weakly coordinating ethereal solvents in which lithium dimethylcuprate is typically used, it is believed that CIPs dominate and that these forms of reagent are responsible for observed reactivity [143].
A number of solution‐state studies on the lithium methylcuprate species (Me m+n Cu m Li n ) have been undertaken. Detailed solution work is covered elsewhere in this volume. However, briefly, 1H and 7Li NMR spectroscopies have revealed that the addition of MeLi to MeCu in THF/Et2O results in an equilibrium between Me2CuLi 83 and Me3Cu2Li 111 plus MeLi, though the existence of this equilibrium has proved to be strongly dependent upon both the solvent (it does not occur in Et2O) and the presence of LiI (which promotes the formation of a different discrete entity). This work highlighted the fact that reagents presumed to be either ‘lower‐order’ or ‘higher‐order’ according to the stoichiometry of their preparation were in fact composed of varying quantities of the same species [145]. More recent DOSY studies using PFG (pulsed field gradient) NMR spectroscopy have indicated the existence of dimethylcuprate aggregates (based on homodimeric cores) larger than dimers in Et2O, though these exhibited depleted reactivity [146]. Likewise, multi‐dimensional NMR spectroscopy showed that the addition of small amounts of THF to Et2O‐based cuprate preparations had surprisingly different effects on aggregation depending on the identity of inorganic Li salts present [147].
Figure 1.14 Structures of (a) SIP [{(Me3Si)3C}2Cu][Li(THF)4] 106, and (b) bent cuprate anion in CIP (fluorenone)CuMe2Li(THF)3110.
Sources: Adapted from Eaborn et al. [140]; Bertz et al. [144].
The dramatic effects on reactivity of incorporating a Li salt with a polar organometallic reagent have already been discussed in the context of magnesium amides and will be returned to in the context of copper amides. The importance of this notion in terms of cuprate chemistry derives from the fact that in in situ cuprate syntheses a Li salt by‐product is often formed and is rarely separated prior to application of the cuprate. Whilst the influence upon and/or inclusion of LiX (X = an inorganic anion, often a halide) in cuprate structures has been subject to several investigations (most recently by in‐depth NMR spectroscopy), solid‐state evidence for association remains rare (X = CN constitutes a special class of cuprate, which is discussed separately). However, the reaction of ortho diamine‐chelated aryllithium reagents with CuBr has given cuprates of formula Ar2Cu(Br)Li2 (Ar = C6H4{CH2N(Me)CH2CH2NMe2}‐2 112 and 1‐C10H6{CH2N(Me)CH2CH2NMe2}‐2 113, Figure 1.15) [148]. Interestingly, it was noted that the benzylic nitrogen centres became stereogenic upon coordination to Li, though only R,R and S,S pairs were observed in the solid‐state, implying selectivity during assembly.
As mentioned above, cyanocuprates are often considered as a distinct class of cuprates. They have been recognized as highly reactive and robust reagents that offer advantages over traditional Gilman reagents in substitution [149] and addition [150] reactions. However, the structures of cyanocuprates proved controversial for many years. Unlike halides, the ability of cyanide to act as a strongly coordinating ligand raised the possibility that it might remain bonded to Cu during cuprate formation. This behaviour has been plainly evidenced over a number of years in a range of lower‐order cyanocuprates (obtained from the stoichiometric reaction of CuCN and RLi) both in the solid state [151–153] and in solution [154]. However, upon adding two equivalents of RLi to CuCN (to give a Lipshutz cuprate, a species of the type R2Cu(CN)Li2), the outcome became less straightforward to predict. Two possibilities arose: (i) expulsion of cyanide as LiCN (or else retention by the cuprate but without a direct Cu–CN interaction) or (ii) retention of a Cu–CN bond to form a higher‐order cuprate. Although 13C NMR spectroscopy initially suggested CN− to be bound to copper [155], subsequent work demonstrated that the 13C NMR chemical shift of CN was indifferent to the organic R groups, arguing against a direct Cu–CN bond [156]. This latter scenario was subsequently supported by extended X‐ray absorption fine structure (EXAFS) measurements [157, 158], IR spectroscopy [159], and calculations [160, 161]. However, the most conclusive evidence disfavouring higher‐order structures arrived with the crystal structures of (DMBA)2Cu(CN)Li2(THF)4114 [162] and [t‐Bu2Cu][CN{Li(THF)(PMDETA)}2] 115 [163]. These structures contrasted; displaying CIP and SIP structures, respectively. However, the lack of Cu–CN bonding in either case was obvious. This was particularly noteworthy in 115, where the absence of a Cu–CN bond contrasted with its presence in the product of the 1 : 1 reaction of t‐BuLi with CuCN; t‐BuCu(CN)Li2(Et2O)2116 (Figure 1.16).
Figure 1.15 Molecular structure of [C6H4{CH2N(Me)CH2CH2NMe2}‐2]2Cu(Br)Li2112.
Source: Adapted from Kronenburg et al. [148].
Figure 1.16 Molecular structures of (a) polymeric (DMBA)2Cu(CN)Li2(THF)4114, (b) [t‐Bu2Cu][CN{Li(THF)(PMDETA)}2] 115 and (c) a cuprophilic aggregate of t‐BuCu(CN)Li2(Et2O)2116.
Sources: Adapted from Kronenburg et al. [162]; Boche et al. [163].
Several explanations have been posited for the apparently higher reactivity of Lipshutz cuprates, though the idea has also been contested [164]. Indeed, it has been suggested that the differing solubility of organic groups may be a contributory factor to observed variations in reactivity. For example, NMR spectroscopy uncovered the possibility that unreactive Cu‐rich cuprates may form in the presence of LiI when the organic groups were solubilizing [165], whereas lower‐order cyanocuprates (which did not interfere with unconsumed reactant) were the preferred sink for organocopper by‐product in the presence of cyanide. Differences in reactivity could then be understood in terms of the ability of the organocopper by‐product to sequester otherwise reactive cuprate. However, while these ideas have been considered in the context of applied conjugate addition, they have yet to be applied in detail to directed deprotonation or to copper‐halogen exchange reactions.
1.3.4 Solid‐phase Synthesis
Solid‐phase synthesis has become a recognized and attractive methodology for constructing libraries of biologically active small molecules in connection with combinatorial chemistry and automated synthesis oriented towards drug discovery research [166]. Various synthetic methodologies have been applied to solid‐phase synthesis [167]; however, organometallic chemistry has not yet been well explored in this area due to the lack of effective preparative
