key: cord-0966233-a26j8eud
authors: Tiekink, Edward R.T.
title: Zero-, one-, two- and three-dimensional supramolecular architectures sustained by Se(…)O chalcogen bonding: A crystallographic survey
date: 2021-01-15
journal: Coord Chem Rev
DOI: 10.1016/j.ccr.2020.213586
sha: b2133cd4ce25cd0da379778972c675062409b747
doc_id: 966233
cord_uid: a26j8eud

The Cambridge Structural Database was evaluated for crystals containing Se(…)O chalcogen bonding interactions. These secondary bonding interactions are found to operate independently of complementary intermolecular interactions in about 13% of the structures they can potentially form. This number rises significantly when more specific interactions are considered, e.g. Se(…)O(carbonyl) interactions occur in 50% of cases where they can potentially form. In about 55% of cases, the supramolecular assemblies sustained by Se(…)O(oxygen) interactions are one-dimensional architectures, with the next most prominent being zero-dimensional assemblies, at 30%.

Being present in the three domains of life, i.e. Archaea, Bacteria and Eukarya, selenocysteine has long being recognised as the 21st proteinogenic amino acid [1] [2] [3] . Natural biological functions of selenocysteine relate to redox moderation and anti-oxidant effects such as in the mammalian oxidoreductase system, thioredoxin reductase (TrxR), where it is present in the active site [4] . In connection with thyroid disease, selenocysteine is also present in the active sites of deiodinase enzymes which can activate or inactivate thyroid hormones [5] . The crucial role of selenium in natural biological functions implies a selenium-deficient diet causes disease and requires intervention [6] . Complimenting dietary supplements, synthetic selenium compounds also play a role/have potential as therapeutics [7] [8] [9] [10] . The most prominent selenium drug is Ebselen TM , i.e. N-phenyl-1,2-benzisoselenazol-3(2H)-one, which is known to exhibit a variety of biological activities, partially owing to its ability to mimic the glutathione peroxidase enzyme, which regulates redox homeostasis and which protects cells from oxidative stress [7] [8] [9] [10] . Other medicinal benefits of Ebselen TM include cytoprotective and neuroprotective properties, and potential therapeutic applications relate to anti-cancer, anti-bacterial and anti-inflammatory activities [7] [8] [9] [10] . With this background, it is not surprising the biological mechanism(s) of Ebselen TM and related species have been investigated thoroughly [11, 12] . These experimental and theoretical investigations often point to the importance of both inter-and intra-molecular Se . . . O interactions in crucial biological processes [11, 12] . Stabilising Se . . . O interactions are now classified among chalcogen bonding interactions, a term possibly first employed in 1998 [15] , whereby the Group XVI element functions as an electrophile [13, 14] . It is stressed that the focus of the present review is upon the role of intermolecular Se . . . O contacts and upon the supramolecular aggregation patterns they sustain. In general terms, chalcogen interactions find very practical applications in a range of contexts beyond biology and medicine [16] [17] [18] , such as in molecular/anion recognition [19] [20] [21] [22] , catalysts [23, 24] and materials science [25, 26] . With this level of activity, it is not surprising there are several authoritative reviews of chalcogen bonding [27] [28] [29] [30] , including reviews of different physiochemical procedures for their detection in phases other than in crystals [31] [32] [33] , the primary importance of X-ray crystallographic investigations notwithstanding.

The most convenient method for identifying chalcogen bonding in the solid-state relies upon crystal structure analysis with the earliest investigations of chalcogen bonding depending on the evaluation of crystal structures for contacts occurring at separations intermediate between the respective sums of the covalent and van der Waals radii for the participating atoms. In these present times where all manner of intermolecular contacts/supramolecular synthons are being ''revealed", it might be tempting to suggest chalcogen bonding, and related tetrel and pnictogen interactions involving, respectively, Group XIV and XV elements acting as the electrophile, are a recent phenomenon. While obviously these interactions already exist in the crystals of the relevant compounds capable of forming such interactions and may not necessarily have been recognised or appreciated as being significant previously, it turns out the discussion of secondary bonding interactions actually goes back well over 50 years. Among the first bibliographic reviews of the topic are those by H.A. Bent [34] , Noble Laureate O. Hassel [35] and N.W. Alcock [36] , with these being followed up by a number of general overviews of the topic [37] [38] [39] [40] . It is likely the first time the term secondary bonding was used in the context of these donor-acceptor interactions appeared in the title of a research paper was in a Conference Abstract published in 1975 [41] and then in a follow-up Journal article in 1977 [42] . The use of secondary bonding as a design element in crystal engineering endeavours was suggested as early as 1999 [43] .

