1,1′-Biisoquinolines—Neglected Ligands in the Heterocyclic Diimine Family That Provoke Stereochemical Reflections

1,1′-Biisoquinolines are a class of bidentate nitrogen donor ligands in the heterocyclic diimine family. This review briefly discusses their properties and the key synthetic pathways available and then concentrates upon their coordination behaviour. The ligands are of interest as they exhibit the phenomenon of atropisomerism (hindered rotation about the C1–C1′ bond). A notation for depicting the stereochemistry in coordination compounds containing multiple stereogenic centers is developed. The consequences of the chirality within the ligand on the coordination behaviour is discussed in detail.


Introduction
The heterocyclic diimines 2,2 -bipyridine (1) and 1,10-phenanthroline (2) and their derivatives are among the commonest chelating nitrogen donor ligands in coordination and organometallic chemistry ( Figure 1) [1][2][3][4][5][6][7][8][9][10]. The heterocyclic diimine metal-binding domain is widely used as a scaffold in supramolecular chemistry and in interfacial science. Compounds 1 and 2 are members of a much larger series of bis(heterocycles) incorporating the N=C-C=N chelating metal-binding motif. This review is concerned with the coordination behavior of one of the less well-known members of this series, 1,1 -biisoquinoline (3) (Figure 1). The 1,1 -biisoquinolines are of especial interest as steric interactions between nitrogen lone pairs, substituents on the nitrogen and between H8 and H8 favour a non-planar geometry in both the free ligands and their chelated metal complexes. The consequences of this are discussed in Section 2. Figure 1. The structures of the "parent" heterocyclic diimines 2,2 -bipyridine (1) and 1,10phenanthroline (2) together with that of 1,1 -biisoquinoline (3), the subject of this review. The IUPAC numbering scheme for derivatives of 1,1 -biisoquinoline is indicated and also shown is an example of the abbreviated nomenclature adopted in this review using 3,3 -Me 2 biiq as an example of an abbreviation for 3,3 -dimethyl-1,1 -biisoquinoline (4).
Derivatives of 3 will generally be named in an abbreviated form utilizing the shortform biiq with the substituents located using the numbering scheme indicated in Figure 1; for example, 3,3 -dimethyl-1,1 -biisoquinoline (4) would be written 3,3 -Me 2 biiq (Figure 1). We note that various abbreviations have been used for 1,1 -biisoquinoline in the literature, including biq and bq, which are also used by other authors for 2,2 -biquinoline.
This review concentrates upon the properties of this interesting class of compounds as ligands and also includes a non-comprehensive overview of their properties and major synthetic routes for their preparation. Condensed and reduced derivatives of biiq are excluded from this review. Much of the interest in 1,1 -biisoquinolines relates to their stereochemical and stereogenic properties, in particular they belong to the class of diaryls which exhibit atropisomerism. In the course of preparing this review, we became aware of a need for a clear notation to describe the stereochemical configuration in coordination compounds containing multiple stereogenic features (centers or axes) and/or chiral ligands. All structural information and figures have been extracted from the Cambridge Structural Database [11] using the Conquest search [12] and Mercury visualization software [13].

