Organolithium reagent

 

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Organolithium_reagent

In organometallic chemistry, organolithium reagents are chemical compounds that contain carbon–lithium (C–Li) bonds. These reagents are important in organic synthesis, and are frequently used to transfer the organic group or the lithium atom to the substrates in synthetic steps, through nucleophilic addition or simple deprotonation. Organolithium reagents are used in industry as an initiator for anionic polymerization, which leads to the production of various elastomers. They have also been applied in asymmetric synthesis in the pharmaceutical industry. Due to the large difference in electronegativity between the carbon atom and the lithium atom, the C−Li bond is highly ionic. Owing to the polar nature of the C−Li bond, organolithium reagents are good nucleophiles and strong bases. For laboratory organic synthesis, many organolithium reagents are commercially available in solution form. These reagents are highly reactive, and are sometimes pyrophoric.

Glass bottles containing butyllithium

A sec-butyllithium aggregate in which each of the four sec-butyl groups is associated with one face of the tetrahedron formed from four lithium atoms

History and development

Studies of organolithium reagents began in the 1930s and were pioneered by Karl Ziegler, Georg Wittig, and Henry Gilman. In comparison with Grignard (magnesium) reagents, organolithium reagents can often perform the same reactions with increased rates and higher yields, such as in the case of metalation. Since then, organolithium reagents have overtaken Grignard reagents in common usage.

Structure

Although simple alkyllithium species are often represented as monomer RLi, they exist as aggregates (oligomers) or polymers. The degree of aggregation depends on the organic substituent and the presence of other ligands. These structures have been elucidated by a variety of methods, notably ⁶Li, ⁷Li, and ¹³C NMR spectroscopy and X-ray diffraction analysis. Computational chemistry supports these assignments.

Nature of carbon–lithium bond

Delocalized electron density in allyllithium reagents

The relative electronegativities of carbon and lithium suggest that the C−Li bond will be highly polar. However, certain organolithium compounds possess properties such as solubility in nonpolar solvents that complicate the issue.  While most data suggest the C−Li bond to be essentially ionic, there has been debate as to how much covalent character exists in it. One estimate puts the percentage of ionic character of alkyllithium compounds at 80 to 88%.

In allyl lithium compounds, the lithium cation coordinates to the face of the carbon π bond in an η³ fashion instead of a localized, carbanionic center, thus, allyllithiums are often less aggregated than alkyllithiums. In aryllithium complexes, the lithium cation coordinates to a single carbanion center through a Li−C σ type bond.

Solid state structures of methyllithium tetramers, n-butyllithium hexamers and polymeric ladder of phenyllithium

Solid state structure

Tetrahedron and octahedron metal cores formed by aggregation of the Li3 triangle - carbanion coordinate complex

Like other species consisting of polar subunits, organolithium species aggregate. Formation of aggregates is influenced by electrostatic interactions, the coordination between lithium and surrounding solvent molecules or polar additives, and steric effects.

A basic building block toward constructing more complex structures is a carbanionic center interacting with a Li₃ triangle in an η³- fashion. In simple alkyllithium reagents, these triangles aggregate to form tetrahedron or octahedron structures. For example, methyllithium, ethyllithium and tert-butyllithium all exist in the tetramer [RLi]₄. Methyllithium exists as tetramers in a cubane-type cluster in the solid state, with four lithium centers forming a tetrahedron. Each methanide in the tetramer in methyllithium can have agostic interaction with lithium cations in adjacent tetramers. Ethyllithium and tert-butyllithium, on the other hand, do not exhibit this interaction, and are thus soluble in non-polar hydrocarbon solvents. Another class of alkyllithium adopts hexameric structures, such as n-butyllithium, isopropyllithium, and cyclohexanyllithium.

LDA dimer with THF coordinated to Li cations

Common lithium amides, e.g. lithium bis(trimethylsilyl)amide and lithium diisopropylamide, are also subject to aggregation. Lithium amides adopt polymeric-ladder type structures in non-coordinating solvent in the solid state, and they generally exist as dimers in ethereal solvents. In the presence of strongly donating ligands, tri- or tetrameric lithium centers are formed. For example, LDA exists primarily as dimers in THF. The structures of common lithium amides, such as lithium diisopropylamide (LDA) and lithium hexamethyldisilazide (LiHMDS) have been extensively studied by Collum and coworkers using NMR spectroscopy. Another important class of reagents is silyllithiums, extensively used in the synthesis of organometallic complexes and polysilane dendrimers. In the solid state, in contrast with alkyllithium reagents, most silyllithiums tend to form monomeric structures coordinated with solvent molecules such as THF, and only a few silyllithiums have been characterized as higher aggregates. This difference can arise from the method of preparation of silyllithiums, the steric hindrance caused by the bulky alkyl substituents on silicon, and the less polarized nature of Si−Li bonds. The addition of strongly donating ligands, such as TMEDA and (-)-sparteine, can displace coordinating solvent molecules in silyllithiums.

Solution structure

Relying solely on the structural information of organolithium aggregates obtained in the solid state from crystal structures has certain limits, as it is possible for organolithium reagents to adopt different structures in reaction solution environment. Also, in some cases the crystal structure of an organolithium species can be difficult to isolate. Therefore, studying the structures of organolithium reagents, and the lithium-containing intermediates in solution form is extremely useful in understanding the reactivity of these reagents.  NMR spectroscopy has emerged as a powerful tool for the studies of organolithium aggregates in solution. For alkyllithium species, C−Li J coupling can often used to determine the number of lithium interacting with a carbanion center, and whether these interactions are static or dynamic. Separate NMR signals can also differentiate the presence of multiple aggregates from a common monomeric unit.