An initially disconcerting feature of many secondary bonding interactions, including halogen bonding [44] , which also comes under the appellation secondary bonding [36] , was that the interaction often occurred between two electron-rich species, i.e. a low oxidation state main group element, implying a lone-pair or even lone-pairs of electrons, and donors also having at least one lonepair of electrons. Through the concept of a r-hole, theory now aids the understanding of this apparent violation of basic electrostatic arguments. Conventionally the bonding in chalcogen bonds was described in terms of charge transfer from a lone-pair of electrons of the donor atom (D) to an anti-bonding orbital of the bond involving the chalcogen atom (A-X), i.e. (D)n 2 ? r*(A-X), but the problem remains in that two electron-rich species are brought into close contact. The r-hole concept, widely employed to explain the bonding in such circumstances [45, 46] , relates to the anisotropic distribution of charge about the bonded chalcogen atom. With reference to the bonding axis of a A-X bond, there is an equatorial band of electron density about the A atom, i.e. perpendicular to the A-X bond, and a significant electron-deficient region at the extension of the bonding axis, the r-hole (or polar cap). It is the latter that can form stabilising interactions with nucleophilic species. The success and general applicability of this approach in rationalising the formation of chalcogen bonds as well as tetrel, pnictogen and halogen bonds [47] notwithstanding, recent studies point to the importance of orbital delocalisation as being relevant [48] . Having a model for bonding, the question then arises as to what are the energies of stabilisation are provided by chalcogen and related interactions. Naturally, the calculated energies will be highly dependent on the nature of the bonds about the interacting atoms, steric profiles of the interacting residues and whether a chalcogen or other intermolecular interaction is operating independently of supporting or competing intermolecular interactions not to mention the level of theory/basis sets employed in the performing of the calculations. Nevertheless, there appears a consensus from calculations [49] [50] [51] [52] [53] that the energies of stabilisation afforded by secondary bonding interactions are comparable and often exceed those provided by conventional hydrogen bonding interactions [54] and which, in turn, are comparable to the energies associated with other supramolecular synthons involving heavy elements such as p(chelate ring) . . . p(chelate) interactions [55] . It was in the context of a long-held interest in secondary bonding interactions and the supramolecular architectures they sustain [56] [57] [58] [59] [60] [61] [62] [63] [64] and in the aforementioned biological relevance of Se . . . O chalcogen bonding interactions that the present survey of Se . . . O interactions operating in crystals was undertaken. This review of the crystallographic literature serves to highlight the diverse nature of selenium atom environments, geometries, oxidation states and numbers and types of Se . . . O secondary bonding interactions formed by selenium and the wide variety of supramolecular architectures these chalcogen bonding interactions sustain.

The Cambridge Structural Database (CSD; version 5.41) [65] was searched employing ConQuest (version 2.0.4) [66] for Se . . . O contacts present in crystals based on the distance criterion that the separation between the selenium and oxygen atoms had to be equal to or less than the sum of the van der Waals radii, i.e. assumed in the CSD as 3.42 Å [65] . Other general criteria were applied in order to keep the number of retrieved structures to a reasonable number and to ensure reliability in the data, namely structures with errors, were salts, polymeric and contained transition metal elements were omitted along with those with R > 0.075. In all 274 structures were retrieved. These were then evaluated manually to ensure that the Se . . . O interaction was operating in isolation of other obvious supramolecular synthons employing PLA-TON [67] , Mercury [68] and DIAMOND [69] .

Three classes of compounds were rejected from further analysis. Firstly, several structures that registered as a hit was in fact a false positive as the putative Se . . . O(hydroxyl) interaction was embedded within a hydroxyl-O-H . . . Se hydrogen bond. This is illustrated in Fig. 1a for (-)-t-butylphenylphosphinoselenoic acid [70] , where hydroxyl-O-H . . . Se hydrogen bonding (Se . . . O = 3.30 Å) occurs between the two independent molecules comprising the asymmetric unit in the crystal. The second scenario leading to the omission of structures also involved hydrogen bonding. Thus, in bi-nuclear 2,2 0 -(diselane-1,2-diyl)bis(pyridin-3-ol) [71] , two centrosymmetrically related molecules are connected into a dimeric aggregate via hydroxyl-O-H . . . N(pyridyl) hydrogen bonds as shown in Fig. 1b Fig. 1c where some of the supramolecular association operating in the 1:1 co-crystal formed between coformers 2,2-dimethyl-N-(7-oxo-6,7-dihydro [1, 2, 5] selenadiazolo [3, 4-d] pyrimidin-5-yl)propanamide and 2,2-dimethylpropanoic acid [72] 

There are a total of 32 selenium(II) species, 1-32 [11, [98] [99] [100] [101] , forming Se . . . O contacts leading to zero-dimensional aggregates. The chemical diagrams for the interacting species in these structures are shown in Fig. 2 . The common feature of mono-selenium(II) molecules 1-5 [11, [73] [74] [75] [76] is that dimeric aggregates are sustained by a single Se . . . O chalcogen bonding interaction; in each of 2-5, the selenium atom is incorporated within a ring. For 2 [74] , 4 [76] and 5 [11] , Fig. 3a , the contact forms between the two independent molecules comprising the crystallographic asymmetric unit. In 1 [73] , there are four independent molecules and two pairs are connected by a single Se . . . O(carbonyl) interaction. In 3 [75] , there are eight independent selenium(II)-containing molecules and four DMSO molecules in the asymmetric unit. In this instance, only one pair of selenium(II)-containing molecules is connected by a single Se . . . O (hydroxyl) contact. This is a relatively rare case as, usually, in cases where multiple molecules comprise the crystallographic asymmet-ric unit, all participate in the formation of Se . . . O contacts (vide infra). In diselenide 6 [77], a Se . . . O(ether) interaction is featured between the two independent molecules of the asymmetric unit, Fig. 3b . Compound 7 [78] features both selenium(II) and selenium(IV) centres connected within a ring with the selenium(II) atom of one of these connecting to an oxygen atom of the second independent molecule via a Se . . . O(N-oxo) contact as shown in Fig. 3c . In 8 [79] , with four independent molecules in the asymmetric unit, two pairs of molecules are connected by a single Se . . . O (methoxy) contact. A similar situation pertains in tri-nuclear 9 [80] , where a single Se . . . O(methoxy) contact links the two independent molecules, Fig. 3d . The molecule of 9 is notable in that in addition to two ring selenium atoms, a phosphorus-bound selenide selenium(II) atom is present but, it is one of the ring selenium The overwhelming majority of mono-nuclear selenium(II) molecules in this category adopt a two-molecule motif sustained by two Se . . . O contacts. This motif is found in the crystals of 10-27 [81] [82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] [96] . Molecules 10-12 feature acyclic, two-coordinated selenium, 13 is a selenide and those of 14-27 are also twocoordinated but with the selenium atom incorporated within a ring. In The ring-selenium atoms are generally incorporated within five-membered rings but form part of a six membered ring in 27 [96] and part of an eight-membered ring in 18 [89] . The molecules in 14 [85] , 16 [87] and 27 [96] , the latter having potential sulphoxide-oxygen atoms capable of forming Se . . . O contacts, Fig. 3h (23) . The two remaining molecules in this section feature adjacent selenium and oxygen atoms in the fivemembered ring and each of these, i.e. 25 [95] and 26 [95] , assemble about a centre of inversion to form a supramolecular fourmembered { . . . Se-O} 2 synthon. In 25, Fig. 3o , there are nitro-and hydroxyl-oxygen atoms also capable of forming Se . . . O interactions but, do not. A related { . . . Se-N} 2 synthon was observed in Fig. 1c and has been discussed in terms of being a reliable synthon in the supramolecular chemistry of selenium-nitrogen materials [97] . The foregoing highlights the fact that a myriad of oxygen atoms can participate in Se . . . O interactions and no definitive preference for one type oxygen atom over another is obvious.

