Chapter 1: An Overview of Organoselenium Chemistry: From Fundamentals to Synthesis

Selenium is a member of the group 16 elements (O, S, Se, Te and radioactive Po), collectively known as chalcogens. It was discovered in 1817 by J.J. Berzelius in the reddish deposits that formed in the lead chambers at his sulfuric acid plant at Gripsholm in Sweden. He named the element selenium in the honour of Greek goddess ‘Selene’ meaning moon.¹ 

The chemistry of selenium compounds was neglected for more than a century; the entire literature²  comprised only ∼200 papers until 1920 and it remained an arcane field of investigation until 1970. This slow development can be attributed to the malodorous reputation of its compounds, toxicity, the instability of certain derivatives as well as the general belief that the chemistry of selenium, due to its proximity to sulfur, would be more or less similar to that of sulfur compounds. However, such beliefs and perceptions for organoselenium compounds were defied by an exponential growth of organoselenium chemistry during past three decades or so. The following three major, interdependent factors have contributed to this rapid development of the field.

• Role in organic chemistry: since its discovery in the early 1930s as an oxidizing agent for organic compounds,³  selenium dioxide (SeO₂) was used predominantly in organic synthesis until the early 1970s. However, around this time several useful reactions and processes were discovered^4–6  and the interest in organoselenium compounds was further catalysed with the publication of a monograph by Klayman and Günther.⁷  Since then, the number of reactions as well as the variety of selenium compounds have grown dramatically.⁸  Selenium can be introduced to a myriad organic substrates as an electrophile, nucleophile or even as a radical in a chemo-, regio- and stereo-selective manner.

• Organometallic chemistry and materials science: although metal complexes of seleno ligands (e.g. [PtCl₂(R₂Se)₂]; R=Me, Et, Prⁿ, Ph) were first synthesized more than a century ago,⁹  reports on organoselenium complexes appeared only sporadically until the early 1990s,¹⁰  possibly due to poorly developed synthetic processes for the desired organoselenium compounds. Selenium ligands quite often show unusual reactivity that differs from their sulfur counterparts.¹¹  Platinum group metal complexes with seleno ligands were developed as catalysts for various reactions since the 1990s,^12–14  and in some cases exhibit even better catalytic activity than the corresponding thio derivatives.¹²  Further impetus to selenium chemistry comes from recent interest in semiconductor metal selenide nano-materials.^15–17  Metal selenolates have emerged as versatile single-source molecular precursors for the synthesis of nano-particles and deposition of thin films of metal selenides.

• Selenium in biology:¹⁸  selenium was long considered a poison until 1957 when Schwarz and Foltz identified it as an essential micronutrient.¹⁹  Fifteen years later selenocysteine, the 21st amino acid, was discovered at the active site of glutathione peroxidase (GPx), establishing the role of selenium in mammals.²⁰  Since then, approximately 40 seleno enzymes, exhibiting a range of functions have been identified.²¹  GPx has been extensively investigated due to its diversity of biological roles. To mimic the functions of GPx and related enzymes, several organoselenium compounds have been designed and developed. Ebselen is a promising candidate as an oxidant.²²  The mechanistic aspects of the antioxidant activity of GPx have been worked out and the formation of several selenium species has been proposed during the catalytic cycle.²³ 

In the light of the above, an overview of organoselenium chemistry is presented in this chapter.

Selenium is a trace element occurring at an average level of 9×10⁻⁵% (0.09 ppm) in the earth's crust. There is substantial geographical variations in agricultural soils, giving selenium-deficient, -adequate and -excess (toxic) regions.²⁴  In general, selenium-deficient and -adequate regions are much more widespread than the selenium-excess regions. Selenium exists in various chemical forms in soil, which influences the availability of the element to plants. Selenium in food grains, legumes and vegetables occurs primarily in organic form (such as MetSe, cysSeMe, cysSeSecys, etc.) and is often referred as dietary selenium.²⁵  Keshan disease, Kashin–Beck disease and several dangerous viral infections (H1N1 influenza, SARS, HIV/AIDS, Ebola, etc.) are associated with selenium deficiency and outbreaks of them have originated either in bio-geo-chemically selenium-poor regions of China or selenium nutrient-depleted sub-Saharan Africa.²⁶  Acute toxicities in grazing animals were first reported in South Dakota in the 1930s, which was locally known as ‘alkali disease’.²⁷  More recently, high selenium content (750–5000 μg day⁻¹ per person) has been reported in food grown in the Punjab province of India.²⁸  Selenium intake varies worldwide, ranging from 7 μg day⁻¹ to 4990 μg day⁻¹.²⁵  In fact, there is a very narrow window between dietary deficiency (<40 μg day⁻¹) and toxic levels (>400 μg day⁻¹) in humans, and the recommended dietary intake of selenium is 50–70 μg day⁻¹.²⁹  For this reason, selenium is referred as an ‘essential poison’.³⁰ 

Selenium occurs in sulfide ores of heavy non-ferrous metals—copper, copper–nickel and multi-metallic sulfides. There is a wide variation in the selenium content of these ores. As there is no primary mineral/ore that contains an economically significant amount of selenium, it is recovered as a by-product, mostly from the anode slimes generated from the electrolytic refining of copper. The selenium content of the slimes vary from 2% to 55%, the average being ∼10%. Although selenium was discovered in 1817, its commercial production in appreciable quantities began only about a century later. Global production of selenium is hard to estimate, because it is a by-product of copper refineries. Nevertheless, it is estimated that in 2013 the global production (excluding USA and China) was >2170 metric tonnes (Figure 1.1a). The first practical application of selenium was realized in 1873 when photo-conducting properties were reported, which were exploited for the development of photo-cells. Since then a wide range of applications have been developed which include (i) electronics and photocopier machines (∼30%); (ii) the glass industry (∼35%); (iii) pigments (∼10%); (iv) metallurgy (∼10%); (v) agriculture and biology (∼10%); and (vi) others (∼5%) (Figure 1.1b).

