Buchwald-Hartwig reaction
Overview
 
The Buchwald–Hartwig reaction is a chemical reaction
Chemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...

 used in organic chemistry
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...

 for the synthesis of carbon–nitrogen bonds via the palladium
Palladium
Palladium is a chemical element with the chemical symbol Pd and an atomic number of 46. It is a rare and lustrous silvery-white metal discovered in 1803 by William Hyde Wollaston. He named it after the asteroid Pallas, which was itself named after the epithet of the Greek goddess Athena, acquired...

-catalyzed
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....

 cross-coupling
Palladium-catalyzed coupling reactions
Palladium compounds are used as a catalyst in many coupling reactions, usually as a homogeneous catalyst. Examples include:* Heck reaction between alkenes and aryl halides* Suzuki reaction between aryl halides and boronic acids...

 of amines with aryl halides. Though publications with similar focus were published as early as 1983, credit for its development is typically assigned to Stephen L. Buchwald and John F. Hartwig, whose publications between 1994 and the late 2000s established the scope of the transformation.
Discussions
Encyclopedia
The Buchwald–Hartwig reaction is a chemical reaction
Chemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...

 used in organic chemistry
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...

 for the synthesis of carbon–nitrogen bonds via the palladium
Palladium
Palladium is a chemical element with the chemical symbol Pd and an atomic number of 46. It is a rare and lustrous silvery-white metal discovered in 1803 by William Hyde Wollaston. He named it after the asteroid Pallas, which was itself named after the epithet of the Greek goddess Athena, acquired...

-catalyzed
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....

 cross-coupling
Palladium-catalyzed coupling reactions
Palladium compounds are used as a catalyst in many coupling reactions, usually as a homogeneous catalyst. Examples include:* Heck reaction between alkenes and aryl halides* Suzuki reaction between aryl halides and boronic acids...

 of amines with aryl halides. Though publications with similar focus were published as early as 1983, credit for its development is typically assigned to Stephen L. Buchwald and John F. Hartwig, whose publications between 1994 and the late 2000s established the scope of the transformation. The reaction's synthetic utility stems primarily from the shortcomings of typical methods (nucleophilic substitution
Nucleophilic substitution
In organic and inorganic chemistry, nucleophilic substitution is a fundamental class of reactions in which an electron nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms called the leaving group; the positive or partially positive...

, reductive amination
Reductive amination
Reductive amination is a form of amination that involves the conversion of a carbonyl group to an amine via an intermediate imine...

, etc.) for the synthesis of aromatic C–N bonds, with most methods suffering from limited substrate scope and functional group tolerance. The development of the Buchwald–Hartwig reaction allowed for the facile synthesis of aryl amines, replacing to an extent harsher methods (the Goldberg reaction, nucleophilic aromatic substitution
Nucleophilic aromatic substitution
right|300px|Aromatic nucleophilic substitutionA nucleophilic aromatic substitution is a substitution reaction in organic chemistry in which the nucleophile displaces a good leaving group, such as a halide, on an aromatic ring...

, etc.) while significantly expanding the repertoire of possible C–N bond formation.
Over the course of its development, several 'generations' of catalyst systems have been developed, with each system allowing greater scope in terms of coupling partners and milder conditions, allowing virtually any amine to be coupled with a wide variety of aryl coupling partners. Because of the ubiquity of aryl C-N bonds in pharmaceuticals and natural product
Natural product
A natural product is a chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical drug discovery and drug design...

s, the reaction has gained wide use in synthetic organic chemistry, finding application in many total syntheses
Total synthesis
In organic chemistry, a total synthesis is, in principle, the complete chemical synthesis of complex organic molecules from simpler pieces, usually without the aid of biological processes. In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often...

 and the industrial preparation of numerous pharmaceuticals. Several reviews have been published.