There are four examples of bi-nuclear selenium(II) species forming centrosymmetric aggregates. In diselenide 28 [98] , Se . . . O (N-oxide) interactions sustain the dimer while Se . . . O(carbonyl) contacts are found in each of 29 [99] and 30 [100] . In 31 [93] , one of the ring-selenium atoms of the bi-nuclear molecule associates with a nitro-oxygen atom, similar to that seen in Fig. 3n . An extraordinary mode of association via Se . . . O(carbonyl) contacts is found in 32 [101] . Here, a four-molecule aggregate is formed about a four-fold rotatory inversion axis (4 À ) as shown in the images of Fig. 3p .

Less common but, nevertheless well represented in this survey are selenium(IV) compounds, which differ by having a single lone-pair of electrons as opposed to two for selenium(II) species. Even less frequently observed herein are selenium(VI) species, devoid of stereochemically-active lone-pairs on the selenium centre. The interactions selenium(VI) species form with oxygen reflect more conventional Lewis acid-Lewis base interactions. There are 18 selenium(IV) species, 33-50 [100, [102] [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] , and five selenium(VI) species, 51-55 [116] [117] [118] [119] , forming Se . . . O contacts leading to zerodimensional aggregates, with the chemical diagrams for the interacting species in these shown in Fig. 4 . being described in 1972. It is also noted here that the authors of this paper discussed the supramolecular association mediated by Se . . . O secondary bonding in their description of the molecular packing in this crystal. Higher nuclearity aggregates are noted in the remaining selenium(IV) structures to be described in this section.

Aggregates of selenium(IV) species sustained by more than two Se . . . O contacts Each of 47 and 48 [113] assemble into tetrameric aggregates in the solid-state. In the crystal of 47, there are two independent molecules in the asymmetric unit. One of these assembles about a centre of inversion by the familiar four-membered { . . . Se-O} 2 synthon. Attached to either side of this aggregate are two of the second independent molecules whereby each selenium of each of the terminal molecules effectively bridges the oxo atom, already engaged in a Se . . . O contact implying this atom is bifurcated, and an alkoxide-oxygen atom of the O,O-chelating ligand, Fig. 5h . The tetrameric aggregate in 48, Fig. 5i , has the same centrosymmetric {Se . . . O} 2 core but, the terminal connections are also of the type {Se . . . O} 2 , also formed by the second independent molecules. This compound is of particular interest as the asymmetric unit comprises four independent molecules. Two engage as shown in Fig. 5i , while the other two engage to form a supramolecular chain as discussed below, see 175 [113] . The last two selenium(IV) aggregates to be described are hexameric.

In the crystal of 49 [114] , three independent molecules comprise the asymmetric unit. A hexagon of selenium atoms, with a pronounced chair conformation, is formed about a centre of inversion, with the connections between them being of the type Se 

There are five selenium(VI) species featuring Se. . .O interactions, each leading to a centrosymmetric, dimeric aggregate. Compounds 51 [116] , 52 [117] , 53 [117] and 54 [118] feature Se(=O) 2 entities, while that of 55 [119] is an adduct of Se(@O) 3 . A { . . . Se-O} 2 core is found in each of the five dimers. In diorgano 51, the selenium atom is incorporated within a six-membered ring, 

The chemical diagrams of the 19 mono-nuclear selenium(II) molecules aggregating to form linear supramolecular chains in their crystals based on Se . . . O chalcogen bonding contacts, i.e. 56-74 [12, [120] [121] [122] [123] [124] [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] , are shown in Fig. 6 .

A variety of selenium(II) and oxygen atom environments participate in Se . . . O contacts leading to linear, one-dimensional chains. The first six molecules have the common feature that they are diorganoselenium(II) species with the selenium atom not enclosed within a ring. The selenium atom is incorporated within a five-membered ring and is flanked by two carbon atoms in five molecules: 64 [127] , 65 [128] , 66 [129] , 67 [130] and 68 [131] . The Se . . . O(carbonyl) contacts in the chain formed by 64 are highlighted in Fig. 7e . The structure of 64 is notable as two independent molecules comprise the asymmetric unit and each self-assembles into a linear supramolecular chain. A similar mode association is found in the crystal of 68, where each of the two independent molecules self-associate into a linear chain. By contrast, in 65-67 the Se . . . O association involves ether-, methoxy-and nitro-oxygen atoms. In 69 [132] , the selenium atom is incorporated within a sixmembered ring and molecules assemble via Se . . . O(carbonyl) contacts, Fig. 7f . In each of the four remaining five-membered ringcontaining molecules, the selenium atom is flanked by carbon and nitrogen atoms. In 70 [133] , 71 [134] and 72 [135] , Fig. 7g , the molecules are linked by Se . . . O(carbonyl) interactions whereas in 73 [136] , Fig. 7h , Se . . . O(nitro) contacts are evident. The last structure is this category to be described is that of 74 [137] where the selenium atom formally carries a positive charge and one of three carboxylic acid substituents is deprotonated. As seen from Fig. 7i , the linear chain is sustained by Se . . . O(carbonyl) interactions; the carboxylate residue is engaged in charge-assisted hydrogen bonding, precluding it from participating in Se . . . O contacts.