The structures of organolithium compounds are affected by the presence of Lewis bases such as tetrahydrofuran (THF), diethyl ether (Et₂O), tetramethylethylene diamine (TMEDA) or hexamethylphosphoramide (HMPA). Methyllithium is a special case, in which solvation with ether, or polar additive HMPA does not deaggregate the tetrameric structure in the solid state. On the other hand, THF deaggregates hexameric butyl lithium: the tetramer is the main species, and ΔG for interconversion between tetramer and dimer is around 11 kcal/mol. TMEDA can also chelate to the lithium cations in n-butyllithium and form solvated dimers such as [(TMEDA) LiBu-n)]₂. Phenyllithium has been shown to exist as a distorted tetramer in the crystallized ether solvate, and as a mixture of dimer and tetramer in ether solution.

Aggregates of some alkyllithiums in solvents

	Solvent	Structure
methyllithium	THF	tetramer
methyllithium	ether/HMPA	tetramer
n-butyllithium	pentane	hexamer
n-butyllithium	ether	tetramer
n-butyllithium	THF	tetramer-dimer
sec-butyllithium	pentane	hexamer-tetramer
isopropyllithium	pentane	hexamer-tetramer
tert-butyllithium	pentane	tetramer
tert-butyllithium	THF	monomer
phenyllithium	ether	tetramer-dimer
phenyllithium	ether/HMPA	dimer

Structure and reactivity

As the structures of organolithium reagents change according to their chemical environment, so do their reactivity and selectivity. One question surrounding the structure-reactivity relationship is whether there exists a correlation between the degree of aggregation and the reactivity of organolithium reagents. It was originally proposed that lower aggregates such as monomers are more reactive in alkyllithiums. However, reaction pathways in which dimer or other oligomers are the reactive species have also been discovered, and for lithium amides such as LDA, dimer-based reactions are common. A series of solution kinetics studies of LDA-mediated reactions suggest that lower aggregates of enolates do not necessarily lead to higher reactivity.

Also, some Lewis bases increase reactivity of organolithium compounds. However, whether these additives function as strong chelating ligands, and how the observed increase in reactivity relates to structural changes in aggregates caused by these additives are not always clear. For example, TMEDA increases rates and efficiencies in many reactions involving organolithium reagents. Toward alkyllithium reagents, TMEDA functions as a donor ligand, reduces the degree of aggregation, and increases the nucleophilicity of these species. However, TMEDA does not always function as a donor ligand to lithium cation, especially in the presence of anionic oxygen and nitrogen centers. For example, it only weakly interacts with LDA and LiHMDS even in hydrocarbon solvents with no competing donor ligands. In imine lithiation, while THF acts as a strong donating ligand to LiHMDS, the weakly coordinating TMEDA readily dissociates from LiHMDS, leading to the formation of LiHMDS dimers that is the more reactive species. Thus, in the case of LiHMDS, TMEDA does not increase reactivity by reducing aggregation state. Also, as opposed to simple alkyllithium compounds, TMEDA does not deaggregate lithio-acetophenolate in THF solution. The addition of HMPA to lithium amides such as LiHMDS and LDA often results in a mixture of dimer/monomer aggregates in THF. However, the ratio of dimer/monomer species does not change with increased concentration of HMPA, thus, the observed increase in reactivity is not the result of deaggregation. The mechanism of how these additives increase reactivity is still being researched.

Reactivity and applications

The C−Li bond in organolithium reagents is highly polarized. As a result, the carbon attracts most of the electron density in the bond and resembles a carbanion. Thus, organolithium reagents are strongly basic and nucleophilic. Some of the most common applications of organolithium reagents in synthesis include their use as nucleophiles, strong bases for deprotonation, initiator for polymerization, and starting material for the preparation of other organometallic compounds.

As nucleophile

Carbolithiation reactions

As nucleophiles, organolithium reagents undergo carbolithiation reactions, whereby the carbon-lithium bond adds across a carbon–carbon double or triple bond, forming new organolithium species. This reaction is the most widely employed reaction of organolithium compounds. Carbolithiation is key in anionic polymerization processes, and n-butyllithium is used as a catalyst to initiate the polymerization of styrene, butadiene, or isoprene or mixtures thereof.

Another application that takes advantage of this reactivity is the formation of carbocyclic and heterocyclic compounds by intramolecular carbolithiation. As a form of anionic cyclization, intramolecular carbolithiation reactions offer several advantages over radical cyclization. First, it is possible for the product cyclic organolithium species to react with electrophiles, whereas it is often difficult to trap a radical intermediate of the corresponding structure. Secondly, anionic cyclizations are often more regio- and stereospecific than radical cyclization, particularly in the case of 5-hexenyllithiums. Intramolecular carbolithiation allows addition of the alkyl-, vinyllithium to triple bonds and mono-alkyl substituted double bonds. Aryllithiums can also undergo addition if a 5-membered ring is formed. The limitations of intramolecular carbolithiation include difficulty of forming 3 or 4-membered rings, as the intermediate cyclic organolithium species often tend to undergo ring-openings. Below is an example of intramolecular carbolithiation reaction. The lithium species derived from the lithium–halogen exchange cyclized to form the vinyllithium through 5-exo-trig ring closure. The vinyllithium species further reacts with electrophiles and produce functionalized cyclopentylidene compounds.

Addition to carbonyl compounds

Nucleophilic organolithium reagents can add to electrophilic carbonyl double bonds to form carbon–carbon bonds. They can react with aldehydes and ketones to produce alcohols. The addition proceeds mainly via polar addition, in which the nucleophilic organolithium species attacks from the equatorial direction, and produces the axial alcohol. Addition of lithium salts such as LiClO₄ can improve the stereoselectivity of the reaction.

When the ketone is sterically hindered, using Grignard reagents often leads to reduction of the carbonyl group instead of addition. However, alkyllithium reagents are less likely to reduce the ketone, and may be used to synthesize substituted alcohols. Below is an example of ethyllithium addition to adamantone to produce tertiary alcohol.

Organolithium reagents are also better than Grignard reagents in their ability to react with carboxylic acids to form ketones. This reaction can be optimized by carefully controlling the amount of organolithium reagent addition, or using trimethylsilyl chloride to quench excess lithium reagent. A more common way to synthesize ketones is through the addition of organolithium reagents to Weinreb amides (N-methoxy-N-methyl amides). This reaction provides ketones when the organolithium reagents is used in excess, due to chelation of the lithium ion between the N-methoxy oxygen and the carbonyl oxygen, which forms a tetrahedral intermediate that collapses upon acidic work up.