History

The first example of a palladium catalyzed C–N cross-coupling reaction was published in 1983 by Migita and coworkers and described a reaction between several aryl bromides and N,N-diethylamino-tributyltin
Tin
Tin is a chemical element with the symbol Sn and atomic number 50. It is a main group metal in group 14 of the periodic table. Tin shows chemical similarity to both neighboring group 14 elements, germanium and lead and has two possible oxidation states, +2 and the slightly more stable +4...

 using 1 mol% PdCl2[P(o-tolyl)3]2. Though several aryl bromides were tested, only electronically neutral, sterically unencumbered substrates gave good yields.
Then, in 1984, Dale L. Boger
Dale L. Boger
Dale Lester Boger is an American medicinal and organic chemist. Dale Boger was born on August 22, 1953, in Hutchinson, Kansas. He studied chemistry at the University of Kansas , Ph.D. 1980, Harvard University, under Professor E. J. Corey...

 and James S. Panek reported an example pf Pd(0)-mediated C–N bond formation in the context of their work on the synthesis of lavendamycin which utilized stoichiometric Pd(PPh3)4. Attempts to render the reaction catalytic were unsuccessful.
In February of 1994, the Hartwig group published a systematic study of the palladium compounds involved in the original Migita paper; their findings indicated that the d10 complex Pd[P(o-Tolyl)3]2 was the active catalyst (with the corresponding chloride entering the catalytic cycle via in situ reduction
Reduction
Reduction, reduced, or reduce may refer to:- Chemistry :* Reduction, part of a reduction-oxidation reaction where oxygen is being removed from a compound.** Reduced gas, a gas with a low oxidation number...

), and supported a catalytic cycle involving oxidative addition
Oxidative addition
Oxidative addition and reductive elimination are two important and related classes of reactions in organometallic chemistry. Oxidative addition is a process that increases both the oxidation state and coordination number of a metal centre...

 of the aryl bromide.
In May of the same year, the Buchwald group published an extension of the Migita paper offering two major improvements over the original paper. First, transamination
Metathesis
Metathesis may refer to:* Metathesis , in phonology, a sound change that alters the order of phonemes in a word...

 of Bu3SnNEt2 followed by argon
Argon
Argon is a chemical element represented by the symbol Ar. Argon has atomic number 18 and is the third element in group 18 of the periodic table . Argon is the third most common gas in the Earth's atmosphere, at 0.93%, making it more common than carbon dioxide...

 purge to remove the volatile diethylamine
Diethylamine
Diethylamine is a secondary amine with the molecular structure CH3CH2NHCH2CH3. It is a flammable, strongly alkaline liquid. It is miscible with water and ethanol. It is a colorless liquid which often appears brown due to impurities...

 allowed extension of the methodology to a variety of secondary amines (both cyclic and acyclic) and primary aniline
Aniline
Aniline, phenylamine or aminobenzene is an organic compound with the formula C6H5NH2. Consisting of a phenyl group attached to an amino group, aniline is the prototypical aromatic amine. Being a precursor to many industrial chemicals, its main use is in the manufacture of precursors to polyurethane...

s. Secondly, the yield for electron rich and electron poor arenes was improved via minor modifications to the reaction procedure (higher catalyst loading, higher temperature, longer reaction time), although no ortho
Arene substitution patterns
Arene substitution patterns are part of organic chemistry IUPAC nomenclature and pinpoint the position of substituents other than hydrogen in relation to each other on an aromatic hydrocarbon.- Ortho, meta, and para substitution :...

-substitured aryl groups were included in this publication.
The following year, back to back studies from each lab showed that the couplings could be conducted with free amines in the presence of a bulky base
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...

 (KOtBu in the Buchwald publication, LiHMDS in the Hartwig publication), allowing for organotin
Organotin
Organotin compounds or stannanes are chemical compounds based on tin with hydrocarbon substituents. Organotin chemistry is part of the wider field of organometallic chemistry. The first organotin compound was diethyltin diiodide, discovered by Edward Frankland in 1849...