Atropisomerism
Before considering the chemistry of the 1,1 -biisoquinolines themselves, it is worth reviewing the concept of atropisomerism.
Atropisomers are stereoisomers which arise as a result of hindered rotation about a single bond, and atropisomerism is a form of axial chirality [14]. In the classical period of organic chemistry, it was assumed that rotation around C-C bonds was, to all intents and purposes, without an energy barrier. Atropisomerism is commonly observed in compounds in which aromatic rings are connected by a single C-C bond, with the barrier to rotation arising from interactions between substituents on the aromatic rings ( Figure 2a). The first compounds exhibiting atropisomerism to be resolved were 6,6 -dinitro-[1,1 -biphenyl]-2,2 -dicarboxylic acid ( Figure 2b) and 4,4 ,6,6 -tetranitro-[1,1 -biphenyl]-2,2 -dicarboxylic acid [15], although the possibility of such forms of enantiomerism has been predicted earlier by a number of authors [16][17][18]. It was left to Werner Kuhn to introduce the term atropisomerism (atropisomerie), derived from the Greek ατρoπoς (atropos) meaning "without turn", to describe this phenomenon [19].
IUPAC recommends the use of the stereochemical descriptors P and M rather than the more commonly encountered R a and S a to denote the stereogenic axis in the Preferred IUPAC Name (PIN) of axially chiral compounds (Rules P-92. 1 Figure 2b) [20]. Standard Cahn-Ingold-Prelog rules are used to determine the priority of substituents treating the compounds as "extended tetrahedra" with R a and S a defining a clockwise or anticlockwise sequence (Figure 2c) [21][22][23][24]. In particular, those rules are used to identify the order of the two groups at one end (a and b in Figure 2c), and the higher ranked group (c) of the two at the other end.
The descriptors P and M refer to plus and minus, relating to a right-or left-handed helicity, respectively. The substituents a, b, c and d are arranged in pairs looking along the chirality axis. The highest priority substituent in each pair is identified, and the chirality is described as M if the path between these two is anticlockwise, and as P if it is clockwise (Figure 2d). We believe that this is easier to apply than the R a /S a approach.
In practical terms, for the isolation of enantiopure forms, the interconversion of atropisomers should exhibit a half-life of at least 1000 s at 300 K which corresponds to an energy barrier for rotation of 93 kJ mol −1 [25,26]. Inorganic chemists are probably most familiar with the phenomenon of atropisomerism in the context of chelating bisphosphane ligands such as BINAP ([1,1 -binaphthalene]-2,2 -diylbis(diphenylphosphane), 6, Figure 3a) [27][28][29][30][31][32][33][34][35]. It is instructive to use ligand 6 to illustrate the consequences of coordination. The free ligand is non-planar as a consequence of the interactions between the 2-PPh 2 and 2 -PPh 2 substituents and also between H8 and H8 ; this is seen in the solid-state structures of (2P)-6 (P2 1 ) [36,37] (2M)-6 (P2 1 ) [37,38] and rac-6 (C2/c) [37,39] which have all been reported. In all cases the two aromatic rings of the 1,1 -binaphthalene scaffold are close to orthogonal in the solid state with torsion angles C2-C1-C1 -C2 in the range 91.536-93.429 • . Upon coordination, the conformation of the ligand will be influenced not only by the steric interactions within the ligand, but also by the optimization of the metal-donor atom bond lengths and ∠P-M-P bond angles. This is clearly seen in the complex [Pd{(2P)-6}Cl 2 ] (Figure 3c), in which the torsion angle C2-C1-C1 -C2 is reduced to 69.9 • enabling optimal Pd-P bond lengths of 2.244 Å, a ∠P-Pd-P bite angle of 92.68 • and a concomitant reduction in the H8-H8 distance of~0.2Å [40]. (a) Steric interactions between the red and blue substituents in biaryls can lead to atropisomerism with the chiral axis being the interannular C-C bond; (b) the first atropisomeric compounds to be resolved were the enantiomers of 6,6 -dinitro-[1,1 -biphenyl]-2,2 -dicarboxylic acid; (c) the Cahn-Ingold-Prelog scheme can be extended to the nomenclature of axially chiral compounds using the usual priority rules for an "extended tetrahedron"; (d) but IUPAC recommends the use of P and M assigned using Cahn-Ingold-Prelog priorities as described in the text.

Atropisomerism in 1,1 -Biisoquinolines
1,1 -Biisoquinolines have a chiral axis defined by the C1-C1 bond (Figure 4a). Attempts to resolve the parent compound 3 via the tartrate salt of the protonated ligand were unsuccessful, with mutorotation occurring in aqueous solution within 80 s in 0.3 M hydrochloric acid [41]. Chiral stationary phases [42] and complexation with chiral palladium complexes [43,44] have been used for the resolution of 3 and 8,8 -dialkyl derivatives [45,46]. Steric interactions are increased with the presence of substituents on the nitrogen atoms, and, in contrast to 3 itself, 1,1 -biisoquinoline N,N'-dioxide [47,48] and 8,8 -(MeO) 2 biiq N,N'-dioxide [42] can also be resolved on chiral solid phases. Somewhat unexpectedly, the rate of racemization increases in the sequence 8,8 -Me 2 biiq < 8,8 -Et 2 biiq < 8,8 -i Pr 2 biiq, with activation energies at 303 K being close to 100 kJ mol -1 [43,46]. Various chiroptical correlations have been used to show that the (+)-forms of 1,1 -biisoquinolines possess the (1M) absolute configuration ( Figure 4) [42,45,46,[49][50][51]. (b) in the free ligand the naphthalene rings are near-orthogonal, minimizing mutual interactions between the substituents, hydrogen atoms omitted for clarity, phosphorus shown as balls, the naphthalene closest to the viewer in 70% space-filling and the remote naphthalene in ball and stick representation; (c) in the complex [Pd{(2P)-6}Cl 2 ] the interannular angle between the naphthalene rings is reduced to 69.9 o allowing Pd-P bond lengths of 2.244 Å and a P-Pd-P bite angle of 92.68 • , hydrogen atoms omitted for clarity, phosphorus, palladium and chlorine shown as balls, the naphthalene closest to the viewer in 70% space-filling and the remote naphthalene in ball and stick representation. Computational chemical studies at the MOMM (molecular orbital molecular mechanics) level have been reported for the free ligand biiq and confirm that the anti pathway for racemization is favoured over the syn pathway, with the barrier for syn rotation being estimated at 163 kJ mol -1 and that for anti rotation as 41.84 kJ mol -1 [52].
Macrocyclic ligands ( Figure 5) incorporating 1,1 -biisoquinoline subunits have been of interest in studying the influence of the additional ring constraints on racemization. Compounds 7 and 8 were prepared from the appropriate open-chain bis(1-haloisoquinolines) using an Ullmann reaction and resolved using HPLC on a chiral phase [53]. Compound 7 racemized in boiling EtOH with a t 1/2 of 64 min (∆G ‡ 110 kJ mol -1 ) whilst 8 is configurationally stable. The larger ring macrocycle 9 exhibits rather more interesting behaviour and displays a dynamic kinetic resolution on treatment with a chiral acid. Rapid racemization takes place in polar and protic solvents, as well as under acidic conditions [54].
One method likely to be of future application in the synthesis of asymmetric 1,1biisoquinolines is presented in Scheme 2: the parent compound 3 is obtained in 46% yield in gram-scale preparations [92,93].

