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By using rapid injection NMR at low temperatures, a variety of π-complexes of lithium dimethylcuprate(I) with C–C, C–N, and C–S double bonds have been prepared and characterized. Complexation is generally accompanied by large upfield changes in chemical shift for the substrate carbon atoms bonded to copper. In the case of α,β-unsaturated carbonyl compounds, the changes for the carbonyl carbons are much smaller in magnitude, which is consistent with the usual η2 representation of these structures. It is possible for one ligand to displace another, and in this way an order of stability can be elucidated. Treatment of selected π-complexes with chlorosilanes or cyanosilanes gives CuIII intermediates.

By using rapid injection NMR, it has now been possible to prepare and characterize the η(3) 'π-allyl' copper(III) intermediate that has been proposed for addition reactions of organocopper(I) reagents and α,β-unsaturated carbonyl compounds.

They "know" where to go: a powerful orientation effect has been observed in complexes of mixed organocuprates [R(T)R(NT)CuLi] and substrates with C-C, C-N, and C-S double bonds (see scheme; Th=thienyl). The preferred geometry of the intermediate complex sets up the facile addition of R(T) to the double bond, rather than addition of the "dummy ligand", R(NT) .

Complexes between copper reagents and double-bonds have been proposed as intermediates in a number of synthetically important reactions. Many h-complexes between organocuprates and carbon–carbon double-bonds, which are intermediates in 1,4-addition reactions of a,b-unsaturated carbonyl compounds, have been observed by using NMR spectroscopy. Moreover, h-O,C-complexes between organocopper compounds and carbon–oxygen double-bonds have been proposed as intermediates in 1,2-additions to carbonyl compounds, for example, copper-catalyzed asymmetric induction reactions. Carbophilic additions to thiocarbonyl compounds, mediated by organocuprates, have been explained in terms of h-S,C-complexes of carbon–sulfur double-bonds. However, there has been no report of an X-ray structure for any of these p-complexes. Therefore, we applied our rapid-injection techniques, which were previously used to prepare several important intermediates, to screen a number of typical aldehydes and ketones for complex formation with Me2CuLi, [9] and we discovered such a species with unusual stability, which has allowed us to prepare it on a larger scale and grow highquality crystals (see the Supporting Information). We now report the first X-ray crystal structure of a cuprate– carbonyl p-complex, 1 (Scheme 1 and Figure 1).

Typical aldehydes and ketones form π complexes with Me2CuLi at low temperatures in tetrahydrofuran. They range in stability from fleeting intermediates at -100 °C to entities that persist up to -20 °C. Three subsequent reaction pathways have been identified.

Mathematics Applied to Synthetic Analysis (MASA) is a useful addition to Logic and Heuristics Applied to Synthetic Analysis (LHASA), as it can be used to calculate the simplification afforded by alternative disconnections of a target molecule. One-bond and two-bond disconnections that are more efficient as far as simplification is concerned than those identified by the LHASA criteria have been found by using MASA. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Complexity and diversity indices based on fundamental mathematical entities (topological invariants) are used to calculate the changes that take place during synthetic reactions, such as the Aldol, Diels–Alder, Wittig, Reppe–Vollhardt, Pauson–Khand and House–Whitesides reactions. Such calculations provide a way to compare the power of various reactions to increase molecular complexity, and they furnish a ‘yardstick’ to gauge the state of the art of synthetic chemistry. Retrosynthetic transforms and disconnections are also evaluated, and in the latter case, topological simplification principles are derived. In this way we may reveal the ‘unseen hand’ of synthesis.

Complexity and diversity indices can be used to evaluate the structural changes that take place during the course of a synthesis. From the generalized ‘complexity versus step’ plot and the definition of the ‘ideal synthesis’ we derive the concept of excess complexity and the heuristic, minimization of excess complexity. Molecular complexity and synthetic complexity are differentiated by identifying them with intrinsic and extrinsic complexity, respectively, and the effect of chirality on each is clarified. The role of symmetry in synthetic analysis is delineated by considering symmetry in molecules, their molecular graphs and the synthesis digraphs for their preparation, which leads to the concept of reflexivity and the heuristic, maximization of reflexivity. Vulnerability and robustness are introduced in connection with linear and convergent syntheses, which are also considered in relation to reflexivity.