-free coupling. Though these improved conditions proceeded at a faster rate, the substrate scope was limited almost entirely to secondary amines due to competitive hydrodehalogenation of the bromoarenes. (See Mechanism below)
These results established the so-called "first generation" of Buchwald–Hartwig catalyst systems. The following years saw development of more sophisticated phosphine
Phosphine
Phosphine is the compound with the chemical formula PH3. It is a colorless, flammable, toxic gas. Pure phosphine is odourless, but technical grade samples have a highly unpleasant odor like garlic or rotting fish, due to the presence of substituted phosphine and diphosphine...

 ligands that allowed extension to a larger variety of amines and aryl groups. Aryl iodide
Iodide
An iodide ion is the ion I−. Compounds with iodine in formal oxidation state −1 are called iodides. This page is for the iodide ion and its salts. For information on organoiodides, see organohalides. In everyday life, iodide is most commonly encountered as a component of iodized salt,...

s, chloride
Chloride
The chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...

s, and triflate
Triflate
Trifluoromethanesulfonate, also known by the trivial name triflate, is a functional group with the formula CF3SO3-. The triflate group is often represented by -OTf, as opposed to -Tf...

s eventually became suitable substrates, and reactions run with weaker bases at room temperature were developed. These advances are detailed in the Scope section below, and the extension to more complex systems remains an active area of research.

Mechanism

The reaction mechanism
Reaction mechanism
In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs.Although only the net chemical change is directly observable for most chemical reactions, experiments can often be designed that suggest the possible sequence of steps in...

 for this reaction has been demonstrated to proceed through steps similar to those known for palladium catalyzed C-C coupling reactions, namely oxidative addition
Oxidative addition
Oxidative addition and reductive elimination are two important and related classes of reactions in organometallic chemistry. Oxidative addition is a process that increases both the oxidation state and coordination number of a metal centre...

, palladium amide formation (rather than transmetallation), and finally reductive elimination. In addition to this, an unproductive side reaction can compete with reductive elimination wherein the amide undergoes beta hydride elimination to yield the hydrodehalogenated arene and an imine
Imine
An imine is a functional group or chemical compound containing a carbon–nitrogen double bond, with the nitrogen attached to a hydrogen atom or an organic group. If this group is not a hydrogen atom, then the compound is known as a Schiff base...

 product.

Over the course of the development of this reaction, there has been a great deal of work to determine the exact palladium species responsible for each of these steps, with several mechanistic revisions occurring as more data was garnered. These studies have revealed a divergent reaction pathways depending on whether monodentate or chelating phosphine ligands are employed in the reaction, and a number of nuanced influences have been revealed (especially concerning the dialkylbiarylphosphine ligands developed by Buchwald).

The catalytic cycle proceeds as follows:
For monodentate ligand systems, monophosphine palladium (0) species is believed to form before oxidative addition, forming the palladium (II) species which is in equilibrium
Chemical equilibrium
In a chemical reaction, chemical equilibrium is the state in which the concentrations of the reactants and products have not yet changed with time. It occurs only in reversible reactions, and not in irreversible reactions. Usually, this state results when the forward reaction proceeds at the same...

 with the μ-halogen dimer. The stability of this dimer decreases in the order of X = I > Br > Cl, and is thought to be responsible for the slow reaction of aryl iodides with the first-generation catalyst system. Amine ligation followed by deprotonation by base produces the palladium amide. (Chelating systems have been shown to undergo these two steps in reverse order, with base complexation preceding amide formation.) This key intermediate reductively eliminates to produce the product and regenerate the catalyst. However, a side reaction can occur wherein β-hydride elimination followed by reductive elimination produces the hydrodehalogenated arene and the corresponding imine. Not shown are additional equilibria wherein various intermediates coordinate to additional phosphine ligands at various stages in the catalytic cycle.

For chelating ligands, the monophosphine palladium species is not formed; oxidative addition, amide formation and reductive elimination occur from L2Pd complexes. The Hartwig group found that "reductive elimination can occur from either a four-coordinate bisphosphine or three-coordinate monophosphine arylpalladium amido complex. Eliminations from the three-coordinate compounds are faster. Second, β-hydrogen elimination occurs from a three-coordinate intermediate. Therefore, β-hydrogen elimination occurs slowly from arylpalladium complexes containing chelating phosphines while reductive elimination can still occur from these four-coordinate species."