Organolithium reagents also react with carbon dioxide to form, after workup, carboxylic acids.

In the case of enone substrates, where two sites of nucleophilic addition are possible (1,2 addition to the carbonyl carbon or 1,4 conjugate addition to the β carbon), most highly reactive organolithium species favor the 1,2 addition, however, there are several ways to propel organolithium reagents to undergo conjugate addition. First, since the 1,4 adduct is the likely to be the more thermodynamically favorable species, conjugate addition can be achieved through equilibration (isomerization of the two product), especially when the lithium nucleophile is weak and 1,2 addition is reversible. Secondly, adding donor ligands to the reaction forms heteroatom-stabilized lithium species which favors 1,4 conjugate addition. In one example, addition of low-level of HMPA to the solvent favors the 1,4 addition. In the absence of donor ligand, lithium cation is closely coordinated to the oxygen atom, however, when the lithium cation is solvated by HMPA, the coordination between carbonyl oxygen and lithium ion is weakened. This method generally cannot be used to affect the regioselectivity of alkyl- and aryllithium reagents.

Organolithium reagents can also perform enantioselective nucleophilic addition to carbonyl and its derivatives, often in the presence of chiral ligands. This reactivity is widely applied in the industrial syntheses of pharmaceutical compounds. An example is the Merck and Dupont synthesis of Efavirenz, a potent HIV reverse transcriptase inhibitor. Lithium acetylide is added to a prochiral ketone to yield a chiral alcohol product. The structure of the active reaction intermediate was determined by NMR spectroscopy studies in the solution state and X-ray crystallography of the solid state to be a cubic 2:2 tetramer.

S_N2 type reactions

Organolithium reagents can serve as nucleophiles and carry out S_N2 type reactions with alkyl or allylic halides. Although they are considered more reactive than Grignard reagents in alkylation, their use is still limited due to competing side reactions such as radical reactions or metal–halogen exchange. Most organolithium reagents used in alkylations are more stabilized, less basic, and less aggregated, such as heteroatom stabilized, aryl- or allyllithium reagents. HMPA has been shown to increase reaction rate and product yields, and the reactivity of aryllithium reagents is often enhanced by the addition of potassium alkoxides. Organolithium reagents can also carry out nucleophilic attacks with epoxides to form alcohols.

As base

Organolithium reagents provide a wide range of basicity. tert-Butyllithium, with three weakly electron donating alkyl groups, is the strongest base commercially available (pKa = 53). As a result, the acidic protons on −OH, −NH and −SH are often protected in the presence of organolithium reagents. Some commonly used lithium bases are alkyllithium species such as n-butyllithium and lithium dialkylamides (LiNR₂). Reagents with bulky R groups such as lithium diisopropylamide (LDA) and lithium bis(trimethylsilyl)amide (LiHMDS) are often sterically hindered for nucleophilic addition, and are thus more selective toward deprotonation. Lithium dialkylamides (LiNR₂) are widely used in enolate formation and aldol reaction. The reactivity and selectivity of these bases are also influenced by solvents and other counter ions.

Metalation

Metalation with organolithium reagents, also known as lithiation or lithium-hydrogen exchange, is achieved when an organolithium reagent, most commonly an alkyllithium, abstracts a proton and forms a new organolithium species.

${\displaystyle \text{R}-\text{H}+{\text{R}}^{\prime }\text{Li}⟶\text{RLi}+{\text{R}}^{\prime }\text{H}}$

(1)

Common metalation reagents are the butyllithiums. tert-Butyllithium and sec-butyllithium are generally more reactive and have better selectivity than n-butyllithium, however, they are also more expensive and difficult to handle. Metalation is a common way of preparing versatile organolithium reagents. The position of metalation is mostly controlled by the acidity of the C-H bond. Lithiation often occurs at a position α to electron withdrawing groups, since they are good at stabilizing the electron-density of the anion. Directing groups on aromatic compounds and heterocycles provide regioselective sites of metalation; directed ortho metalation is an important class of metalation reactions. Metalated sulfones, acyl groups and α-metalated amides are important intermediates in chemistry synthesis. Metalation of allyl ether with alkyllithium or LDA forms an anion α to the oxygen, and can proceed to 2,3-Wittig rearrangement. Addition of donor ligands such as TMEDA and HMPA can increase metalation rate and broaden substrate scope. Chiral organolithium reagents can be accessed through asymmetric metalation.

Directed ortho metalation is an important tool in the synthesis of regiospecific substituted aromatic compounds. This approach to lithiation and subsequent quenching of the intermediate lithium species with electrophile is often better than the electrophilic aromatic substitution due to its high regioselectivity. This reaction proceeds through deprotonation by organolithium reagents at the positions α to the direct metalation group (DMG) on the aromatic ring. The DMG is often a functional group containing a heteroatom that is Lewis basic, and can coordinate to the Lewis-acidic lithium cation. This generates a complex-induced proximity effect, which directs deprotonation at the α position to form an aryllithium species that can further react with electrophiles. Some of the most effective DMGs are amides, carbamates, sulfones and sulfonamides. They are strong electron-withdrawing groups that increase the acidity of alpha-protons on the aromatic ring. In the presence of two DMGs, metalation often occurs ortho to the stronger directing group, though mixed products are also observed. A number of heterocycles that contain acidic protons can also undergo ortho-metalation. However, for electron-poor heterocycles, lithium amide bases such as LDA are generally used, since alkyllithium has been observed to perform addition to the electron-poor heterocycles rather than deprotonation. In certain transition metal-arene complexes, such as ferrocene, the transition metal attracts electron-density from the arene, thus rendering the aromatic protons more acidic, and ready for ortho-metalation.