π-Complexes of mixed organocuprate(I) reagents with α,β-unsaturated carbonyl compounds can undergo ligand exchange to give the corresponding homocuprate–olefin π-complexes. The mechanism of this metathesis, which has profound implications for synthetic applications, involves a second-order reaction of the mixed cuprate with the mixed cuprate–olefin π-complex.

Iodo-Gilman reagents Me2- CuLi · LiI, Bu2CuLi · LiI, and BuThCu- Li · LiI and cyano-Gilman reagents (nee "higher order cyanocuprates" Me2Cu- Li · LiCN, Bu2CuLi · LiCN, and BuTh- CuLi · LiCN react with 2-cyclohexenone at various rates, which depend upon the R groups (Me, Bu, Tha thienyl), Li salt (LiI vs. LiCN), solvent (ether vs. THF), and amount of trimethylsilyl chloride (TMSCl) additive. The effect of the Li salt (CuI vs. CuCN precursor) is less than that of solvent or TMSCl. The butylcuprate-iodocyclohexane reaction has also been examined as a function of Li salt, solvent, and TMSCl additive, and similar effects are observed. The reactivity matrix R with elements ri,j is a convenient way to store and present a large amount of relative reactivity data. Entry ri,j is the ratio of the rate with reagent i to the rate with reagent j, which we approximate by using yields meas- ured after a short time (4 s). The loga- rithmic reactivity profile (LRP) pro- vides an efficient means for determining yields under conditions where such comparisons are valid. The results of a large number of 4-point LRPs and related reactions are tabulated and an- alyzed to provide a clearer picture of organocuprate reactivity.

Structure 1 is the major component obtained by the reaction of two equivalents of RLi and one equivalent of CuCN; other proposed structures can now be ruled out on the basis of 15 N NMR spectroscopic and theoretical studies. Thus, these useful synthetic reagents should be considered as cyano-Gilman reagents R2 CuLi⋅LiCN and not "higher order cyanocuprates" R2 Cu(CN)Li2 .

1 ist die Hauptkomponente, die nach der Reaktion von 2 Aquiv. RLi mit 1 Aquiv. CuCN erhalten wird; andere vorgeschlagene Strukturen konnten jetzt auf der Grundlage von 15N-NMR-spektroskopischen und theoretischen Untersuchungen ausgeschlossen werden. Demnach lassen sich die praparativ nutzlichen Reagentien R2CuLi⋅LiCN als Cyano-Gilman-Reagentien auffassen und sind keine Cyanocuprate hoherer Ordnung.

An efficient stereospecific method to prepare (E)- and (Z)-configurated title compounds is reported.

The configurational isomers of the title compounds consist of four fused five-membered rings. They contain tightly coupled 1H NMR spin systems, which provide excellent models for establishing the relationships between coupling constants and conformation. Complete chemical shift assignments and spin–spin coupling constants are reported for the title compounds by using high-field (500 MHz) 1H NMR techniques (e.g., 2D homonuclear and heteronuclear experiments, difference NOE enhancements, and computational spin simulations). In addition to the more familiar two- and three-bond couplings, the spectra of 1 and 2 also contain a number of long-range (four- and five- bond) couplings, which provide a stringent test of Barfield's theoretical treatment of four-bond couplings.

There has been a great deal of ferment in ‘Complexity Science’ in recent years, as chronicled in the proceedings of the New England Complex Systems Institute’s International Conference on Complex Systems [Minai & Bar-Yam 2006, 2008] and those of the Santa Fe Institute [Nadel & Stein 1995, Cowan 1994]. We have been primarily focused on developing metrics of complexity relevant to chemistry, especially synthetic chemistry [Bertz 2003a–c]. Our approach involves abstracting a molecule or a plan for its synthesis as a graph and then using the tools of graph theory to characterize its complexity and diversity.