Scope

Although the scope of the Buchwald–Hartwig amination has been expanded to include a wide variety of aryl and amine coupling partners, the conditions required for any particular reactants are still largely substrate dependent. Various ligand systems have been developed, each with varying capabilities and limitations, and the choice of conditions requires consideration of the steric and electronic properties of both partners. Detailed below are the substrates and conditions for the major generations of ligand systems. (Not included herein are N-heterocyclic carbene ligands and ligands with wide bite angle
Bite angle
The bite angle is a geometric parameter used to classify chelating ligands in inorganic and organometallic chemistry. Together with ligand cone angle, this parameter is relevant to diphosphine ligands, which are used in industrial processes such as hydroformylation and hydrocyanation...

s such as Xantphos
Xantphos
Xantphos is an organophosphorus compound derived from the heterocycle xanthene. It is used as a bidentate ligand and is noteworthy for having a particularly wide bite angle. Such ligands are useful in the hydroformylation of alkenes. Illustrative of its wide bite angle, it forms both cis and...

 and Spanphos
SPANphos
SPANphos is an organophosphorus compound used as a ligand in organometallic and coordination chemistry. This compound is a rare example of a trans-spanning ligand and rigidly links mutually trans coordination sites. By virtue of its chiral backbone that forms a chiral cavity over the face of a...

 which also have been developed considerably.)

First-generation catalyst system

The first generation (Pd[P(o-Tolyl)3]2) catalyst system was found to be effective for the coupling of both cyclic and acyclic seconary amines bearing both alkyl and aryl functionality (though not diarylamines) with a variety of aryl bromides. In general, these conditions were not able to couple primary amines due to competitive hydrodehalogenation of the arene.

Aryl iodides were found to be suitable substrates for the intramolecular
Intramolecular
Intramolecular in chemistry describes a process or characteristic limited within the structure of a single molecule, a property or phenomenon limited to the extent of a single molecule.- Examples :...

 variant of this reaction, and importantly, could be coupled intermolecularly only if dioxane was used in place of toluene as a solvent, albeit with modest yields.

Bidentate phosphine ligands

The development of diphenylphosphinobinapthyl (BINAP)
BINAP
BINAP is an abbreviation for the organophosphorus compound 2,2'-bis-1,1'-binaphthyl. This chiral ligand is widely used in asymmetric synthesis. It consists of a pair of 2-diphenylphosphinonaphthyl groups linked at the 1 and 1´ positions. This C2-symmetric framework lacks stereogenic atom, but...

 and diphenylphosphinoferrocene (DPPF)
1,1'-Bis(diphenylphosphino)ferrocene
1,1'-Bisferrocene, commonly abbreviated dppf, is a substituted phosphine commonly used, as are other phosphines, as a ligand in organometallic chemistry...

 as ligands for the Buchwald–Hartwig amination provided the first reliable extension to primary amines and allowed efficient coupling of aryl iodides and triflates. (It is believed that the bidentate ligands prevent formation of the palladium iodide dimer after oxidative addition, speeding up the reaction.) These ligands typically produce the coupled products at higher rates and better yields than the first generation of catalysts. The initial reports of these ligands as catalysts were somewhat unexpected given the mechanistic evidence for monoligated complexes serving as the active catalysts in the first-generation system. In fact, the first examples from both labs were published in the same issue of JACS
Journal of the American Chemical Society
The Journal of the American Chemical Society is a weekly peer-reviewed scientific journal that was established in 1879 by the American Chemical Society. The journal has absorbed two other publications in its history, the Journal of Analytical and Applied Chemistry and the American Chemical Journal...

.
The chelation from these ligands is thought to suppress β-hydride elimination by preventing an open coordination site. In fact, α-chiral amines were found not to racemize when chelating ligands were employed, in contrast to the first-generation catalyst system.