Structural Studies
A number of 1,1 -biisoquinolines and derivatives has been structurally characterized and relevant data are presented in Tables 1 and 2. Table 1 presents "simple" 1,1biisoquinolines and Table 2 comprises quaternized and related derivatives. Structurally characterized metal complexes are discussed individually in the relevant sections. In all cases, the individual biisoquinoline ring systems are near-planar and torsion angle N2-C1-C1 -N2 is used as a measure of the relative orientation of the rings about the interannular C-C bond that defines the chiral axis. It is also worth commenting that no structure of an enantiopure 1,1 -biisoqiuinoline has been reported to date, with all structures being in non-Sohncke space groups and containing both atropisomers. The structure of the (1P)and (1M)-enantiomers of biiq are presented in Figure 8.

A Note on Stereochemical Nomenclature
In preparing this article, we became aware of the need to describe stereochemical arrangements in coordination entities containing multiple stereogenic features. Rigorous examination and consideration of the nomenclature challenges inherent in these situations has been limited, and the development and codification of required nomenclature has also lagged. As a consequence, ad hoc and mutually inconsistent approaches have been developed by individual research groups to address their particular needs [115][116][117][118][119][120][121][122][123]. It is clear that these situations are certainly not adequately covered in the standard recommendations from IUPAC [20,124]. This short section describes the approach we have adopted.
Although IUPAC defines the descriptors ∆ and Λ which describe the configuration of tris(bidentate) coordination entities, it neither tells you where to put the descriptor in the formula of the compound, nor the associated grammar (IR-9.3.4.1, IR-9.3.4.11, IR-9.3.4.12, IR-9.3.4.14) [124]. However, throughout the section dealing with stereochemical description of coordination entities (IR-9.3), the configuration index and other descriptors that relate to the configuration of ligands around the central atom are placed as prefixes to names and formulae. Due to this, and following general practice in the community, we prefer to place the configurational descriptors ∆ and Λ before the name or formula of the coordination entity. For consistency with organic nomenclature [20], we have placed stereochemical descriptors preceding a name or formula in enclosing marks. Thus, the two enantiomers of the [Ru(bpy) 3   An anti-clockwise rotation of the right-hand structure will "dig" the propeller into the page. This is the Λ-isomer. The mirror-image propeller on the left must be rotated clockwise to do so, and is the denoted ∆-isomer.
A bulk material containing equal amounts of the two enantiomers of a compound is described as a racemate and can be denoted by the stereochemical descriptor rac-(P-91.2.1.1 [20]) combined with the stereodescriptor for the stereogenic site (P-93.1.3) [20]. The prefix racis defined as indicating the configuration of an entire molecule (P-93.1.3) [20]. This descriptor is particularly useful when applied to single crystals of materials in non-Sohncke space groups which contain equal amounts of the two enantiomers. However, while we could use the notation rac-(∆)-[Ru(bpy) 3 ] 2+ as a description of a bulk material containing equal amounts of the ∆ and Λ enantiomers, we prefer the notation (∆Λ)-[Ru(bpy) 3 ] 2+ for such simple systems.
Where a stereogenic center (or axis, or plane) is associated with a ligand in a coordination entity, we have adopted the convention of associating the appropriate stereochemical descriptors using standard IUPAC protocols with the ligand. Although there are arguments for placing all of the stereochemical descriptors before the coordination entity, it will not always be clear which descriptor is associated with which ligand. Thus, we will use {(1M)-biiq} and {(1P)-biiq} to represent the chirality of biiq ligands in coordination entities. If the bulk material contains equal amounts of (1M)-biiq and (1P)-biiq we use the notation {(1MP)-biiq}. Remember that the term racemic refers to a property of a molecule or coordination entity as a whole: thus, the free ligand could be described as rac-(1M)-biiq but this notation should not be used within a formula for a related complex.
The question of relative stereochemistry is more complex and we enter terra incognita in the context of coordination entities. IUPAC has yet to examine and codify the ways of representing and distinguishing the subtly different stereochemical situations that are possible in these complex systems.
Consider the complex cation [Ru(biiq) 3 ] 2+ , where this formulation encompasses any or all of the set of eight stereoisomers (four diastereoisomers and their enantiomers) In a formula, {(1MP)-biiq} means that the biiq ligand is present in equal numbers in the bulk material with 1M or 1P chirality. This will not necessarily be the case in diastereoisomers and we need a notation for a ligand which may possess either chirality, but not necessarily with equal numbers with 1M or 1P chirality. This we denote in a formula as {(1M/1P)-biiq}. Similarly, ∆Λ denotes equal amounts of the ∆ and Λ configurations, whereas ∆/Λ will be used for not necessarily equal amounts of either configuration, being present.
The racemate of a particular diastereoisomer is represented by adding the racdescriptor in front of a formula or name of a defined stereoisomer, so that rac-(∆)-[Ru{(1M)- The set of notations described above will be used where the stereochemical properties of the complexes are known or are of interest. Where no stereochemical information is known or implied, we simply use the abbreviation biiq.