The chemical diagrams of the 32 mono-nuclear selenium(II) molecules, i.e. 75-106 [11, 74, 101, 133, , forming zigzag supramolecular chains in their crystals based on Se . . . O chalcogen bonding contacts are shown in Fig. 8 . With two exceptions, as detailed below, the zig-zag chains are propagated by crystallographic glide symmetry.

Seven compounds have the selenium atom not constrained within a ring while the remaining 25 feature cyclised selenium, usually within a five-membered ring. A representative example of a zig-zag chain is shown in Fig. 9a , for 75 [138] . Here, Se . . . O(carbonyl) interactions are in play, as in crystals of 76 [139] and 77 [140] . In 78 [141] , Fig. 7b , an example rich in heteroatoms, Se . . . O(sulphoxide) interactions are evident, as they are in 79 [142] , Fig. 9c , with a rare C,S-donor set for selenium. The structures of 80 [143] and 81 [144] are examples of selenides are engaged in Se . . . O interactions. In 80, there are two independent molecules in the asymmetric unit and each of these self-associates into a supramolecular chain via C@Se . . . O(nitro) interactions, one of these is shown in Fig. 9d . In 81, where the selenide is phosphorus-bound, the zig-zag chain, Fig. 9e , arises as a result of P@S . . . O(ether) contacts. The remaining molecules to be covered have the selenium atom incorporated with a ring.

In the next six molecules, each selenium(II) atom has a C,Cdonor set. The selenium atom in 82 [74] forms part of a fourmembered ring and the molecules assemble into a zig-zag chain via Se . . . O(sulphoxide) contacts, Fig. 9f Fig. 9g , is one of two molecules in this section assembling into a zig-zag chain not propagated by glide symmetry. In this case, there are two independent molecules which associate to form the supramolecular chain.

Next, is a series of molecules constructed about a 5selanylidene-1H-pyrrol-2-one core, i.e. 88-99 [11, [149] [150] [151] [152] [153] [154] [155] [156] [157] , featuring a variety of substituents, R, at the nitrogen atom: R = CH 2 Ph (88) [149] , Ph, polymorphs 89 [11] and 90 [150] , Ph-C(=O)OH-4 (91) [151] , Ph-Br-4 (92) [152] , Me (93) [153] , H, acid 94 [152] , Ph-Br-2 (95) [154] , Ph-Me-3 (96) [155] , Ph-Me-2 (97) [156] , Ph-OH-3 (98) [11] and, lastly, R = a fused 1-ethylpiperidine-2,6-dio ne/naphthalene derivative (99) [157] . The common mode of the supramolecular association is the formation of Se . . . O(carbonyl) interactions, as illustrated for 95 [154] in Fig. 9h . Generally, these contacts are short, ranging from 2.53 Å in 88 [149] to 2.86 Å for 99 [157] , suggesting considerable covalent character in these secondary bonding interactions. As indicated above, 89 and 90 are polymorphs. These exhibit the same supramolecular aggregation via Se . . . O(carbonyl) interactions with very similar Se . . . O separations of 2.53 and 2.57 Å, respectively. Of interest is the R = H derivative, 94, i.e. the acid form, where three independent molecules comprise the asymmetric unit. One molecule self-assembles into a zig-zag chain (glide symmetry). The two other molecules associate via a Se . . . O(carbonyl) interaction and the resultant dimeric aggregates assemble into a zig-zag chain, again propagated by glide symmetry. Variations of the above are seen in 100 [133] , where the fused C 6 ring carries a nitro substituent, and 101 [158] , where the fused C 6 ring is fused to a second C 6 ring, and in 102 and 103 [159] , where the fused C 6 ring is substituted by a thienyl ring; each of the resultant zig-zag chains are sustained by Se . . . O(carbonyl) interactions. The Se . . . O(carbonyl) interactions persist in 104 [160] , where the fused C 6 ring of the above examples is now a pyridyl ring and 105 [161] , where the selenium atom is incorporated into a six-membered ring. The final molecule in this section, 106 [162] , Fig. 9i , is notable in that the selenium atom, embedded within a four-membered ring, forms two Se . . . O(sulphoxide) interactions to sustain the zig-zag chain.

The chemical diagrams of the mono-nuclear selenium(II) molecules, i.e. 107-123 [152, [163] [164] [165] [166] [167] [168] [169] [170] [171] [172] [173] [174] [175] [176] [177] and 124-126 [159, 178, 179] , forming, respectively, helical and twisted supramolecular chains in their crystals based on Se . . . O chalcogen bonding contacts are shown in Fig. 10 .

The supramolecular chains with helical symmetry are typically propagated by crystallographic 2 1 screw symmetry, with two exceptions only, and, while less numerous than zig-zag supramolecular chains sustained by Se The five-membered rings in 113 [169] , 114 [170] and 115 [171] also feature C 2 donor sets as does the selenium atom in 116 [172] , Fig. 11c , which is now incorporated within a sixmembered ring. The donor atoms forming the Se . . . O interactions [179] , assembling in their crystals to form twisted chains. In 124, Fig. 10g , and 125, two independent molecules comprise the asymmetric unit with the twisted arrangement arising due to the relative orientations of the independent molecules in the chains propagated by translational symmetry; chains are sustained by Se . . . O(carbonyl) contacts. The molecule in 126, Fig. 10h , has crystallographic two-fold symmetry with the selenium atom lying on the axis. Each selenium atom forms two Se . . . O(nitro) contacts with centrosymmetrically related molecules.

Most of the molecules in this category are bi-nuclear but, there are several examples of tri-and tetra-nuclear selenium(II) compounds. The chemical structures for the molecules forming the supramolecular chains, i.e. 127-159 [80, 92, 95, 104, , are shown in Fig. 12 .