Superbases

Main article: Superbase

Addition of potassium alkoxide to alkyllithium greatly increases the basicity of organolithium species. The most common "superbase" can be formed by addition of KOtBu to butyllithium, often abbreviated as "LiCKOR" reagents. These "superbases" are highly reactive and often stereoselective reagents. In the example below, the LiCKOR base generates a stereospecific crotylboronate species through metalation and subsequent lithium-metalloid exchange.

Asymmetric metalation

Enantioenriched organolithium species can be obtained through asymmetric metalation of prochiral substrates. Asymmetric induction requires the presence of a chiral ligand such as (-)-sparteine. The enantiomeric ratio of the chiral lithium species is often influenced by the differences in rates of deprotonation. In the example below, treatment of N-Boc-N-benzylamine with n-butyllithium in the presence of (-)-sparteine affords one enantiomer of the product with high enantiomeric excess. Transmetalation with trimethyltinchloride affords the opposite enantiomer.

Enolate formation

Lithium enolates are formed through deprotonation of a C−H bond α to the carbonyl group by an organolithium species. Lithium enolates are widely used as nucleophiles in carbon–carbon bond formation reactions such as aldol condensation and alkylation. They are also an important intermediate in the formation of silyl enol ether.

Lithium enolate formation can be generalized as an acid–base reaction, in which the relatively acidic proton α to the carbonyl group (pK =20-28 in DMSO) reacts with organolithium base. Generally, strong, non-nucleophilic bases, especially lithium amides such LDA, LiHMDS and LiTMP are used. THF and DMSO are common solvents in lithium enolate reactions.

The stereochemistry and mechanism of enolate formation have gained much interest in the chemistry community. Many factors influence the outcome of enolate stereochemistry, such as steric effects, solvent, polar additives, and types of organolithium bases. Among the many models used to explain and predict the selectivity in stereochemistry of lithium enolates is the Ireland model.

In this assumption, a monomeric LDA reacts with the carbonyl substrate and form a cyclic Zimmerman–Traxler type transition state. The (E)-enolate is favored due to an unfavorable syn-pentane interaction in the (Z)-enolate transition state.

Addition of polar additives such as HMPA or DMPU favors the formation of (Z) enolates. The Ireland model argues that these donor ligands coordinate to the lithium cations, as a result, carbonyl oxygen and lithium interaction is reduced, and the transition state is not as tightly bound as a six-membered chair. The percentage of (Z) enolates also increases when lithium bases with bulkier side chains (such as LiHMDS) are used. However, the mechanism of how these additives reverse stereoselectivity is still being debated.

There have been some challenges to the Ireland model, as it depicts the lithium species as a monomer in the transition state. In reality, a variety of lithium aggregates are often observed in solutions of lithium enolates, and depending on specific substrate, solvent and reaction conditions, it can be difficult to determine which aggregate is the actual reactive species in solution.

Lithium–halogen exchange

Main article: Metal-halogen exchange § Lithium-halogen exchange

Lithium–halogen exchange involves heteroatom exchange between an organohalide and organolithium species.

${\displaystyle \text{R}-\text{Li}+{\text{R}}^{\prime }-\text{X}⟶\text{R}-\text{X}+{\text{R}}^{\prime }-\text{Li}}$

(2)

Lithium–halogen exchange is very useful in preparing new organolithium reagents. The application of lithium–halogen exchange is illustrated by the Parham cyclization.

Transmetalation

Organolithium reagents are often used to prepare other organometallic compounds by transmetalation. Organocopper, organotin, organosilicon, organoboron, organophosphorus, organocerium and organosulfur compounds are frequently prepared by reacting organolithium reagents with appropriate electrophiles.

${\displaystyle \text{R}-\text{M}+\mathit{\text{n-}}\text{BuLi}⟶\text{R}-\text{Li}+\mathit{\text{n-}}\text{BuM}}$

(3)

Common types of transmetalation include Li/Sn, Li/Hg, and Li/Te exchange, which are fast at low temperature. The advantage of Li/Sn exchange is that the tri-alkylstannane precursors undergo few side reactions, as the resulting n-Bu₃Sn byproducts are unreactive toward alkyllithium reagents. In the following example, vinylstannane, obtained by hydrostannylation of a terminal alkyne, forms vinyllithium through transmetalation with n-BuLi.

Organolithium can also be used in to prepare organozinc compounds through transmetalation with zinc salts.

Lithium diorganocuprates can be formed by reacting alkyl lithium species with copper(I) halide. The resulting organocuprates are generally less reactive toward aldehydes and ketones than organolithium reagents or Grignard reagents.

Preparation

Most simple alkyllithium reagents, and common lithium amides are commercially available in a variety of solvents and concentrations. Organolithium reagents can also be prepared in the laboratory. Below are some common methods for preparing organolithium reagents.

Reaction with lithium metal

Reduction of alkyl halide with metallic lithium can afford simple alkyl and aryl organolithium reagents.

${\displaystyle \text{R}-\text{X}+2\text{Li}⟶\text{R}-\text{Li}+\text{Li}-\text{X}}$

(4)

Industrial preparation of organolithium reagents is achieved using this method by treating the alkyl chloride with metal lithium containing 0.5–2% sodium. The conversion is highly exothermic. The sodium initiates the radical pathway and increases the rate. The reduction proceeds via a radical pathway. Below is an example of the preparation of a functionalized lithium reagent using reduction with lithium metal. Sometimes, lithium metal in the form of fine powders are used in the reaction with certain catalysts such as naphthalene or 4,4’-di-t-butylbiphenyl (DTBB). Another substrate that can be reduced with lithium metal to generate alkyllithium reagents is sulfides. Reduction of sulfides is useful in the formation of functionalized organolithium reagents such as alpha-lithio ethers, sulfides, and silanes.

Metalation

Further information: Metalation § Reactivity and applications

A second method of preparing organolithium reagents is a metalation (lithium hydrogen exchange). The relative acidity of hydrogen atoms controls the position of lithiation.