Selenium has several allotropic forms in both the amorphous and crystalline states at room temperature and adopts either helical polymeric chain or Se₈ ring structures with Se–Se distances varying between 2.32 and 2.37 Å.^1,31,32  The density of selenium varies between 4.20 and 4.81 g cm⁻³. The following modifications of selenium are now well recognized: (i) amorphous or α-selenium (red and black forms); (ii) vitreous or glassy selenium (ordinary commercial form); (iii) crystalline monoclinic or β-selenium (red α-form and deep-red β-form); and (iv) trigonal grey or γ-selenium. The latter form (grey selenium), comprising of helical polymeric chains, is a p-type semiconductor and shows appreciable photoconductivity, whereas other modifications are insulators.

Selenium can adopt a range of integral and fractional formal oxidation states. The main integral oxidation states are −2 (e.g. sodium selenide, Na₂Se), −1 (e.g. disodium diselenide, Na₂Se₂), 0 (e.g. Se₈), +1 (e.g. diselenium dichloride, Se₂Cl₂), +2 (e.g. selenium dichloride, SeCl₂), +4 (e.g. sodium selenite, Na₂SeO₃) and +6 (e.g. sodium selenate, Na₂SeO₄); the latter oxidation state being less stable than the corresponding known sulfur compounds. The fractional oxidation states are reported in polyselenium-cations (Se_n²⁺; n=4 (oxidation state +½) and n=8 (oxidation state +¼))^33–35  and -anions (Se_n²⁻; n=3–11, 16).^34–36  The hypervalent nature of selenium based on 3c–4e interactions is also encountered in its compounds.³⁷  In the divalent state, selenium can either weakly donate its electron pair (a Lewis base) to a metal centre (M) or partially accept a lone pair (a Lewis acid) from another atom (Y, such as H, N, O, S, Cl, I, etc.) (Scheme 1.1). The latter interaction results in a linear C–Se⋯Y bond, which is thought to be responsible for the bioactivity of these compounds.³⁷  Redox cycling of selenium between various oxidation states occurs readily (Scheme 1.2).³⁸  Accordingly, selenium can act as an oxidant as well as reductant in many reactions. Various single-bond energies involving selenium, such as Se–H (66 kcal mol⁻¹), Se–C (56 kcal mol⁻¹), Se–Se (46 kcal mol⁻¹), are intermediate between corresponding sulfur and tellurium compounds.³⁹ 

Out of six naturally occurring isotopes of selenium, only the ⁷⁷Se isotope has spin quantum number ½ with natural abundance of 7.58%. It has favorable nuclear magnetic resonance (NMR) properties that include a positive magnetogyric ratio (5.101) and 5.26×10⁻⁴ relative receptivity with respect to proton.⁴⁰  The nuclear Overhauser effects are absent, while longitudinal relaxation times (T₁) are usually a few seconds (1–30 s), are influenced by spin-rotation (small molecules) and chemical shift anisotropy (larger molecules) mechanisms.⁴¹  Accordingly, ⁷⁷Se NMR spectroscopy has emerged as a powerful diagnostic tool in organoselenium chemistry and its popularity is growing,^42,43  although initial progress was sluggish—only ∼300 articles were published before 1985.⁴²  Different materials have been used as a reference; dimethylselenide (Me₂Se) is now universally accepted, but being malodorous and volatile, a secondary reference, diphenyldiselenide (Ph₂Se₂; δ ⁷⁷Se=463 ppm) in C₆D₆ is commonly used.