The dimerization of triquinacene (C10H10) to dodecahedrane (C20H20) has been a goal of organic chemists for more than three decades. An attempted synthesis of dodecahedrane from triquinacene using high pressure and near-UV radiation was not successful, but both hydrocarbons survived the 15 GPa treatment. There is no evidence for a pressure-induced transition in either of the materials. The results of high-pressure Raman spectroscopic investigations to 20 GPa on triquinacene and dodecahedrane are reported. Liquid triquinacene crystallizes near 0.2 GPa at 295 K and the Raman peaks associated with the molecular modes sharpen strikingly. In the crystal the external mode peaks exhibit a large pressure dependence, as expected, but the surprising fact is that the C—H stretching modes behave likewise. In dodecahedrane a similar effect is observed for the C—H stretching modes, but no external mode peaks are observed. The Raman data on dodecahedrane are compared with earlier results and calculations, which support the Ih symmetry for the molecule and an fcc lattice for the crystal.

The dimerization of triquinacene (C10H10) to dodecahedrane (C20H20) has been a goal of organic chemists for more than three decades. An attempted synthesis of dodecahedrane from triquinacene using high pressure and near-UV radiation was not successful, but both hydrocarbons survived the 15 GPa treatment. There is no evidence for a pressure-induced transition in either of the materials. The results of high-pressure Raman spectroscopic investigations to 20 GPa on triquinacene and dodecahedrane are reported. Liquid triquinacene crystallizes near 0.2 GPa at 295 K and the Raman peaks associated with the molecular modes sharpen strikingly. In the crystal the external mode peaks exhibit a large pressure dependence, as expected, but the surprising fact is that the C—H stretching modes behave likewise. In dodecahedrane a similar effect is observed for the C—H stretching modes, but no external mode peaks are observed. The Raman data on dodecahedrane are compared with earlier results and calculations, which support ...

Upon rapid injection, a variety of thiocarbonyl compounds react with the Gilman reagent Me(2)CuLi at -100 degrees C inside the probe of an NMR spectrometer to give high yields of complexes. Typical examples of substrates include carbon disulfide, methyl dithioacetate, methyl dithiobenzoate, thiobenzophenone, ethylene trithiocarbonate, and phenyl isothiocyanate. Evidence suggesting the formal oxidation state of copper in these complexes to be Cu(III) is presented. The last example was particularly interesting, since it involved a transient intermediate that was identified as a complex with a C-N double bond. Methyl isothiocyanate gave a stable C-N double-bond complex.

Lithium tetramethylcuprate(III), Me(4)CuLi, the Cu(III) analog of the Gilman reagent, has been prepared in high yield from halo-Gilman reagents Me(2)CuLi.LiX (X = Cl, Br, I) and 2,3-dichloropropene and found to have surprising thermal stability. The cyano-Gilman reagent (X = CN) follows a different pathway.

Treatment of iodocyclohexane with Bu 2 CuLi.LiI yields substantial amounts of butylcyclohexane, cyclohexane, cyclohexene, bicyclohexyl, and octane. Trapping experiments demonstrate that the bulk of these products derive from cyclohexyl radicals, indicating that an electron-transfer mechanism is operative. Some of the cyclohexane and bicyclohexyl is traced to transmetalation. Likewise, 1-methyl-1-cyclohexyl iodide and 2-heptyl iodide react via electron transfer, whereas cyclohexyl bromide, 1-heptyl iodide, and 1-heptyl bromide do not. These results are in harmony with House's hypothesis that electron transfer from organocuprates occurs when the reduction potentials of the substrates are more positive than −2.35 V