A linear chain is observed in crystals of 127 [180] , Fig. 13a , an example whereby the selenium atom is not embedded within a ring and where only one of the selenium atoms is engaged in a Se . . . O contact; in this case the donor is a carbonyl-oxygen atom. When embedded within a five-membered ring, the selenium atoms can be next to each other as in 128 [181] and 129 [182] , Fig. 13b , or in a six-membered ring, i.e. 130 [183] . Again, only In 131 [184] , the association leading to a linear chain involves both selenium atoms connecting to the carbonyl-oxygen atom of a translationally related molecule, Fig. 13c . A double-chain is noted for 132 [185] , Fig. 13d . Here, two selenium atoms occur diagonally opposite positions in a centrosymmetric C 2 Se 2 square, and each forms a Se . . . O(carbonyl) interaction to form a linear chain. Two independent molecules also comprise the asymmetric unit of 133 [186] . One of these self-associates into a linear chain via Se [189] . A variation is noted for 138 [95] , Fig. 13g , where the selenium atoms are connected by an oxo-bridge and one of these forms Se . . . O(nitro) contacts. The selenium atoms are adjacent to each other in the five-membered ring of 139 [190] and one of these participates in Se . . . O(sulphoxide) interactions to form the zig-zag chain. In the five-membered rings of each of 140 [191] and 141 [192] , Fig. 13h , the selenium atoms are separated by a carbon atom, and the chain is mediated by Se . . . O(carbonyl) interactions. In 142 [80] , Se . . . O(hydroxyl) interactions involving the ring-bound selenium atom mediate the formation of the zig-zag chain rather than putative interactions involving the phosphorus-bound selenide atom. A variation in the general theme of one Se . . . O link per molecule to sustain the zig-zag chain is noted for 143 and 144 [190] , Fig. 13i , where each selenium atom, occupying adjacent positions in a fivemembered ring, participates in Se . . . O(sulphoxide) interactions with the same sulphoxide-oxygen atom. The common feature of the seven helical chains formed by binuclear selenium(II) molecules is that each is propagated by 2 1 screw symmetry. The first six molecules employ a single selenium atom in forming the Se . . . O chalcogen bond: 145, 146 [193] , Fig. 14a , 147 [194] , 148 [195] , 149 [196] and 150 [197] . The oxygen donors span a range of types, i.e. sulphoxide (145 and 146), ether (147) and carbonyl (148 and 150) and phenoxide (149) . In 151 [198] , Fig. 14b , the adjacent selenium atoms are embedded within a five-membered ring and form contacts to the same carbonyloxygen atom to form the helical chain, i.e. bearing a close resemblance to the aggregation pattern seen in 143 and 144, Fig. 13i . The bi-nuclear molecule in 152 [199] , has two-fold symmetry with the axis bisecting the Se-Se bond, and each selenium atom forms a Se . . . O(nitro) contact to a centrosymmetrically related molecule with the result a twisted chain ensues, Fig. 14c .

There are two tri-nuclear selenium(II) species forming supramolecular chains in their crystals. As a result of Se . . . O(carbonyl) interactions whereby two of the three selenium atoms, each within a five-membered ring, form a contact to the same carbonyl-oxygen atom, a linear chain is formed in the crystal of 153 [152] , Fig. 14d . In 154 [200] , where there is an ''open" selenium atom and two selenium atoms within five-membered rings, it is the former that forms a Se . . . O(ether) contact to generate a zig-zag chain via glide symmetry, Fig. 14e .

The remaining five selenium(II)-containing species in this section are tetra-nuclear. In 155 [201] , two five-membered rings, each with a 1,3-disposition of selenium atoms, are connected to form the tetra-nuclear molecule. In the crystal, only one of the selenium atoms forms a Se . . . O(carbonyl) interaction with translationally related molecules so that a linear chain is formed, Fig. 14f . The macrocyclic compound, 156 [202] , employs two of its selenium atoms to sustain a linear assembly via Se . . . (methoxy) interactions and eight-membered { . . . SeC 2 O} 2 synthons, Fig. 14g . The molecule 157 [203] is clearly related to 155 but, in this case, this assembles into a zig-zag chain (glide symmetry), Fig. 14h . The remaining molecules, 158 [204] , and 159 [205] , assemble into helical chains, for 158, Fig. 14i , propagated by 2 1 screw symmetry. An interesting variation is noted for 159 in that the four selenium atoms line up in a chain within an eight-membered ring; two independent molecules comprise the asymmetric unit. The independent molecules assemble via a Se . . . O(carbonyl) contact and the resultant dimeric aggregate then assembles, via additional Se . . . O(carbonyl) contacts, into a supramolecular helical chain propagated by 3 1 screw symmetry, Fig. 14j Fig. 16f , for which two independent molecules comprise the asymmetric unit.

One of the independent molecules assembles to form a dimer and translationally related dimers are bridged by a pair of the second independent molecule. There are six independent Se . . . O contacts involving oxide-(4) and alkoxide-oxygen (2) donors, and each selenium atom participates in three Se . . . O interactions.

Molecules 169 [93] , 170 [113] , Fig. 16g , and 171 [113] , each with C 2 O donor sets, assemble into zig-zag chains mediated by a [217] two independent molecules comprise the asymmetric unit and each selenium atom participates in two Se . . . O(carbonyl) interactions with the chain, propagated by translational symmetry, having a twisted topology owing to the relative orientation of the independent molecules comprising the repeat unit.

When Se . . . O chalcogen bonding extends in two dimensions, supramolecular layers are formed: this has been noted in a total of 20 crystals, with 12 selenium(II) and eight selenium(IV) examples.

The chemical diagrams for 181-200 [95,113,133,186,218-231] are shown in Fig. 17 .