Like any other heavy nuclei, the ⁷⁷Se NMR chemical shifts cover a large spectral window of ∼3300 ppm, bridging selenides being most shielded (e.g. [{CpW(CO)₂}₂(μ-Se)] δ ⁷⁷Se=−900 ppm), while selenoaldehydes are most deshielded (e.g. 2,4,6-Bu^t₃C₆H₂–C(H)Se; δ ⁷⁷Se=2398 ppm).⁴²  The large chemical shift range is advantageous in the dispersion of resonances of closely related species; even a small chemical shift difference of diastereomeric diselenides can be resolved. For instance, for a mixture of regio-isomeric diselenides (Scheme 1.3), closely spaced (∼1 ppm) resonances for two distinct selenium centers for each isomeric diselenide have been reported.⁴⁴  The ⁷⁷Se NMR chemical shifts are highly sensitive to oxidation state, the stereochemistry of selenium and its local environment.^45–48  Larger δ values (deshielding) are usually associated with a decrease in electron density of selenium. A wide variation in ⁷⁷Se NMR chemical shifts with respect to the chemical state of selenium can be noted in biologically important compounds: H₃N⁺CH₂CH₂SeH (δ ⁷⁷Se=−81.6 ppm), H₃N⁺CH₂CH₂Se⁻ (δ ⁷⁷Se=−245.6 ppm), (H₃N⁺CH₂CH₂Se)₂ (δ ⁷⁷Se=251.3 ppm), H₃N⁺CH₂CH₂Se–SCH₂CH₂NH₃⁺(δ ⁷⁷Se=322.7 ppm)⁴⁸  and H₂NCH₂CH₂SeO₂H (δ ⁷⁷Se=1226 ppm).⁴⁷  The effect of the local environment on ⁷⁷Se NMR chemical shifts, as an example, is evident in o-carbonyl benzeneselenenyl compounds,⁴⁵  2-RC₆H₄SeX. With a given R the shifts are spread over >800 ppm on changing X (X=Cl, Br, SCN, CN, Me) (R=Ac, X=Cl (δ, 1087 ppm); X=Me (δ, 282 ppm)), while this variation is ∼100 ppm upon varying R and keeping the X group reserved. The intra-molecular non-bonding Se⋯X interaction, resulting from a n_x-σ*Se orbital interaction leads to a downfield shift of the ⁷⁷Se NMR resonance.⁴⁹  Approximate linear correlation between the ⁷⁷Se NMR shifts and the strength of non-bonding Se⋯X interaction has been found using theoretical calculations.^50  77Se NMR spectroscopy is gaining momentum for understanding various process, like conformational mobility, molecular interactions of selenocysteine (sec) in biological macromolecules etc., involving selenoproteins in biological samples.⁵¹  Site-specific pK_a values of multiple sec-incorporated peptides have been determined using ⁷⁷Se NMR spectroscopy, which differ (3.3 and 4.3) depending on its position in the polypeptide, and are significantly lower than the values for free sec (5.2–5.6).⁵²  Peroxidase activity of selenosubtilisin and selenonicotinamide has been investigated using ⁷⁷Se NMR spectroscopy and the involvement of selenol (RSeH), selenenic acid (RSeOH), selenenyl sulfide (RSeSR′) and seleninic acid (RSe(O)OH), have been identified in the catalytic cycle.^53,54 

The presence of other nuclear spin 1/2 nuclei results in spin–spin couplings which appear as satellite peaks and provide invaluable information about the structure and stereochemistry of the molecule. Almost all coupling constants ⁿJ(⁷⁷Se–X) are now reported. The ¹J(⁷⁷Se–¹H) coupling constants for selenol range between 44 and 65 Hz. The ¹J(⁷⁷Se–¹³C) couplings in organoselenium compounds vary in the range 45–90 Hz,^55,56  whereas these values are much larger (127–250 Hz) in fluorinated selenium compounds and selenocynates.⁵⁷  The ²J(⁷⁷Se–¹³C) couplings in alkylseleno-ethers and dialkyldiselenides are 4–15 Hz.⁵⁵  Selenium–phosphorus couplings have been extensively investigated. The magnitude of ¹J(⁷⁷Se–³¹P) couplings falls in the range 200–500 Hz and 500–∼1000 Hz for formal selenium–phosphorus single and double bonds, respectively. The ²J(⁷⁷Se–³¹P) values vary from few hertz to a few tens of hertz and have great diagnostic importance in determining the stereochemistry of the molecule⁵⁸  (e.g. ²J(⁷⁷Se–³¹P) values for cis and trans isomers of [Pt(SePh)₂(PPh₃)₂] are 45 Hz and 7 Hz, respectively^58a ). The ¹J(⁷⁷Se–⁷⁷Se) couplings in diselenides and inorganic seleno-cations fall in the range of 11–400 Hz; cations and cyclic diselenides showing larger coupling constants.^56,59  Single bond coupling with heavier nuclei can run in several hundreds of hertz. The ¹J(¹¹⁹Sn–⁷⁷Se) in diorganotin selenolates (e.g. [Me₂Sn{SeC₄H(Me-4,6)₂N₂}₂], ¹J(¹¹⁹Sn–⁷⁷Se)=725 Hz) varies in the range 595–1000 Hz.^17,60  Similarly, the ¹J(¹⁹⁵Pt–⁷⁷Se) coupling constants range from ∼100 Hz to several hundred hertz (e.g. ¹J(¹⁹⁵Pt–⁷⁷Se) for trans-[Pt(SeC₅H₄N-4)₂(PEt₃)₂] is 81 Hz and for [Pt₂Cl₂(μ-SeBz)₂(PPr₃)₂] is 134 229 Hz).⁶¹ 

Naturally occurring selenium is a mixture of six isotopes: ⁷⁴Se (0.87%), ⁷⁶Se (9.02%), ⁷⁷Se (7.58%), ⁷⁸Se (23.52%), ⁸⁰Se (49.82%) and ⁸²Se (9.19%). This distribution gives rise to characteristic isotopic patterns in mass spectra of selenium compounds. Mass spectrometry has therefore emerged as one of the principal techniques for characterization of selenium-containing molecules. Besides its routine use in synthetic organic chemistry of selenium, its use for the characterization of selenium-containing metabolites in Se-rich yeast, as well as in biological samples is growing.^62,63 