Sterically hindered ligands

More recently, bulky tri- and di-alkyl phosphine ligands have been shown to be remarkably active catalysts, allowing the coupling of a wide range of amines (primary, secondary, electron withdrawn, heteocyclic, etc.) with aryl chlorides, bromides, iodides, and triflates. Additionally, reactions employing hydroxide
Hydroxide
Hydroxide is a diatomic anion with chemical formula OH−. It consists of an oxygen and a hydrogen atom held together by a covalent bond, and carrying a negative electric charge. It is an important but usually minor constituent of water. It functions as a base, as a ligand, a nucleophile, and a...

, carbonate
Carbonate
In chemistry, a carbonate is a salt of carbonic acid, characterized by the presence of the carbonate ion, . The name may also mean an ester of carbonic acid, an organic compound containing the carbonate group C2....

, and phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...

 bases in place of the traditional alkoxide and silylamide bases have been developed. The Buchwald group has developed a wide range of dialkylbiaryl
Biphenyl
Biphenyl is an organic compound that forms colorless crystals. It has a distinctively pleasant smell. Biphenyl is an aromatic hydrocarbon with a molecular formula 2...

phosphine ligands, while the Hartwig group has focused on ferrocene
Ferrocene
Ferrocene is an organometallic compound with the formula Fe2. It is the prototypical metallocene, a type of organometallic chemical compound consisting of two cyclopentadienyl rings bound on opposite sides of a central metal atom. Such organometallic compounds are also known as sandwich compounds...

-derived and and trialkyl phosphine ligands.
The dramatic increase in activity seen with these ligands is attributed to their propensity to sterically favor the monoligated palladium species at all stages of the catalytic cycle, dramatically increasing the rate of oxidative addition, amide formation, and reductive elimination. Several of these ligands also seem to enhance the rate of reductive elimination relative to β-hydride elimination via the electron donating arene-palladium interaction.

Even electron withdrawn amines and heterocyclic substrates can be coupled under these conditions, despite their tendency to deactivate the palladium catalyst.

Ammonia Equivalents

Despite progress made thus far, Ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...

 remains one of the most challenging coupling partners for Buchwald–Hartwig amination reactions due to its tight binding with palladium complexes; several strategies have been developed to overcome this based on reagents that serve as ammonia equivalents. The use of a benzophenone
Benzophenone
Benzophenone is the organic compound with the formula 2CO, generally abbreviated Ph2CO. Benzophenone is a widely used building block in organic chemistry, being the parent diarylketone.-Uses:...

 imine
Imine
An imine is a functional group or chemical compound containing a carbon–nitrogen double bond, with the nitrogen attached to a hydrogen atom or an organic group. If this group is not a hydrogen atom, then the compound is known as a Schiff base...

 or silylamide can overcome this limitation, with subsequent hydrolysis furnishing the primary aniline
Aniline
Aniline, phenylamine or aminobenzene is an organic compound with the formula C6H5NH2. Consisting of a phenyl group attached to an amino group, aniline is the prototypical aromatic amine. Being a precursor to many industrial chemicals, its main use is in the manufacture of precursors to polyurethane...

.
Notably, the Hartwig group has recently developed a catalyst system that can directly couple ammonia using a Josiphos-type ligand.

Variations

Under similar conditions to those employed for amination, alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....

s and can be coupled with aryl halides to produce the corresponding aryl ether
Ether
Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...

s. This serves as a convenient replacement for harsher analogues of this process such as the Ullmann condensation
Ullmann condensation
The Ullmann condensation or Ullmann ether synthesis is a variation of the Ullmann reaction, in which a phenol is coupled to an aryl halide to create a diaryl ether in the presence of a copper compound, named after Fritz Ullmann...

.
Enolates and other similar carbon nucleophiles can also be coupled to produce α-aryl ketones, malonates, nitriles, etc. The scope of this transformation is similarly ligand-dependent and a number of systems have been developed. Several enantioselective methods for this process have been developed.
Several versions of the reaction employing complexes of copper
Copper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...

 and nickel
Nickel
Nickel is a chemical element with the chemical symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel belongs to the transition metals and is hard and ductile...

rather than palladium have also been developed.

External links

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