Several different motifs are noted in the two-dimensional arrays formed by the compounds in this section. In the crystal of mono-nuclear 181 [218] , Fig. 18a , molecules assemble about a centre of inversion, being connected by Se . . . O(nitro) interactions and eight-membered { . . . Se . . . ONO} 2 synthons. The connections extend laterally as each selenium forms two contacts as does each nitro group, via both oxygen atoms, with the resultant layer being corrugated. The selenium atom also forms two contacts in 182 [219] but, with the same, bifurcated carbonyl-oxygen atom to sustain a flat, hexagonal-like grid, Fig. 18b . In the following structures, disparate Se . . . O interactions sustain the resulting two-dimensional array. In 183 [220] , the selenium atom forms two interactions with carbonyl-and hydroxyl-oxygen atoms, derived from symmetry related molecules, which are linked by a hydroxyl-O-H . . . O(carbonyl) hydrogen bond. In 184 [133] , the connections are of the type Se . . . O(carbonyl) and Se . . . O(nitro), and analogous contacts are formed in 185 [221] , Fig. 18c . The layers in each of 183-185 have a jagged topology. There are two bi-nuclear selenium(II) compounds adopting two-dimensional aggregation patterns. In the first of these, 186 [222] , each selenium atom forms a contact to a carbonyl-oxygen atom of two different molecules, Fig. 18d , leading to a flat, hexagonal pattern akin to that for 182, Fig. 18b . In a variation, in 187 [223] , each selenium atom again forms a single contact but, two different carbonyl-oxygen atoms, Fig. 18e , leading to a corrugated topology. A polymorph of 187 exists, i.e. 132, which Somewhat squarer arrangements are seen in the crystals of binuclear 188 [224] , Fig. 19a , where each molecule participates in four Se . . . O(carbonyl) interactions, with one of the selenium atoms forming two interactions and one of the carbonyl-oxygen atoms forming two interactions; the layer is corrugated. An even more square appearance is seen for 189 [186] , Fig. 19b , where the central atom of the tri-nuclear molecule participates in two Se . . . O(sulphoxide) interactions with two different molecules while at the same time donating two sulphoxide-oxygen atoms to another two symmetry related molecules; the resultant layer is flat. In tri-nuclear 190 [225] , which has two-fold symmetry with the central selenium atom lying on the axis, it is the external selenium atoms of the Se 3 chain that each form a single Se . . . O(carbonyl) interaction and each of the carbonyl-oxygen atoms also participates in a Se . . . O contact, Fig. 19c , leading to a corrugated layer. In tri-nuclear 191 [226] , which has mirror symmetry with the central selenium lying on the plane, the selenide atoms lie to the periphery of the Se@P-Se-P@Se hetero-chain. In this instance, Fig. 19d . The final selenium(II) compound adopting a two-dimensional array in its crystal is also the only example of a tetra-nuclear compound in this category, 192 [205] . Here, the four selenium atoms are in a Se 4 chain and, as seen from Fig. 20 , it is the 1,3-selenium atoms forming the Se . . . O(carbonyl) interactions with two different carbonyl-atoms that are responsible for the formation of the layer, which has a distinctive saw-tooth topology. The selenium atom in 197 [113] is incorporated within a sixmembered ring and forms a total of three Se . . . O interactions in the crystal, Fig. 22a . Centrosymmetrically related molecules are connected by via Se . . . O(alkoxide) interactions, forming the shorter distances, and these are connected into a flat, two-dimensional array by Se . . . O(oxide) interactions. Two independent molecules comprise the asymmetric unit of 198 [229] and these are connected by Se . . . O(carbonyl) interactions to form the array shown in Fig. 22b ; the topology of the layer is flat. The selenium atom in the first independent molecule forms two Se . . . O contacts and the carbonyl-O atom one, with the second independent molecule follows the opposite trend. This flexibility in association via Se . . . O contacts is reflected in the following observation. Compound 198 is of particular interest as three polymorphs have been reported. Earlier in this survey, aggregation patterns were reported for the first two of these, i.e. 172 and 173, Fig. 16h , each of which adopts a zigzag chain in their crystal sustained, on average, by one and two Se . . . O(carbonyl) interactions, respectively. The selenium atom in 199 [230] is bis-chelated by C,O-donors and lies on a two-fold axis of symmetry. The selenium atom forms two Se . . . O(contacts) to form a flat, two-dimensional array, Fig. 22c . The only bi-nuclear compound in this section is found in 200 [231] where diagonally opposite selenium atoms are incorporated within a fourmembered ring; the molecule has mirror symmetry with the nitrogen atoms of N 2 Se 2 core lying on the plane. Each of the selenium and carbonyl-oxygen atoms forms a single Se . . . O(carbonyl) contact extending laterally to form a corrugated layer, Fig. 22d. 6. Three-dimensional assemblies mediated by Se . . .

There are only three examples of selenium compounds comprising one chemical entity in the crystal assembling into a three-dimensional architecture based on Se . . . O chalcogen bonding. The chemical structures for these oxide-rich molecules, i.e. 201-203 [118, 232] , are shown in Fig. 23 .

Only one selenium(II) molecule assembles to form a threedimensional architecture in its crystal, namely 201 [232] . The binuclear molecule has mirror symmetry containing both selenium atoms and relating the two cyclobutadiene residues. Here, each selenium atom forms four Se . . . O(carbonyl) interactions and each of the carbonyl-oxygen atoms forms two interactions to selenium as highlighted in Fig. 24a . The resulting architecture resembles a skewed honeycomb array. The two remaining molecules feature selenium(VI) centres, i.e. tri-nuclear 202 [118] and tetra-nuclear 203 [118] . In the former, which lacks symmetry, only the oxideoxygen atoms participate in Se . . . O interactions with each forming a single contact and each selenium atom forming two Se . . . O(oxide) contacts, Fig. 24b . Layers with a zig-zag topology are discernible in the packing, Fig. 24b , being connected by three distinct Se . . . O(oxide) contacts. The molecule in 204 is disposed about a four-fold centre of inversion (4 À ) with each Se(=O) 2 unit involved in two donor and two acceptor Se . . . O(oxide) contacts, Fig. 24c . The resulting architecture comprises tetra-nuclear molecules assembled into columns, with a square appearance, connected orthogonally by the [118, [233] [234] [235] [236] [237] [238] [239] [240] [241] [242] [243] [244] [245] are shown in Fig. 25 .