In addition to the ⁷⁷Se NMR and mass spectral investigations on selenium compounds, a rapid progress can also be attributed to X-ray crystallography. A search of the Cambridge Structural Database (2015) revealed that there were ∼300 structural data on selenium compounds before 1980, which increased rapidly after 2000. The database now covers >11 000 structures (Figure 1.2). The structures of selenium compounds in all covalencies from one to six, as well as cyclic ring compounds are reported. Structures, in general, are consistent with the valence shell electron pair repulsion model where a stereochemically active lone pair of electrons is involved. The C–Se distances fall in the region 1.89–1.98 Å with C_alkyl–Se being longer than the C_aryl–Se distances. Compounds containing hydroxyl, carboxyl and amino groups are associated in the solid state through intra- and/or inter-molecular hydrogen bonding, resulting in dimeric⁶⁴  to infinite⁶⁵  chains. The stereochemistry of selenium compounds is quite diverse (Table 1.1).^66–74 

Diorganodiselenides, like other dichalcogenides, have skewed structures in solution and in the solid state, and both the enantiomeric forms display chiral P and M helical configurations (Scheme 1.4a). Racemization of these forms is quite facile due to the low barrier of rotation of the Se–Se bond (e.g. the energy barrier in the cisoid and transoid forms of Ph₂Se₂ is 8.2 kcal mol⁻¹ and 5.2 kcal mol⁻¹, respectively⁷⁵ ). The Se–Se distance in diselenides ranges from 2.24 to 2.39 Å and is dependent on the nature of the substituent,¹⁶  the bond being shorter for more electronegative R groups (e.g. for Se₂Br₂ the Se–Se=2.241 Å⁷⁶ ). Shorter (2.265(1) Å) and quite long (2.974(1) Å) Se⋯Se distances between the two molecular halves of dimeric rectangular dication [RSe]₄²⁺ (Scheme 1.4c), obtained by one-electron oxidation of diorganodiselenide by NO⁺OTF⁻ or XeF₂/BF₃·OEt₂, have been reported.⁷⁷  The dihedral angle (Scheme 1.4b) in diorganodiselenides deviates significantly from the idealized value of 90°, depending on the nature of the organic groups and on the existence of other secondary interactions. In most cases the C–Se–Se–C angle¹⁶  lies in the range 70–100°, while intra-molecular Se⋯N interactions (as in [(3,5-Me₂C₅H₂N)₂Se₂] and [{2-NC₅H₃(3-CONHPh)}₂Se₂]⁷⁸ ) or sterically bulky groups (as in [{(Me₃Si)₃C}₂Se₂]⁷⁹ ) result in the opening of the angle to 180°. Polymorphism in diorganodiselenides is also encountered, and examples include [2-py₂Se₂]⁸⁰  and [{2-(3-H₂NCOC₅H₃N)}₂Se₂].⁸¹ 

A large number of symmetrical and unsymmetrical diorganoselenides (Scheme 1.5) have been structurally characterized. These compounds adopt a V-shaped geometry with C–Se–C angles¹⁶  varying in the range 95–104°. Diorganoselenoxides adopt a trigonal pyramidal shape, but considering the role of a stereochemically active lone pair of electrons, structures can be defined as distorted tetrahedral. The Se–O distances are in the range 1.62–1.69 Å and the C–Se–C angles are similar to parent selenides, while the C–Se–O angles lie at ∼102°. These compounds are often associated in the solid state through weak inter-molecular hydrogen C–H⋯O or Se⋯O interactions to give dimers,⁸²  star-shaped hexamers⁸³  or infinite strings.⁸⁴  The hydrated selenoxides (R₂SeO·H₂O, misrepresented in older literature as R₂Se(OH)₂), show extensive hydrogen bonding with water molecules (Se–O⋯H–O).⁸⁴  The Se–O bond lengths are little influenced by such secondary bonding interactions. The Se–O distances in seleninic acids (RSe(O)OH) are similar to selenoxides; however the Se–OH distance (1.74 Å), being the single bond, is longer.⁸⁵ 

Diorganodiselenides are yellow to orange-red, shelf-stable compounds and are important precursors in synthetic chemistry; diphenyldiselenide is the most extensively used reagent. Several synthetic approaches are in practice for the preparation of diorganodiselenides. The most commonly used method is the reaction of Li₂Se₂ or Na₂Se₂, prepared in several different ways (Scheme 1.6), with an appropriate alkyl or aryl halide followed by aerial oxidation.^86–95  Diazonium salts, in place of an organic halide, can also be used for the synthesis of diaryldiselenides.⁹⁶  Most of these reactions are quite often accompanied by the formation of selenides (R₂Se) in variable amounts, and hence the purification of diselenides is essential.