This is the most common method for preparing alkynyllithium reagents, because the terminal hydrogen bound to the sp carbon is very acidic and easily deprotonated. For aromatic compounds, the position of lithiation is also determined by the directing effect of substituent groups. Some of the most effective directing substituent groups are alkoxy, amido, sulfoxide, sulfonyl. Metalation often occurs at the position ortho to these substituents. In heteroaromatic compounds, metalation usually occurs at the position ortho to the heteroatom.

Lithium–halogen exchange

See lithium–halogen exchange (under Reactivity and applications)

A third method to prepare organolithium reagents is through lithium halogen exchange.

tert-butyllithium or n-butyllithium are the most commonly used reagents for generating new organolithium species through lithium halogen exchange. Lithium–halogen exchange is mostly used to convert aryl and alkenyl iodides and bromides with sp2 carbons to the corresponding organolithium compounds. The reaction is extremely fast, and often proceed at −60 to −120 °C.

Transmetalation

Further information: Transmetalation § Applications

The fourth method to prepare organolithium reagents is through transmetalation. This method can be used for preparing vinyllithium.

Shapiro reaction

In the Shapiro reaction, two equivalents of strong alkyllithium base react with p-tosylhydrazone compounds to produce the vinyllithium, or upon quenching, the olefin product.

Handling

Organolithium compounds are highly reactive species and require specialized handling techniques. They are often corrosive, flammable, and sometimes pyrophoric (spontaneous ignition when exposed to air or moisture). Alkyllithium reagents can also undergo thermal decomposition to form the corresponding alkyl species and lithium hydride. Organolithium reagents are typically stored below 10 °C. Reactions are conducted using air-free techniques. The concentration of alkyllithium reagents is often determined by titration.

Organolithium reagents react, often slowly, with ethers, which nonetheless are often used as solvents.

Approximate half-lives of common lithium reagents in typical solvents

Solvent	Temp	n-BuLi	s-BuLi	t-BuLi	MeLi	CH2=C(OEt)-Li	CH2=C(SiMe3)-Li
THF	−40 °C			338 min
THF	−20 °C			42 min
THF	0 °C	17 h
THF	20 °C	107 min				>15 h	17 h
THF	35 °C	10 min
THF/TMEDA	−20 °C	55 h
THF/TMEDA	0 °C	340 min
THF/TMEDA	20 °C	40 min
Ether	−20 °C			480 min
Ether	0 °C			61 min
Ether	20 °C	153 h		<30 min			17 d
Ether	35 °C	31 h
Ether/TMEDA	20 °C	603 min
DME	−70 °C		120 min	11 min
DME	−20 °C	110 min	2 min	≪2 min
DME	0 °C	6 min

Nuclide

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Nuclide

A nuclide (or nucleide, from nucleus, also known as nuclear species) is a class of atoms characterized by their number of protons, Z, their number of neutrons, N, and their nuclear energy state.

The word nuclide was coined by Truman P. Kohman in 1947. Kohman defined nuclide as a "species of atom characterized by the constitution of its nucleus" containing a certain number of neutrons and protons. The term thus originally focused on the nucleus.

Nuclides vs isotopes

A nuclide is a species of an atom with a specific number of protons and neutrons in the nucleus, for example carbon-13 with 6 protons and 7 neutrons. The nuclide concept (referring to individual nuclear species) emphasizes nuclear properties over chemical properties, while the isotope concept (grouping all atoms of each element) emphasizes chemical over nuclear. The neutron number has large effects on nuclear properties, but its effect on chemical reactions is negligible for most elements. Even in the case of the very lightest elements, where the ratio of neutron number to atomic number varies the most between isotopes, it usually has only a small effect, but it matters in some circumstances. For hydrogen, the lightest element, the isotope effect is large enough to affect biological systems strongly. In the case of helium, helium-4 obeys Bose–Einstein statistics, while helium-3 obeys Fermi-Dirac statistics. Since isotope is the older term, it is better known than nuclide, and is still occasionally used in contexts in which nuclide might be more appropriate, such as nuclear technology and nuclear medicine.

Types of nuclides

Although the words nuclide and isotope are often used interchangeably, being isotopes is actually only one relation between nuclides. The following table names some other relations.

Designation	Characteristics	Example	Remarks
Isotopes	equal proton number (Z1 = Z2)	12 6C , 13 6C , 14 6C
Isotones	equal neutron number (N1 = N2)	13 6C , 14 7N , 15 8O
Isobars	equal mass number (Z1 + N1 = Z2 + N2)	17 7N , 17 8O , 17 9F	see beta decay
Isodiaphers	equal neutron excess (N1 − Z1 = N2 − Z2)	13 6C , 15 7N , 17 8O	Examples are isodiaphers with neutron excess 1. A nuclide and its alpha decay product are isodiaphers.
Mirror nuclei	neutron and proton number exchanged (Z1 = N2 and Z2 = N1)	3 1H , 3 2He
Nuclear isomers	same proton number and mass number, but with different energy states	99 43Tc , 99m 43Tc	m=metastable (long-lived excited state)

A set of nuclides with equal proton number (atomic number), i.e., of the same chemical element but different neutron numbers, are called isotopes of the element. Particular nuclides are still often loosely called "isotopes", but the term "nuclide" is the correct one in general (i.e., when Z is not fixed). In similar manner, a set of nuclides with equal mass number A, but different atomic number, are called isobars (isobar = equal in weight), and isotones are nuclides of equal neutron number but different proton numbers. Likewise, nuclides with the same neutron excess (N − Z) are called isodiaphers. The name isotone was derived from the name isotope to emphasize that in the first group of nuclides it is the number of neutrons (n) that is constant, whereas in the second the number of protons (p).

See Isotope#Notation for an explanation of the notation used for different nuclide or isotope types.

Nuclear isomers are members of a set of nuclides with equal proton number and equal mass number (thus making them by definition the same isotope), but different states of excitation. An example is the two states of the single isotope ⁹⁹
₄₃Tc
shown among the decay schemes. Each of these two states (technetium-99m and technetium-99) qualifies as a different nuclide, illustrating one way that nuclides may differ from isotopes (an isotope may consist of several different nuclides of different excitation states).