The first pi-allyl complexes of CuIII have been prepared and characterized by using rapid injection nuclear magnetic resonance spectroscopy (RI-NMR). The prototype, (eta3-allyl)dimethylcopper(III), was prepared by injection of allyl chloride into a THF-d8 solution of iodo-Gilman reagent, Me2CuLi.LiI (A), spinning in the probe of an NMR spectrometer at -100 degreesC. A sigma-allyl ate complex, lithium (eta1-allyl)trimethylcuprate(III), was prepared in high yield by including 1 equiv of tributylphosphine in the reaction mixture or by using allyl acetate as the substrate. Cyano ate complex, lithium cis-(eta1-allyl)cyanodimethylcuprate(III) was obtained in high yield by injecting allyl chloride or allyl acetate into the cyano-Gilman reagent, Me2CuLi.LiCN (B), in THF-d8 at -100 degrees C. Reactions of A with allylic substrates show a definite dependence on leaving group (chloride vs acetate), whereas those of B do not. Moreover, these reagents have different regioselectivities, which in the case of A vary with temperature. Finally, the exclusive formation of cis-cyano sigma-allyl CuIII intermediates in both the 1,4-addition of B to alpha-enones and its SN2alpha reaction with allylic substrates now makes sense in terms of pi-allyl intermediates in both cases, thus unifying the mechanisms of these two kinds of conjugate addition.

The intramolecularly H-bonded cis enolic form of malondialdehyde in chloroform is converted to an intermolecularly H-bonded trans enol by methoxy compounds such as methanol and 3,3-dimethoxypropanal. «Polar impurities» such as acetone and dioxane do not induce this effect

[7758-89-6] ClCu (MW 99.00) InChI = 1S/ClH.Cu/h1H;/q;+1/p-1 InChIKey = OXBLHERUFWYNTN-UHFFFAOYSA-M (catalyst for diazo and diazonium chemistry; for use with Grignard reagents1) Alternate Name: cuprous chloride. Physical Data: mp 430 °C; d 4.140 g cm−3. Solubility: insol H2O and most organic solvents; partially sol dimethyl sulfide (DMS). Form Supplied in: light green-tinged white solid; 99.99% grade available commercially. Handling, Storage, and Precautions: maintenance of a dry N2 or Ar atmosphere is recommended.

[544-92-3] CCuN (MW 89.57) InChI = 1S/CN.Cu/c1-2; InChIKey = DULSAGLWMRMKCQ-UHFFFAOYSA-N (·NaCN) [13715-19-0] C2CuN2Na (MW 138.58) InChI = 1S/2CN.Cu.Na/c2*1-2; InChIKey = NGRSIWGPWLJMKS-UHFFFAOYSA-N (·LiCl) [59219-07-7] CClCuLiN (MW 131.96) InChI = 1S/CN.ClH.Cu.Li/c1-2;;;/h;1H;;/q;;;+1/p-1 InChIKey = HTYULWBPSSSTKF-UHFFFAOYSA-M (·2LiCl) [121340-53-2] CCl2CuLi2N (MW 174.35) InChI = 1S/CN.2ClH.Cu.2Li/c1-2;;;;;/h;2*1H;;;/q;;;;2*+1/p-2 InChIKey = QGXKBLXNBYNHBV-UHFFFAOYSA-L (·2LiBr) [129126-28-9] CBr2CuLi2N (MW 263.25) InChI = 1S/CN.2BrH.Cu.2Li/c1-2;;;;;/h;2*1H;;;/q;;;;2*+1/p-2 InChIKey = CJIBYPVCFACANM-UHFFFAOYSA-L (useful precursor for organocopper(I) and organocuprate(I) reagents1) Alternate Name: cuprous cyanide. Physical Data: mp 474 °C; d 2.920 g cm−3. Solubility: insol H2O and most organic solvents. The lithium halide complexes are sol THF. Form Supplied in: off-white solid. Handling, Storage, and Precautions: highly toxic; must be handled with care.