Sodium borohydride reduces elemental selenium to NaSeH or Na₂Se₂, depending on the molar ratio of the reactants. Sodium hydrogen selenide (NaSeH), generated either by NaBH₄ reduction of selenium⁹⁰  or by the reaction of H₂Se with NaOEt in ethanol,⁹⁷  has also been used for the synthesis of diselenides. For instance, the reaction of NaSeH with 6-tosyl β-cyclodextrin in phosphate buffer followed by aerial oxidation yields cyclodextrin-based diselenides (Scheme 1.7, I), which shows 4.3-fold higher GPx activity than that of ebselen.⁹⁸  Other cylcodextrin-based diselenides have also been synthesized and characterized.²¹ 

Another promising approach for the synthesis of various aromatic diselenides has been heteroatom-directed aromatic lithiation.^99–101  Ortho deprotonation of the aromatic substrate by alkyllithium reagent, usually ⁿBuLi, followed by treatment with selenium and aerial oxidation results in the corresponding diselenides (Scheme 1.8). A variety of substrates, such as N-substituted benzylamines, 2-phenyloxazolines, 1-dimethylamino naphthalene, 1-bromobenzaldehyde, aromatic Schiff bases, ferrocenes and 3-substituted thiophenes, have been used successfully in these reactions.

Acid (e.g. HCl) and base (e.g. KOH, NaOMe) hydrolysis of selenosulfates (RSeSO₃K)⁴⁸  and selenocyanates (RSeCN),^102,103  respectively, has also been employed for the preparation of diselenides (Scheme 1.9).

Other, less frequently employed methods for the synthesis of diorganodiselenides include the reduction of selenium with carbon monoxide and aromatic aldehyde as substrates,¹⁰⁴  and use of CuO nano-powder as a catalyst in the reaction of selenium in KOH solution with an organic halide (Scheme 1.10).¹⁰⁵ 

Diorganodiselenides show remarkable redox behaviour. They can conveniently be oxidized to electrophilic states (e.g. RSeX or RSeX₃) and reduced to nucleophilic selenolate ions by the cleavage of the Se–Se bond. Cyclic voltammetric measurements of diselenides reveal that reversible electron transfer is typical for selenol/diselenide couples and is more negative than those for the corresponding thiol/disulfide couples.¹⁰⁶  Single-electron oxidation results in a radical cation intermediate species (Scheme 1.11).¹⁰⁷  Diselenides, like (HOOCCH₂CH₂Se)₂, react with one-electron oxidants (e.g. hydroxyl radicals produced during pulse radiolysis) to give diselenide radical cations with an absorption maximum at 560 nm.¹⁰⁸  However, the radical cations with simple alkyl derivatives, [Me₂Se₂]˙⁺, dimerize as a rectangular dicationic species, [Me₂Se₂]₂²⁺ by π*–π* interaction with long Se–Se bonds.⁷⁷ 

Deselenization of diselenides can take place under photolytic or thermolytic conditions. Under photolytic conditions in the presence of tertiary phosphine, they yield the selenides (R₂Se) and R₃PSe.¹⁰⁹  Selenium is extruded from dibenzyldiselenide under photolytic as well as thermolytic conditions.¹¹⁰ 

Diorganodiselenides are used as a catalyst in a number of organic transformations.¹¹¹  For example, dipyridyldiselenide is used as a catalyst in the Staudinger–Vilarrasa reaction between carboxylic acids and azides in the presence of PMe₃ at room temperature (Scheme 1.12).¹¹²  Diorganodiselenides are versatile synthons for the preparation colloidal semiconductor nano-crystals.¹¹³ 

Selenols, selenium analogues of alcohols and thiols, are stronger acids than the corresponding thiols (pK_a 5.9 and 6.5 for PhSeH and PhSH, respectively). They are readily oxidized by atmospheric oxygen to diselenides and are therefore usually generated in situ for a chemical reaction. There are several methods to prepare selenols (Scheme 1.13);^114–117  the general routes for their synthesis are as follows.

• Reaction of Grignard reagent or organolithium with elemental selenium followed by hydrolysis with dilute acid yields RSeH. The reaction is often accompanied with the formation of selenides, diselenides and H₂Se as by-products. For instance, carboraneselenol, B₁₀H₁₁C₂SeH, is prepared by the reaction of 1,2-dicarba-closo-dodecaborane with ⁿBuLi in DME followed by treatment with selenium powder and subsequent hydrolysis by HCl.¹¹⁸  In this reaction diselenide is also formed as a by-product.

• Reaction of organic halides^80b,119  or aromatic diazonium bromide¹²⁰  with NaSeH/Na₂Se₂ is another common route for the synthesis of selenols. In general, organic bromides and iodides are employed in this reaction.

• Diselenides, being stable compounds, are reduced conveniently to afford the corresponding selenols. Several reducing agents are used for the reduction of diselenides; among them sodium borohydride¹²¹  and hypophosphorus acid (H₃PO₂) in hydrochloric acid/organic solvents^120,122  are common reducing agents. Thiols (such as PhSH, dithiothreitol)^123,124  and Bu₃SnH¹²⁵  have also been used for reduction of diselenides, but in these reactions selenenyl sulfides (RSeSR′) and Bu₃SnSeAr, respectively, are also formed.

• Basic hydrolysis or reduction of selenocyanates has been employed for the synthesis of selenols.^116,126  Aliphatic and aromatic selenocyanates, RSeCN, which are easily obtained by the reaction of aliphatic halides or aromatic diazonium salts with KSeCN, are reduced by zinc in acidic medium.

• The reaction of alkylsulfate with potassium selenide and reaction between selenourea and tert-butylmalonodialdehyde¹¹⁹  in refluxing ethanol are other protocols used for the synthesis of selenols.