The longest-lived non-ground state nuclear isomer is the nuclide tantalum-180m (^180m
₇₃Ta
), which has a half-life in excess of 1,000 trillion years. This nuclide occurs primordially, and has never been observed to decay to the ground state. (In contrast, the ground state nuclide tantalum-180 does not occur primordially, since it decays with a half life of only 8 hours to ¹⁸⁰Hf (86%) or ¹⁸⁰W (14%).)

There are 251 nuclides in nature that have never been observed to decay. They occur among the 80 different elements that have one or more stable isotopes. See stable nuclide and primordial nuclide. Unstable nuclides are radioactive and are called radionuclides. Their decay products ('daughter' products) are called radiogenic nuclides.

Origins of naturally occurring radionuclides

Natural radionuclides may be conveniently subdivided into three types. First, those whose half-lives t_1/2 are at least 2% as long as the age of the Earth (for practical purposes, these are difficult to detect with half-lives less than 10% of the age of the Earth) (4.6×10⁹ years). These are remnants of nucleosynthesis that occurred in stars before the formation of the Solar System. For example, the isotope ²³⁸
U
(t_1/2 = 4.5×10⁹ years) of uranium is still fairly abundant in nature, but the shorter-lived isotope ²³⁵
U
(t_1/2 = 0.7×10⁹ years) is 138 times rarer. About 34 of these nuclides have been discovered (see List of nuclides and Primordial nuclide for details).

The second group of radionuclides that exist naturally consists of radiogenic nuclides such as ²²⁶
Ra
(t_1/2 = 1602 years), an isotope of radium, which are formed by radioactive decay. They occur in the decay chains of primordial isotopes of uranium or thorium. Some of these nuclides are very short-lived, such as isotopes of francium. There exist about 51 of these daughter nuclides that have half-lives too short to be primordial, and which exist in nature solely due to decay from longer lived radioactive primordial nuclides.

The third group consists of nuclides that are continuously being made in another fashion that is not simple spontaneous radioactive decay (i.e., only one atom involved with no incoming particle) but instead involves a natural nuclear reaction. These occur when atoms react with natural neutrons (from cosmic rays, spontaneous fission, or other sources), or are bombarded directly with cosmic rays. The latter, if non-primordial, are called cosmogenic nuclides. Other types of natural nuclear reactions produce nuclides that are said to be nucleogenic nuclides.

An example of nuclides made by nuclear reactions, are cosmogenic ¹⁴
C
(radiocarbon) that is made by cosmic ray bombardment of other elements, and nucleogenic ²³⁹
Pu
which is still being created by neutron bombardment of natural ²³⁸
U
as a result of natural fission in uranium ores. Cosmogenic nuclides may be either stable or radioactive. If they are stable, their existence must be deduced against a background of stable nuclides, since every known stable nuclide is present on Earth primordially.

Artificially produced nuclides

Beyond the naturally occurring nuclides, more than 3000 radionuclides of varying half-lives have been artificially produced and characterized.

The known nuclides are shown in Table of nuclides. A list of primordial nuclides is given sorted by element, at List of elements by stability of isotopes. List of nuclides is sorted by half-life, for the 905 nuclides with half-lives longer than one hour.

Summary table for numbers of each class of nuclides

This is a summary table for the 905 nuclides with half-lives longer than one hour, given in list of nuclides. Note that numbers are not exact, and may change slightly in the future, if some "stable" nuclides are observed to be radioactive with very long half-lives.

Stability class	Number of nuclides	Running total	Notes on running total
Theoretically stable to all but proton decay	90	90	Includes first 40 elements. Proton decay yet to be observed.
Energetically unstable to one or more known decay modes, but no decay yet seen. Spontaneous fission possible for "stable" nuclides from niobium-93 onward; other mechanisms possible for heavier nuclides. All considered "stable" until decay detected.	161	251	Total of classically stable nuclides.
Radioactive primordial nuclides.	35	286	Total primordial elements include bismuth, thorium, and uranium, plus all stable nuclides.
Radioactive (half-life > 1 hour). Includes most useful radioactive tracers.	619	905	Carbon-14 (and other cosmogenic nuclides generated by cosmic rays); daughters of radioactive primordials, such as francium, etc., and nucleogenic nuclides from natural nuclear reactions that are other than those from cosmic rays (such as neutron absorption from spontaneous nuclear fission or neutron emission). Also many synthetic nuclides.
Radioactive synthetic (half-life < 1 hour).	>2400	>3300	Includes all well-characterized synthetic nuclides.

Nuclear properties and stability

Stability of nuclides by (Z, N), an example of a table of nuclides:
Black – stable (all are primordial)
Red – primordial radioactive
Other – radioactive, with decreasing stability from orange to white

See also: Stable nuclide

Atomic nuclei other than hydrogen ¹
₁H
have protons and neutrons bound together by the residual strong force. Because protons are positively charged, they repel each other. Neutrons, which are electrically neutral, stabilize the nucleus in two ways. Their copresence pushes protons slightly apart, reducing the electrostatic repulsion between the protons, and they exert the attractive nuclear force on each other and on protons. For this reason, one or more neutrons are necessary for two or more protons to be bound into a nucleus. As the number of protons increases, so does the ratio of neutrons to protons necessary to ensure a stable nucleus (see graph). For example, although the neutron–proton ratio of ³
₂He
is 1:2, the neutron–proton ratio of ²³⁸
₉₂U
is greater than 3:2. A number of lighter elements have stable nuclides with the ratio 1:1 (Z = N). The nuclide ⁴⁰
₂₀Ca
(calcium-40) is observationally the heaviest stable nuclide with the same number of neutrons and protons. All stable nuclides heavier than calcium-40 contain more neutrons than protons.