Each of the mono-, bi-and tri-nuclear selenium(II) compounds, i.e. 204 [233] , 205 [234] and 206 [235] , illustrated in Fig. 26a -c, respectively, feature a single Se . . . O contact between the molecule and solvent, i.e. dimethylformamide in 204 and 206, and methanol in 205. In tetra-nuclear 207 [235] , which is disposed about a centre of inversion, there are two co-crystallised dimethylformamide molecules and the oxygen atom from each of these symmetrically spans two selenium atoms to form a three-molecule aggregate shown in Fig. 26d .

A one-dimensional chain with a zig-zag topology (glide symmetry) is formed in the crystal of 208 [236] whereby the dimethylsulphoxide-oxygen atom symmetrically bridges two selenium atoms to form the arrangement shown in Fig. 26e .

The focus now turns towards selenium(IV) species. A threemolecule aggregate is formed in 209 [237] where the dioxane molecule, situated about a centre of inversion, bridges two molecules as shown in Fig. 26f . A hydrated, linear supramolecular chain is formed in the crystal of 210 [238] . The water molecule is connected to the selenium atom, being separated by 2.92 Å, and the resultant two molecule aggregates assemble into a chain via Se . . . -O(hydroxyl) chalcogen bonds (3.03 Å) as shown in Fig. 26g .

In the mono-selenium(IV) compound 211 [239] , linear chains are sustained by Se . . . O(oxide) contacts and these are connected into a three-dimensional array by links provided by bridging dioxane molecules, Fig. 27a There are two mixed selenium(IV)/(VI) compounds in this category, i.e. 212 [118] and 213 [118] , and a pivotal role for the cocrystallised dioxane molecules is evident in each. The tetranuclear molecule in 212 is disposed about a centre of inversion. There are two molecules of solvent for each tetra-nuclear molecule and it is the selenium(IV) centres that associate with two symmetry dioxane molecules to form a two-dimensional grid, Fig. 27b . In the second mixed valence compound, 213 [118] , two tri-nuclear molecules and four dioxane molecules comprise the asymmetric unit. As shown in the left-hand image of Fig. 27c, 

In this final section, a number of selenium(II) and selenium(IV) aggregates are described, with all but one example being zerodimensional in consideration of Se . . . O interactions alone. The selenium(II) atom in mono-nuclear 215 [240] forms four Se . . . O(ether) contacts to sustain a two-molecule aggregate, Fig. 28a . The asymmetric unit of 216 [241] comprises two selenium(II) molecules and the organic co-former, i.e. is a 2:1 co-crystal, one of the selenium(II) molecules makes a single Se . . . O(hydroxyl) interaction to form the two-molecule aggregate shown in Fig. 28b . In the 1:2 co-crystal 217 [242] , each of the selenium atoms in the binuclear molecule forms a Se . . . O(carbonyl) interaction to form a three-molecule aggregate, Fig. 28c . Another bi-nuclear molecule where the selenium atoms are connected to each other within a five-membered ring, 218 [243] , forms a 2:1 co-crystal with a with selenium in the + VI (8) oxidation state; two mixed valent selenium(IV)/(VI) compounds are also included in the survey. Over two-thirds of molecules are mono-nuclear (161) , with decreasing numbers of bi-, tri-and tetra-molecules, i.e. 43, 11 and nine, respectively. A full range of zero-, one-, two-and threedimensional patterns are noted with the majority, i.e. over 55% (128 examples favourably to the 6% of selenium(lone-pair) . . . p(arene) interactions in crystals where these interactions can potentially form [248, 249] . Over and above different chemical composition, as alluded to above, secondary bonding interactions, including chalcogen bonding interactions, are notoriously subject to steric effects in that these interactions are mitigated when bulky metal-bound and/ or ligand-bound substituents are present [54, [56] [57] [58] [59] [60] [61] [62] [63] . To probe further the likely adoption of Se . . . O interactions in crystals, the likelihood of specific classes of compounds to form Se . . . O chalcogen bonds was ascertained.

As noted above, Se . . . O(carbonyl) interactions featured in 41% of the crystals in the present survey. Hence, the CSD was searched for ''selenium" and ''carbonyl-oxygen" using the established protocols. This indicated that almost 50% of all crystals having these two components actually formed Se . . . O(carbonyl) interactions. An analogous search for residues containing Se@O, often observed in the selenium(IV) compounds included herein, was conducted. This analysis indicated a smaller percentage adoption of about 25%. Throughout this survey, the 5-selanylidene-1H-pyrrol-2-one core, as found in Ebselen TM , has been mentioned a good number of times. This core has a three-bond separation between the selenium and carbonyl-oxygen atoms, and with these acceptor and donor atoms largely constrained to a fixed disposition owing to their relationship through the five-membered ring. A search of the CSD revealed this core features in 52 crystals. With Se . . . O(carbonyl) interactions forming in 25 examples, the percentage adoption is over 48%. Interestingly, five others of these structures formed Se . . . O interactions in their crystals but, with selenide-(1), nitro-(1) and hydroxyl-oxygen (3) donors. With this relatively high adoption rate, the propensity of selenium molecules with selenium incorporated within a five-membered ring comprising four unspecified atoms and unspecified bonds between them was then evaluated. The CSD has about 945 ''hits" for this fragment and with 102 examples having unassisted Se . . . O chalcogen bonding interactions, the percentage adoption is at least 10%, indicating this fragment alone does not promote Se . . . O interactions.