Selenols are readily deprotonated in alkaline solution to give selenolate ions. Selenols containing unsaturated/N-heterocyclic rings tautomarize to the corresponding selone (CSe linkage).^127,128  The selenol and selone can exist as discrete species, e.g. 2-pridyl selenol and 2-pryridylselone (Scheme 1.14).¹²⁷ 

Selenols and their conjugate bases, selenolates (RSe⁻) have high energy highest occupied molecular orbitals and are weak bases but powerful nucleophiles and react readily with electrophilic inorganic and organic compounds.^114,115  Selenols are remarkable reagents for the introduction of organoselenium groups to organic molecules either through addition to carbon–carbon multiple bonds or by reaction with organic halides, carboxylic acid chlorides, epoxides, etc. Selenols undergo addition of the Se–H bond to alkynes to give α,β-unsaturated compounds.¹²⁹  The non-catalytic (radical or base initiated) addition proceeds non-stereoselectively to give a mixture of anti-Markovnikov products, while palladium-catalyzed reactions result in Markovnikov products (Scheme 1.15).¹³⁰ 

Diorganoselenides are the oldest organoselenium compounds, prepared as early as 1836 by Löwig, who described the synthesis of diethylselenium.¹³¹  These compounds are the most prevalent organoselenium derivatives and are also called as selenoethers. A myriad symmetrical and unsymmetrical selenides,^8a,116,132  which include acyclic alkyl, aryl, cyclic with varying ring sizes,¹³³  functionalized,^16,134  macrocyclic,¹³⁵  bi- and multi-selenium centred (e.g. RSe(CH₂)_nSeR), have been synthesized. These compounds are extensively used as ligands in coordination and organometallic chemistry^11c,128  and as a nucleophile in numerous organic reactions.^8a,116 

Although several protocols have been adopted for the synthesis of diorganoselenides, the most commonly employed methods are depicted in Scheme 1.16. The reaction of sodium selenide (Na₂Se), generated in several ways, with an organic halide in the appropriate solvent has been used to prepare a wide range of symmetrical as well as functionalized selenides.^{8a,11c,65a,116,132,134–136}  Both symmetrical and unsymmetrical selenides are conveniently synthesized by treatment of selenolate ion with non-activated organic halides (aromatic, hetero-aromatic, vinyl, etc.).^14b,65a,137  The selenolate ion is usually generated by reductive cleavage of the Se–Se bond of a diselenide. Sodium borohydride^14b  and hydrazine in the presence of NaOH in DMF are the common reducing agents. Diarylselenides can also be obtained by the reaction of selenolates with diazonium compounds.⁷  Unsymmetrical aromatic selenides have been prepared by the reaction of ArSeX (X=H, Br, CN) with an organolithium compound or a Grignard reagent.

Several synthetic approaches have been adopted for the preparation of selenides using selenocyanates.^138,139  Functionalized selenides are efficiently prepared by ring opening of epoxides, aziridines and related molecules with selenols.^116,140  For example, β-hydroxyaryl selenides are conveniently obtained by regio-selective ring opening of epoxide with selenophenol (Scheme 1.17).¹⁴⁰  Electrophilic (RSeX; X=Cl or Br) (Scheme 1.17)^139,141  and nucleophilic (RSeH) selenium compounds add to alkynes, alkenes and carbonyl compounds to give functionalized selenides. Redox transmetalation of Ag(C₅H₄N) with red selenium in EtCN at room temperature yields (NH₄C₅)₂Se, but at 50 °C diselenide is formed.¹⁴² 

Diorganoselenides undergo a variety of reactions. They are readily oxidized by one- and two-electron oxidants. Oxidation of Ph₂Se by one-electron oxidants (e.g. OH˙, Br₂˙⁻, N₃˙) generated on pulse radiolysis, gives radical cation,¹⁴³  Ph₂Se˙⁺. The redox potential of the Ph₂Se˙⁺/Ph₂Se couple is 1.37 V. One-electron oxidation of 1,8-bis(phenylselenyl)naphthalene, napSe₂Ph₂ by NO[Al(OR)₄] (R=C(CF₃)₃) gives a blue-colored paramagnetic radical cation, [napSe₂Ph₂]˙⁺ containing a Se∴Se three-electron σ-bond which dimerizes to a brown diamagnetic species in the solid state.¹⁴⁴  Oxidation by two-electron oxidants results in Se(iv) compounds. Oxidation by H₂O₂ and alkyl halides yields selenoxides (R₂SeO) and selenonium salts ([R₂SeR′]⁺X⁻), respectively. Selenides containing α-hydrogen on treatment with strong bases like lithium diisopropylamide (LDA) results in deprotonation to give the corresponding carbanions (RCH–SeAr).