Even and odd nucleon numbers

Main article: Even and odd atomic nuclei

 

Even/odd Z, N, and A

A	Even		Odd		Total
Z,N	EE	OO	EO	OE
Stable	145	5	53	48	251
	150		101
Long-lived	22	4	4	5	35
	26		9
All primordial	167	9	57	53	286
	176		110

The proton–neutron ratio is not the only factor affecting nuclear stability. It depends also on even or odd parity of its atomic number Z, neutron number N and, consequently, of their sum, the mass number A. Oddness of both Z and N tends to lower the nuclear binding energy, making odd nuclei, generally, less stable. This remarkable difference of nuclear binding energy between neighbouring nuclei, especially of odd-A isobars, has important consequences: unstable isotopes with a nonoptimal number of neutrons or protons decay by beta decay (including positron decay), electron capture or more exotic means, such as spontaneous fission and cluster decay.

The majority of stable nuclides are even-proton–even-neutron, where all numbers Z, N, and A are even. The odd-A stable nuclides are divided (roughly evenly) into odd-proton–even-neutron, and even-proton–odd-neutron nuclides. Odd-proton–odd-neutron nuclides (and nuclei) are the least common.

Grignard reagent

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Grignard_reagent

Usually Grignard reagents are written as R-Mg-X, but in fact the magnesium(II) centre is tetrahedral when dissolved in Lewis basic solvents, as shown here for the bis-adduct of methylmagnesium chloride and THF.

A Grignard reagent or Grignard compound is a chemical compound with the general formula R−Mg−X, where X is a halogen and R is an organic group, normally an alkyl or aryl. Two typical examples are methylmagnesium chloride Cl−Mg−CH₃ and phenylmagnesium bromide (C₆H₅)−Mg−Br. They are a subclass of the organomagnesium compounds.

Grignard compounds are popular reagents in organic synthesis for creating new carbon-carbon bonds. For example, when reacted with another halogenated compound R'−X' in the presence of a suitable catalyst, they typically yield R−R' and the magnesium halide MgXX' as a byproduct; and the latter is insoluble in the solvents normally used. In this aspect, they are similar to organolithium reagents.

Pure Grignard reagents are extremely reactive solids. They are normally handled as solutions in solvents such as diethyl ether or tetrahydrofuran; which are relatively stable as long as water is excluded. In such a medium, a Grignard reagent is invariably present as a complex with the magnesium atom connected to the two ether oxygens by coordination bonds. Some Grignard compounds exhibit chemiluminescence.

The discovery of the Grignard reaction in 1900 was awarded with the Nobel Prize in 1912. For more details on the history, see Victor Grignard.

Synthesis

From Mg metal

Traditionally Grignard reagents are prepared by treating an organic halide (normally organobromine) with magnesium metal. Ethers are required to stabilize the organomagnesium compound. Water and air, which rapidly destroy the reagent by protonolysis or oxidation, are excluded using air-free techniques. Although the reagents still need to be dry, ultrasound can allow Grignard reagents to form in wet solvents by activating the magnesium such that it consumes the water.

As is common for reactions involving solids and solution, the formation of Grignard reagents is often subject to an induction period. During this stage, the passivating oxide on the magnesium is removed. After this induction period, the reactions can be highly exothermic. This exothermicity must be considered when a reaction is scaled-up from laboratory to production plant. Most organohalides will work, but carbon-fluorine bonds are generally unreactive, except with specially activated magnesium (through Rieke metals).

Magnesium

Typically the reaction to form Grignard reagents involves the use of magnesium ribbon. All magnesium is coated with a passivating layer of magnesium oxide, which inhibits reactions with the organic halide. Many methods have been developed to weaken this passivating layer, thereby exposing highly reactive magnesium to the organic halide. Mechanical methods include crushing of the Mg pieces in situ, rapid stirring, and sonication. Iodine, methyl iodide, and 1,2-dibromoethane are common activating agents. The use of 1,2-dibromoethane is advantageous as its action can be monitored by the observation of bubbles of ethylene. Furthermore, the side-products are innocuous:

Mg + BrC₂H₄Br → C₂H₄ + MgBr₂

The amount of Mg consumed by these activating agents is usually insignificant. A small amount of mercuric chloride will amalgamate the surface of the metal, enhancing its reactivity. Addition of preformed Grignard reagent is often used as the initiator.

Specially activated magnesium, such as Rieke magnesium, circumvents this problem. The oxide layer can also be broken up using ultrasound, using a stirring rod to scratch the oxidized layer off, or by adding a few drops of iodine or 1,2-Diiodoethane. Another option is to use sublimed magnesium or magnesium anthracene.

Mechanism

In terms of mechanism, the reaction proceeds through single electron transfer:

R−X + Mg → R−X^•− + Mg^•+

R−X^•− → R^• + X⁻

R^• + Mg^•+ → RMg⁺

RMg⁺ + X⁻ → RMgX

Mg transfer reaction (halogen–Mg exchange)

An alternative preparation of Grignard reagents involves transfer of Mg from a preformed Grignard reagent to an organic halide. Other organomagnesium reagents are used as well. This method offers the advantage that the Mg transfer tolerates many functional groups. An illustrative reaction involves isopropylmagnesium chloride and aryl bromide or iodides:

i-PrMgCl + ArCl → i-PrCl + ArMgCl

From alkylzinc compounds (reductive transmetalation)

A further method to synthesize Grignard reagents involves reaction of Mg with an organozinc compound. This method has been used to make adamantane-based Grignard reagents, which are, due to C-C coupling side reactions, difficult to make by the conventional method from the alkyl halide and Mg. The reductive transmetalation achieves:

AdZnBr + Mg → AdMgBr + Zn

Testing Grignard reagents

Because Grignard reagents are so sensitive to moisture and oxygen, many methods have been developed to test the quality of a batch. Typical tests involve titrations with weighable, anhydrous protic reagents, e.g. menthol in the presence of a color-indicator. The interaction of the Grignard reagent with phenanthroline or 2,2'-biquinoline causes a color change.

Reactions of Grignard reagents

Grignard reagent reactions
Named after	Victor Grignard
Reaction type	Coupling reaction
Reaction
Carbon electrophiles + R-MgX + (H3O+) ↓ Coupling Product

With carbonyl compounds

Grignard reagents react with a variety of carbonyl derivatives.