Group 8
In the first paper describing the synthesis of biiq, Case reported that the compound did not give a typical ferroin coloration on treatment with iron(II) salts [81]. It was only many years later that iron complexes of biiq and its derivatives were prepared and characterized. The blue-green spin-crossover complexes [Fe(biiq) 3 ]X 2 ·2.5H 2 O (X = BF 4 , ClO 4 ) are obtained directly from the reaction of biiq with the appropriate iron(II) salts [77]. Detailed magnetic and Mössbauer data for the compounds were reported, consistent with thermal population of the 5 T 2 state from the 1 A 1 ground state at higher temperatures. As might be expected for a sterically hindered heterocyclic diimine ligand, there is appreciable dissociation in acetone solutions of the complexes [77] and no complex ions were reported in electrospray MS studies of methanol solutions containing iron(II) chloride and biiq [126]. The complex [Fe 2 (H 2 O) 2 {6,6 ,7,7 -(MeO) 4 biiq} 4 (µ-O)]Cl 4 ·4H 2 O is reported to be an effective catalyst for the selective oxidation of primary and secondary alcohols to aldehydes and ketones, respectively [127].

Group 11
Until recently, the only biiq complex containing copper (outside the patent literature) was the red copper(I) compound [Cu(biiq) 2 ](ClO 4 ) obtained from the reaction of biiq with [Cu(CH 3 CN) 4 ](ClO 4 ) in MeCN [146]. The compound is relatively air-sensitive. We recently reported the preparation, characterization and photophysical properties of  Electrospray and collision-induced dissociation MS studies of methanol solutions containing CuCl 2 and biiq exhibited ions assigned to the species [Cu(biiq) 2 Cl] + , [Cu(biiq)Cl] + and [Cu 2 (biiq) 2 (Cl) 3 ] + [126]. In an extension to this work, heteroleptic and homoleptic complexes incorporating biiq and functionalized derivatives, bpy and phen were studied using ESMS and in situ complexation. Collision-induced decomposition measurements were used to determine the relatives tabilities of the copper(II) complexes [84].
The preferred geometry for gold(I) is linear two-coordinate and the biiq ligand cannot, therefore, coordinate in a chelating bidentate mode. Two types of discrete complexes are found with gold(I) centers. A monodentate biiq ligand is found in [Au(biiq-κN)(C 6 F 5 )] and also in the structurally characterized compound [Au(biiq-κN)(PPh 3

Conclusions
This review has attempted to present a comprehensive discussion of the chemistry, particularly the coordination chemistry of 1,1 -biisoquinoline. The consequences of coordination of these atropisomeric ligands identified the need for a refinement and clarification of the stereochemical nomenclature for complexes with multiple stereogenic sites and we offer a first approach.
Author Contributions: All authors contributed to the conceptualization and writing of this article and agreed to the published version of the manuscript.
Funding: This research received no external funding.