Consideration is now directed towards the geometric parameters characterising the observed Se . . . O secondary bonding interactions. The Se . . . O separations span a wide range, i.e. from a short 2.40 Å, indicative of some covalent character, right out to the van der Waals limit of 3.42 Å; the average distance of a Se. . .O interaction computes to 3.11 Å and the median value is 3.17 Å. It is noted that while many of the shorter interactions were in the dioxane adducts, such as 212 which exhibited the short contact cited above, short contacts were often noted in one-dimensional chains involving molecules incorporating the 5-selanylidene-1H-pyrrol-2-one core, e.g. the next shortest separation of 2.41 Å is observed in 118. However, these are only generalisations, with each class of molecule, respectively, also having longer contacts, e.g. 3.35 Å in 8 and 3.38 Å in 23. This observation is entirely consistent with the well-known axiom in supramolecular chemistry that geomet-ric correlations of weak intermolecular interactions are not generally possible unless the molecules/interactions are very closely related/isostructural [245] [246] [247] . In the present case, the lack of systematic trends is not surprising considering the different chemical composition of the interacting species, different oxidation states and geometries, and range of oxygen donors engaged in the Se . . . O interactions.

Up to this point, no specific mention of the angles associated with the supramolecular Se . . . O interactions has been made; key angles subtended at oxygen donor atoms and selenium acceptor atoms are collated in Appendix A. Just as distance correlations are not reliable for intermolecular interactions [245] [246] [247] , correlations involving angles are also problematic, as commented upon recently for secondary bonding interactions formed between selenium and the heavier main group elements [250] . This is because, as for distances, angles are going to be moderated by the chemical/electronic environment of the participating atoms. Based on the assumption that for the specified Se . . . O contacts, the oxygen atom is the Lewis base, providing the charge to the r-hole located on the selenium atom of the Lewis acid, there are several variables impacting upon the magnitude of the Se . . . O interaction and the angles subtended at the interacting oxygen atom. In the case of the oxygen donor, these factors include but, are not limited to the steric and electronic profiles of the residues bound to oxygen, the hybridisation of the oxygen atom and, when the interacting oxygen atom is part of a nitro group, for example, the partial charge on the oxygen atom. For the selenium acceptor, again the steric and electronic profiles of bound atoms/groups come into play, as does the ligand donor set about the selenium atom along with the oxidation state of the selenium atom which, in turn, impacts on the number of sterically active lone-pairs of electrons about the selenium atom and therefore, stereochemistry. These points are highlighted in the following observations on the sub-set of structures where the donor oxygen and acceptor selenium atoms participate in one contact only. Considering the angles subtended at the oxygen donors first, in the surveyed structures featuring a single contact between the participating atoms, the minimum angle of 82.4°(the Se . . . O separation is 3.38 Å) was found in 105 where the donor atom is a carbonyl-O to a selenium(II) centre, and the maximum angle of 160.2°(Se . . . O = 2.83 Å) is seen in 217 where a carbonyl-O atom is the donor and the acceptor is a selenium(II) atom flanked by nitrogen and sulphur atoms within a five-membered ring. The large range observed overall is also reflected in more specific contacts, for example S-O . . . Se contacts with a range of over 70°, i.e. from 87.7°in 2 to 159.7°in 78 with a spread of values within this range for the 10 structures having the oxygen and selenium atoms forming a single contact only. The above notwithstanding, the following represents an analysis of specific types of Se . . . O interactions. From the A-Se . . . O data included in Appendix A, it is a generalisation that the angle about the selenium atom, regardless of oxidation state, generally lies between 140 and 180°. This observation is consistent with expectation in terms of the r-hole model to explain the nature of these interactions [45] [46] [47] 251] . It might be concluded that while to a first approximation, there is a general understanding of the mode of bonding leading to Se . . . O and related secondary bonding interactions, further investigations, such high-level crystallographic, including charge density studies and analysis [11, 252, 253] , along with reliable computational chemistry studies [254] [255] [256] are required in order to gain a more complete picture of Se . . . O interactions. Also of interest would be the determination, experimental and theoretical, of the energies of stabilisation provided by specific Se . . . O contacts. Thus far, these are comparatively rare, e.g. 10-40 kJ/mol for molecules based on the Ebselen TM (89 & 90) structure [11] , i.e. as noted previously [54] , an energy in the range observed for conventional hydrogen bonding interactions.

Finally, while the focus of the present review has been upon the identification of intermolecular Se . . . O interactions in crystals of molecular selenium compounds, the relevance of Se . . . O secondary bonding interactions in the biological context was alluded to in the Introduction. With the present covid-19 pandemic confronting the World, it is not surprising that Ebselen TM and analogues have already been evaluated as potential inhibitors of the active site of the main protease (M pro ) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [257] in a classic case of drug repurposing [258] . On-going crystallographic, spectroscopic, e.g. 77 Se NMR [259] , and computational studies [260, 261] should also be alert for the potential influence of Se . . . O interactions in providing stability to poses adopted by selenium compounds in relevant active sites of target macromolecules.

Chalcogen bonding of the type Se . . . O contribute to the stability of crystals where they can form and are shown to sustain a full range of supramolecular aggregates: any complete analysis of the molecular packing of relevant compounds should include an analysis of these and other secondary bonding interactions. In the same way, any evaluations of the biological mechanisms of action, catalytic processes, rationalisation of chemical reactivity, etc. should be on the alert to the possible role of Se . . . O secondary bonding. Most notably by the prevalence of linear A-Se . . . O angles, for A = C, N, S and Se, the concept of the r-hole provides a key impetus for the rationalisation of these interactions for selenium(II)-and selenium(IV)-containing compounds in the above contexts. However, further studies are required, both experimental and computational, for a more complete understanding of the formation of Se . . . O interactions and the energies of their association.

The author declares that there are no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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The author gratefully acknowledges Sunway University Sdn Bhd (Grant no. STR-RCTR-RCCM-001-2019) for support of crystallographic studies.