The most common application of Grignard reagents is the alkylation of aldehydes and ketones, i.e. the Grignard reaction:

Note that the acetal function (a protected carbonyl) does not react.

Such reactions usually involve an aqueous acidic workup, though this step is rarely shown in reaction schemes. In cases where the Grignard reagent is adding to an aldehyde or a prochiral ketone, the Felkin-Anh model or Cram's Rule can usually predict which stereoisomer will be formed. With easily deprotonated 1,3-diketones and related acidic substrates, the Grignard reagent RMgX functions merely as a base, giving the enolate anion and liberating the alkane RH.

Grignard reagents are nucleophiles in nucleophilic aliphatic substitutions for instance with alkyl halides in a key step in industrial Naproxen production:

Reactions as a base

Grignard reagents serve as a base for protic substrates (this scheme does not show workup conditions, which typically includes water). Grignard reagents are basic and react with alcohols, phenols, etc. to give alkoxides (ROMgBr). The phenoxide derivative is susceptible to formylation by paraformaldehyde to give salicylaldehyde.

Alkylation of metals and metalloids

Like organolithium compounds, Grignard reagents are useful for forming carbon–heteroatom bonds.

${\displaystyle \begin{array}{c}{\text{R}}_4^{}{\text{B}}^{-}\\ {\text{Et}}_2^{}\text{O}\cdot {\text{BF}}_3^{}\text{or}{\text{NaBF}}_4^{}\uparrow {\text{Et}}_2^{}\text{O}\cdot {\text{BF}}_3^{}\text{or}{\text{NaBF}}_4^{}\\ {\text{Ph}}_2^{}\text{PR}\stackrel{{\text{Ph}}_2^{}\text{PCl}}{\leftarrow }\text{RMgX}\stackrel{{\text{Bu}}_3^{}\text{SnCl}}{\to }{\text{Bu}}_3^{}\text{SnR}\\ \text{B}{(\text{OMe})}_3^{}\downarrow \text{B}{(\text{OMe})}_3^{}\\ \text{RB}{(\text{OMe})}_2^{}\end{array}}$

Grignard reagents react with many metal-based electrophiles. For example, they undergo transmetallation with cadmium chloride (CdCl₂) to give dialkylcadmium:

2 RMgX + CdCl₂ → R₂Cd + 2 Mg(X)Cl

Schlenk equilibrium

Most Grignard reactions are conducted in ethereal solvents, especially diethyl ether and THF. Grignard reagents react with 1,4-dioxane to give the diorganomagnesium compounds and insoluble coordination polymer MgX₂(dioxane)₂ and (R = organic group, X = halide):

2 RMgX + dioxane ⇌ R₂Mg + MgX₂(dioxane)₂

This reaction exploits the Schlenk equilibrium, driving it toward the right.

Precursors to magnesiates

Grignard reagents react with organolithium compounds to give ate complexes (Bu = butyl):

BuMgBr + 3 BuLi → LiMgBu₃ + BuBr

Coupling with organic halides

Grignard reagents do not typically react with organic halides, in contrast with their high reactivity with other main group halides. In the presence of metal catalysts, however, Grignard reagents participate in C-C coupling reactions. For example, nonylmagnesium bromide reacts with methyl p-chlorobenzoate to give p-nonylbenzoic acid, in the presence of Tris(acetylacetonato)iron(III) (Fe(acac)₃), after workup with NaOH to hydrolyze the ester, shown as follows. Without the Fe(acac)₃, the Grignard reagent would attack the ester group over the aryl halide.

For the coupling of aryl halides with aryl Grignard reagents, nickel chloride in tetrahydrofuran (THF) is also a good catalyst. Additionally, an effective catalyst for the couplings of alkyl halides is the Gilman catalyst lithium tetrachlorocuprate (Li₂CuCl₄), prepared by mixing lithium chloride (LiCl) and copper(II) chloride (CuCl₂) in THF. The Kumada-Corriu coupling gives access to [substituted] styrenes.

Oxidation

Treatment of a Grignard reagent with oxygen gives the magnesium organoperoxide. Hydrolysis of this material yields hydroperoxides or alcohol. These reactions involve radical intermediates.

${\displaystyle \begin{array}{lcrll}\text{R}-\text{MgX}+{\text{O}}_2^{}⟶\text{R}\cdot +{\text{O}}_2^{\cdot -}+{\text{MgX}}^{+}⟶& \text{R}-\text{O}-\text{O}-\text{MgX}& +{\text{H}}_3^{}{\text{O}}^{+}& ⟶\text{R}-\text{O}-\text{O}-\text{H}& +\text{HO}-\text{MgX}+{\text{H}}^{+}\\ & \downarrow \text{R}-\text{MgX}\\ & \text{R}-\text{O}-\text{MgX}& +{\text{H}}_3^{}{\text{O}}^{+}& ⟶\text{R}-\text{O}-\text{H}& +\text{HO}-\text{MgX}+{\text{H}}^{+}\end{array}}$

The simple oxidation of Grignard reagents to give alcohols is of little practical importance as yields are generally poor. In contrast, two-step sequence via a borane (vide supra) that is subsequently oxidized to the alcohol with hydrogen peroxide is of synthetic utility.

The synthetic utility of Grignard oxidations can be increased by a reaction of Grignard reagents with oxygen in presence of an alkene to an ethylene extended alcohol. This modification requires aryl or vinyl Grignards. Adding just the Grignard and the alkene does not result in a reaction demonstrating that the presence of oxygen is essential. The only drawback is the requirement of at least two equivalents of Grignard although this can partly be circumvented by the use of a dual Grignard system with a cheap reducing Grignard such as n-butylmagnesium bromide.

Elimination

In the Boord olefin synthesis, the addition of magnesium to certain β-haloethers results in an elimination reaction to the alkene. This reaction can limit the utility of Grignard reactions.

Industrial use

An example of the Grignard reaction is a key step in the (non-stereoselective) industrial production of Tamoxifen (currently used for the treatment of estrogen receptor positive breast cancer in women):