Diorganoselenoxides (R₂SeO; R=alkyl or aryl) are among the best-known organoselenium compounds¹⁴⁵  and find extensive applications in chemical synthesis as oxygen transfer agents in organic¹⁴⁶  and organometallic synthesis¹⁴⁷  and as oxygen donor ligands in coordination chemistry.¹⁴⁸ 

Selenoxides are conveniently obtained by the oxidation of selenides. Several oxidizing agents, such as hydrogen peroxide,¹⁴⁹  peroxy acids (e.g. m-chloroperbenzoic acid¹⁵⁰ ), ozone, sodium hypochlorite (NaOCl) in DMF¹⁵¹  or tert-butylhypochlorite¹⁵⁰  are generally employed for the oxidation of selenides. Alternatively, selenoxides can be prepared by hydrolysis of diorganoselenium dichlorides using alkali metal hydroxides, sodium acetate and silver oxide in aqueous medium. Rearrangement in selenoxides containing protic organic groups (e.g. OH, COOH) may take place during oxidation.^152,153  For example oxidation of di(3-hydroxypropyl)selenide with tert-butylhydroperoxide results in to the formation of expected selenoxide, di(3-hydroxypropyl)selenoxide, which readily undergoes intra-molecular dehydration to yield a spiro-selenurane (Scheme 1.18).¹⁵²  Similarly 3,3′-selenodipropionic acid on oxidation readily yields a dehydrated cyclized product, whereas the homologous 4,4′-selenodibutyric acid and 5,5′-seleno divaleric acid yield corresponding selenoxides.¹⁵³  Further oxidation of selenoxides is a slow process and requires strong oxidizing agents like peroxy acids. Unsymmetrical selenoxides are chiral molecules and are stable towards pyramidal inversion at room temperature, but racemization is facilitated in the presence of an acid (Scheme 1.19).¹⁵⁴ 

Diorganoselenenyl sulfides (RSeSR′) are considered to be important intermediates during catalytic cycle of GPx. The high reactivity of diselenides with thiols has been exploited for the synthesis of selenenyl sulfides.¹⁵⁵  This method has been employed successfully for the preparation of slenenyl sulfide glycopeptides¹⁵⁶  and selenenyl sulfide-bearing lipids¹⁵⁷  which have been characterized using mass spectroscopic techniques. The reaction of ebselen and its analogues with aromatic thiols yields selenenyl sulfides (Scheme 1.20), which exhibit strong Se⋯O intra-molecular interactions.¹⁵⁸  These interactions prevent the regeneration of catalytically active selenol species; as a consequence, low catalytic activity of ebselen analogues in the presence of thiols is observed and such species are considered as the dead-end products.¹⁵⁸  This type of hypervalent T-shaped selenenyl sulfides, , showing weak intra-molecular Se⋯N (∼2.67 Å) interactions,¹⁵⁹  have been isolated by redistribution reactions between diorganodiselenides and bis(diorganophosphinothioyl)disulfanes, . Diorganoselenenyl sulfides have also been synthesized by the reaction of RSeX with the sodium salt of a thiol.

Organoselenium halides find extensive applications as electrophilic reagents to introduce selenium into organic molecules, and are found in +2 (RSeX) and +4 (RSeX₃; R₂SeX₂ and R₃SeX) oxidation states. The stability of a particular compound depends on the nature of X as well as the organic group attached to selenium. Compounds in the +4 oxidation state are less stable. For instance, oxidative addition of bromine to R₂Se results in to diorganoselenium dibromide, R₂SeBr₂, which tends to decompose on standing (lose bromine and/or bromoalkanes) and is therefore used in situ for organic synthesis.¹⁶⁰  Similarly, PhSeCl₃, obtained by the reaction of Ph₂Se₂ with SO₂Cl₂ in 1 : 3 ratio in chloroform, is used for selenium insertion in to the α-position of a ketonic substrate.¹⁶¹  The trihalides (RSeX₃) upon heating in a vacuum above their melting points decompose to selenenyl halides and halogens. Selenenyl halides are relatively stable and are primarily used as electrophilic reagents for selenenylation.

Selenenyl halides (RSeX) are prepared by the reactions of diorganodiselenides with halogens or halogenating agents such as sulfuryl chloride (Scheme 1.21). The products are isolated in quantitative yields. Selenocyanates (RSeCN) can be cleaved by chlorine or bromine in chloroform solution to yield selenenyl halides.

Selenenyl halides have low-lying lowest unoccupied molecular orbitals and are therefore powerful electrophiles. Phenyl selenenyl halides (PhSeX; X=Cl or Br) are the common electrophilic reagents used for selenenylation of olefins and carbonyl compounds.^162,163  However, the nucleophilicity of the halide in RSeX often gives rise to side reactions in organic synthesis. Accordingly, several non-halide compounds have been developed which show similar behaviour to RSeX; the trifilate (RSeOTf) being the most preferred reagent. These compounds are isolated by the reaction of RSeX with appropriate silver salts (Scheme 1.22).^164–168 

The reaction of selenium electrophiles with alkenes takes place in a stereo-specific manner and proceeds via a seleniranium ion intermediate. The latter is opened in the presence of a nucleophile to give addition products (Scheme 1.23).¹⁶³  α-Phenylselenocarbonyl compounds are widely used to give olefins via selenoxide elimination. The 2- and 4-pyridyl seleno group is a better leaving group than the phenyl seleno group in selenoxide elimination (Scheme 1.24).^169–171  The pyridylseleno compounds afford enones in excellent yields, even in cases where satisfactory results are not obtained with α-phenylselenocarbonyl compounds.