[7681-65-4] CuI (MW 190.45) InChI = 1/Cu.HI/h;1H/q+1;/p-1/fCu.I/h;1h/qm;-1 InChIKey = LSXDOTMGLUJQCM-RKNFSRNDCT (·PBu3) [21591-31-1] C12H27CuIP (MW 392.81) InChI = 1/C12H27P.Cu.HI/c1-4-7-10-13(11-8-5-2)12-9-6-3;;/h4-12H2,1-3H3;;1H/q;+1;/p-1/fC12H27P.Cu.I/h;;1h/q;m;-1 InChIKey = UKSFURGLGLVJNV-CCJSSQOTCH (·(SBu2)2) [35907-81-4] C16H36CuIS2 (MW 483.11) InChI = 1/2C8H18S.Cu.HI/c2*1-3-5-7-9-8-6-4-2;;/h2*3-8H2,1-2H3;;1H/q;;+1;/p-1/f2C8H18S.Cu.I/h;;;1h/q;;m;-1 InChIKey = PKMNFCJJZXEQGN-LRIRGEDQCV (the classical precursor for organocopper(I) and organocuprate reagents1) Alternate Name: cuprous iodide. Physical Data: mp 605 °C; d 5.620 g cm−3. Solubility: insol in H2O and most organic solvents; partially sol in dimethyl sulfide (DMS). Form Supplied in: off-white to grayish solid; 99.999% grade available. Handling, Storage, and Precautions: maintenance of a dry N2 or Ar atmosphere is recommended.

Under the conditions of a rapid injection experiment, the conjugate addition reactions of butyl Gilman reagents with 2-cyclohexenone undergo oscillations of a complex nature.

The reactions of Bu(2)CuLi[middle dot]LiI and Bu(2)CuLi.LiCN with cyclohexyl iodide are critically dependent upon subtle factors such as the surface properties of the reaction vessel, nature of the solvent still and lot of 'ultrapure' copper salt in addition to major effects such as the Li counterion.

[7787-70-4] BrCu (MW 143.45) InChI = 1/BrH.Cu/h1H;/q;+1/p-1/fBr.Cu/h1h;/q-1;m InChIKey = NKNDPYCGAZPOFS-ZFYMQJCYCJ CuBr·SMe2 [54678-23-8] C2H6BrCuS (MW 205.59) InChI = 1/C2H6S.BrH.Cu/c1-3-2;;/h1-2H3;1H;/q;;+1/p-1/fC2H6S.Br.Cu/h;1h;/q;-1;m InChIKey = PMHQVHHXPFUNSP-GUDWEBAYCB (precursor for organocopper(I) reagents and organocuprates;1a–f catalyst for diazo chemistry) Alternate Name: cuprous bromide. Physical Data: mp 504 °C; the complex with dimethyl sulfide (DMS) decomposes at ca. 130 °C; d 4.720 g cm−3. Solubility: insoluble in H2O and most organic solvents; partially soluble in dimethyl sulfide. Form Supplied in: light green or blue-tinged white solid. 99.999% grade available. The DMS complex is a white solid. Preparative Methods: commercial copper bromide is often contaminated; the use of freshly prepared or purified copper bromide is strongly advised. Copper bromide can be prepared by reduction of CuBr238 or CuSO4–NaBr.39 Purity: the colored impurities in the title reagent can be removed from the commercial samples by dissolving an appropriate quantity of CuBr in a saturated aqueous solution of KBr over 30 min. Subsequent cooling, treating with charcoal, filtering, and diluting with water allows for the formation of the CuBr precipitate.40 Traces of iron salts can be removed via the sulfide complex.41 Alternatively, copper bromide can be purified by precipitation from 48% HBr. The precipitate is filtered and washed sequentially with water, ethanol, and ether, then finally dried under vacuum.42 Handling, Storage, and Precautions: maintenance of a dry N2 or Ar atmosphere is recommended. The DMS complex must be tightly sealed to prevent loss of DMS. Storage of this complex in a cold place is recommended.

The LHASA rules for finding strategic bonds in polycyclic target structures are analyzed with respect to the following question: Do the strategic bonds tend to give the greatest simplification upon disconnection, as measured by recently introduced indices of molecular complexity? The answer is yes, at least for the more general rules. This result implies that the bonds most useful for retrosynthetic disconnection can now be identified by a simple calculation rather than by application of a body of rules. It is concluded that organic synthesis, as far as described by these rules, has a mathematical basis and consequently can be considered a science as well as an art.

