=Alexander R.|issue=7|pmid=18335944 |last2=Petersen}}</ref>

==See also==
* [[Chan-Lam coupling]]
* [[Heck reaction]]
* [[Hiyama coupling]]
* [[Kumada coupling]]
* [[Negishi coupling]]
* [[Petasis reaction]]
* [[Sonogashira coupling]]
* [[Stille reaction]]
* [[List of organic reactions]]

==References==
{{Reflist|30em}}

== External links ==
* {{cite web | url = https://www.youtube.com/watch?v=0yFEaE5y4E4 | title = Mechanism In Motion: Suzuki coupling| website = [[YouTube]]| date = 15 December 2012}}
* [https://www.organic-chemistry.org/namedreactions/suzuki-coupling.shtm Suzuki coupling]
* [https://www.sciencedaily.com/releases/2011/08/110801114123.htm A Bit of Boron, a Pinch of Palladium: One-Stop Shop for the Suzuki Reaction]

{{Authority control}}

[[Category:Carbon-carbon bond forming reactions]]
[[Category:Palladium]]
[[Category:Substitution reactions]]
[[Category:Name reactions]]