The selenenyl halides, RSeX (X=Cl or Br), are discrete molecules, but the corresponding iodo compounds exhibit considerable structural diversity. Compounds derived from bulky organic groups¹⁷²  or aryl groups containing hetero-atoms (O or N) on the pendant arms^173,174  usually exist as RSeI with a covalent Se–I bond. The majority of iodo compounds are charge-transfer (CT) species in which the Se–Se bond of the diselenide remains intact. The I₂ molecule interacts either with one selenium atom (e.g. Me₂Se₂·I₂, (4-FC₆H₄)₂Se₂·I₂)^175,176  to give a three-coordinate spoke structure or binds with both the selenium atoms to result in a centrosymmetric dimer (e.g. (Ph₂Se₂·I₂)₂).¹⁷⁷  The electron-donating R groups which increase the basicity of Se in general results in CT compounds.¹⁷⁸  A 1 : 1 CT compound containing a covalent Se–I bond, p-ClC₆H₄SeI·I₂ is isolated by the reaction of (p-ClC₆H₄Se)₂ with I₂ in a 1 : 3 molar ratio.¹⁷⁶  The existence of Se⋯X (X=N, O, S) non-bonding interactions in a number of organoselenenyl halides has been reported by several authors and has been probed by X-ray crystallography, NMR and density functional theory calculations.³⁷ 

Selenenic acids (RSeOH) (Scheme 1.25; selenenic (II), seleninic (III) and selenonic (IV) acids) are highly reactive intermediates and are generated during the oxidation of selenols and diselenides. They are postulated in a number of reactions such as selenoxide syn elimination, etc. and are thought to be the active species in the catalytic cycle of GPx. These compounds are highly unstable and undergo disproportionation, possibly involving V and VI intermediates, to the corresponding diselenides and seleninic acids or anhydrides (Scheme 1.26).

The existence of several arylselenenic acids stabilized by the coordination of nitro, carbonyl or amine groups in solution has been reported,¹⁷⁹  but in no case has alkylselenenic acid been detected. With bulky aryl groups,¹⁸⁰  e.g. 2,4,6-Prⁱ₃C₆H₂ and triptycyl (trip),¹⁸¹  ArSeOH has been characterized using NMR spectroscopy, and even the redox behavior of tripSeOH has been investigated.¹⁸²  A stable selenenic acid derived from a bowl-shaped organic group, BmtSeOH (Scheme 1.27, VII), has been isolated by the direct oxidation of selenol with H₂O₂ and structurally characterized. The compound shows remarkable stability both in solution and in the solid state.¹⁸³ 

Hydrolysis of selenenyl halides or the reduction of seleninic acids/anhydrides also yields selenenic acids. The reaction has been used to generate selenenic acids in situ. 2-Nitrobenzene seleninic acid on reduction with NaH₂PO₂ yields the corresponding selenenic acid.^179a  Hydrolysis of selenenyl bromide (VIII) during crystallization leads to the formation of selenenate esters (IX) (Scheme 1.28).¹⁸⁴  Oxidation of secondary and tertiary amide based diselenides with hydrogen peroxide has been investigated.¹⁸⁵  In these reactions the involvement of selenenic acid has been suggested. In the case of the secondary amide group, rapid cyclization takes place to produce seleneyl amides which on oxidation with excess H₂O₂ yield seleninic acids. The seleninic acids of tertiary amides undergo further oxidation with an excess of H₂O₂ to afford selenonic acids (Scheme 1.29). The seleninic acids show intra-molecular Se⋯O interactions.¹⁸⁵ 

Unlike selenenic acids, seleninic and selenonic acids are stable, isolable, colorless and odorless solids. They are used as oxidants in organic synthesis. Both aliphatic and aromatic seleninic acids are obtained by oxidation of diselenides or selenocyanates with concentrated HNO₃, 30% H₂O₂, potassium permanganate in acetic acid, chlorine in aqueous medium (Scheme 1.30). Nitration of aromatic groups can be observed on oxidation of aromatic selenium compounds with HNO₃.¹⁸⁶  Hydrolysis of organoseleniumtrihalides yields seleninic acids. Isolation of trihalides can be avoided if chlorination or bromination of diselenides is performed in aqueous medium.¹⁸⁷  Other oxidants, such as dimethyldioxirane (DMD)^181,188  and ozone,¹⁸⁹  have also been used for conversion of selenium compounds to seleninic acids. Oxidation of tripSeOH with DMD affords the corresponding seleninic acid, tripSe(O)OH quantitatively.¹⁸¹  Similarly, polyfunctionalseleno esters, such as Se-glucopyranosylphenyl seleno acetate, are oxidized by DMD to seleninic acid.¹⁸⁸  Further oxidation of seleninic acid, e.g. PhSe(O)OH, with H₂O₂ results in peroxyseleninic acids, RSe(O)OOH, which find applications in Baeyer–Villiger oxidation of various carbonyl compounds.¹⁹⁰ 

Seleninic acids are optically active molecules, although isolation of optically pure seleninic acid is a tedious process due to their facile racemization. Kamigata and co-workers obtained enantiomeric pure forms of seleninic acids by using either a chiral column in medium-pressure liquid chromatography or chiral crystallization (e.g. MeSe(O)OH).^75,191 

Oxidation of seleninic acids with strong oxidizing agents, like KMnO₄ in aqueous KOH, results into the formation of potassium salts of selenonic acid, RSe(O)₂OK. They are strong oxidizing agents and can be reduced to seleninic acids in concentrated HCl.