Isomorphism is an equivalence relation that is less stringent than identity (equality), and it is useful for synthetic analysis, since it allows one to find reflexive routes for targets even when they do not have an element of symmetry.

Condensation of Dimethyl 1,3-Acetonedicarboxylate with 1,2-Dicarbonyl Compounds: cis-Bicyclo[3.3.0]octane-3,7-diones intermediate: Tetramethyl 3,7-dihydroxybicyclo[3.3.0]octa-2,6-diene-2,4,6,8-tetracarboxylate product: cis-Bicyclo[3.3.0]octane-3,7-dione intermediate: Tetramethyl 3,7-dihydroxy-1,5-dimethylbicyclo[3.3.0]octa-2,6-diene-2,4,6,8-tetracarboxylate product: cis-1,5-Dimethylbicyclo[3.3.0]octane-3,7-dione intermediate: C16H16O10Na2·H2O Keywords: annulation, carbocyclic-[M,N]; annulation, carbocyclic-[M,N]; cyclization, condensation; cyclization, condensation; decarboxylation; decarboxylation; hydrolysis, esters and lactones; hydrolysis, esters and lactones; ethanol

Rapid-injection is a very useful technique for the preparation of temperature-sensitive and air-sensitive compounds in the cold, nitrogen-filled probe of an NMR spectrometer. We have used this method to prepare solutions of pi-complexes from 2-cyclohexenone and prototypical cuprates Me2CuLi.LiI and Me2CuLi.LiCN, and we have assigned structures on the basis of 1H and 13C NMR. In each case two pi-complexes were observed, and in the former, their rates of formation were measured by rapid-injection 1H NMR and EXSY spectroscopy. These results provide insights into the normal and anomalous conjugate addition reactions of organocuprates.

Structure 1 is the major component obtained by the reaction of two equivalents of RLi and one equivalent of CuCN; other proposed structures can now be ruled out on the basis of

Scalemic N-silylamidocuprates, prepared from O-methylnorephedrine in a two-flask procedure, are exceedingly reactive and give excellent enantiomeric excesses with chalcone, a classic substrate for studies of organocuprate conjugate addition. For example, the butyl N-diphenylmethylsilylamidocuprate (T = Bu) affords a 99.2% ee (99% yield) of (S)-3-butyl-1,3-diphenyl-1-propanone. The remarkably high yields with this and other silyl ligands are attributed to the extraordinary activating effect of a beta-silicon atom on organocuprate reactions. The high ee is a consequence of the larger size of the silyl ligands compared to that of the unsubstituted or methyl-substituted analogues.

Rapid injection of pyruvonitrile or benzoyl cyanide into solutions of Me2CuLi in THF-d8 at -100 °C gave complexes that were stable at this temperature. 1D NMR with multiply labelled substrates ((13)C/(15)N) and 2D NMR ((1)H/(13)C) identified them as the first cuprate-carbonyl π-complexes.

Isomorphism is an equivalence relation that is less stringent than identity (equality), and it is useful for synthetic analysis, since it allows one to find reflexive routes for targets even when they do not have an element of symmetry.

Bond covers based on substructures can be used to guide retrosynthetic analysis and give greater insight into the principle of convergence.

Lithium tetramethylcuprate(III) 1 reacts readily at -100 degrees C with appropriate sources of H(+) or X(+) (X = Br, I) to remove a methyl and in some cases incorporate the counterion (e.g., arylthio or cyano) to give stable complexes. These derivatives can in turn serve as starting materials for other Cu(III) complexes.

Neutral organocopper(III) complexes have been prepared from organocuprate(I) reagents and alkyl halides in the presence of certain strongly electron donating ligands.

The enumeration of all possible subgraphs of the molecular graph is the basis for new complexity indices NS (number of kinds of subgraphs) and NT (total number of subgraphs) that are useful for synthetic analysis, e.g. the determination of topological strategic bonds.

In this paper we answer the question recently posed by Lipshutz and James (see title), and we present a mechanism which explains why the cuprates prepared from CuCN have a greater product-forming ability in many reactions.