Cubane Skeleton Research Articles

Cuneanes as Potential Benzene Bioisosteres Having Chirality

AbstractCuneane, a structural isomer of cubane, possesses C 2v symmetry, unlike the Oh symmetry of cubane. It can exhibit chirality with only a single substituent, differentiating it from cubane. Consequently, cuneane is being explored as a potential benzene bioisostere in pharmaceutical molecules, adding complexity such as chirality through isomerization of the cubane skeleton. Although there has been limited research on the synthesis of cuneane, recent years have seen increased attention devoted to this cage hydrocarbon. In this short review, we will discuss recent advances in the synthesis, utilization, and transformations of the cuneane framework into other cage hydrocarbons.1 Introduction: Absolute Configuration Notation2 Preparation of 1,3- and 2,6-Disubstituted Cuneanes by Constitutional Isomerization of 1,4-Disubstituted Cubanes3 Preparation of 1,2-Disubstituted Cuneanes from 1-Cuneanecarboxamide via Directed ortho-Metalation4 Investigation of the Potential as a Benzene Bioisostere5 Asymmetric Synthesis of Cuneanes6 Cuneane Scaffold Editing7 Conclusion

How to Set the “Chirality” of Polyhedral Small Molecule Hydrocarbons: Decoration and Editing of Cubane Skeleton

AbstractSmall polyhedral hydrocarbons represented by cubane have attracted attention as potential molecular scaffolds for pharmaceuticals as benzene bioisoster. Cubane is also expected to be used as a chiral scaffold, but due to its high symmetry, it is necessary to introduce chirality by sequential site‐selective introduction of substituents. Furthermore, polyhedral desymmetrized isomers of cubane, such as cuneane and semibullvalene, and extended cage compounds, such as bishomocubane and homocuneane, exhibit chirality and are also expected to be used as new optically active scaffolds. In this concept, we would like to explain the synthetic routes we have planned, specifically, the decoration and editing of the cubane skeleton.

Chiral Auxiliary-Directed Site-Selective Deprotonation of the Cubane Skeleton.

The first diastereoselective synthesis of trisubstituted cubanes was achieved using a chiral auxiliary. To establish chirality within the cubane skeleton, at least three substituents must be introduced at the appropriate positions. Ready conversion of cubane carboxylic acid to a chiral amide followed by sequential ortho-selective deprotonations and electrophilic trapping afforded the corresponding 1,2,3-trisubstituted cubanes with high diastereoselectivity. This route opens new possibilities for the preparation of enantio-enriched cubanes.

Unmasking Inherent Chirality within the Cubane Skeleton

AbstractCubane, a hexahedral hydrocarbon, can be converted into an asymmetric molecule with a minimum of three substituents. The resulting chiral cubane can be used as a pharmacophore or a chiral ligand. Starting from the cubane carboxamide, the 1,2,3‐substituted compound was synthesized by sequential ortho‐metalation. The 1,3,5‐substituted compound was synthesized by combining site‐selective halogenation and halogen‐metal exchange and the resulting racemate was subjected to enantiomeric resolution by HPLC.

Substituent effects in cubane and hypercubane: a DFT and QTAIM study

Using the quantum theory of atoms in molecules in combination with density functional theory, we investigate the charge densities of different cubane and hypercubane derivatives in which all the terminal hydrogen atoms of the title hydrocarbons are replaced by an equal number of substituents (F, Cl, Br, CH3, and NO2). The analysis of the charge densities of the bond, ring, and cage critical points indicates that these substituents have the ability to alter the charge density of the cubane skeleton, thereby enhancing the strain of its carbon–carbon bonds. Also, the change in the charge density as a function of the expansion and contraction of the cubane cage indicates that the persubstituted derivatives respond differently to the deformation of their carbon cages. A linear correlation between the one-bond nuclear spin–spin coupling constant 1J(13C13C) and the charge densities calculated at the bond critical points suggests the possibility of employing this NMR parameter for studying the effects of substituents in cage hydrocarbons.

Cage-Shaped Molecules Derived by Applying the Edge Strategy to a Cubane Skeleton

Cage-Shaped Molecules Derived by Applying the Edge Strategy to a Cubane Skeleton

Symmetry-Itemized Enumeration of Cubane Derivatives as Three-Dimensional Entities by the Elementary-Superposition Method of the USCI Approach

Abstract Cubane derivatives with a given chemical formula and a given symmetry are enumerated by applying the elementary-superposition method (S. Fujita, Theor. Chim. Acta1992, 82, 473–498) of the unit-subduced-cycle-index (USCI) approach to a cubane skeleton of the point group Oh. A cycle index (CI) for a regular or an irregular case of chiral and achiral ligands is calculated in accord with such a given chemical formula. The CI is superposed elementarily onto respective subduced cycle indices with chirality fittingness (SCI-CFs), which are calculated by starting from unit subduced cycle indices with chirality fittingness (USCI-CFs). Thereby, the numbers of fixed points (derivatives) are obtained with respect to the respective SCI-CFs to give a fixed-point vector (FPV). The resulting FPV is multiplied by an inverse matrix of the mark table of Oh to give an isomer-counting vector (ICV), which contains the numbers of 3D-structural isomers in an itemized fashion with respect to point-group symmetries. The concept of prochirality is examined by using cubane derivatives enumerated by the ICV.

Symmetry-Itemized Enumeration of Cubane Derivatives as Three-Dimensional Entities by the Partial-Cycle-Index Method of the USCI Approach

Abstract By placing chiral and achiral proligands on the eight positions of a cubane skeleton of Oh, resulting cubane derivatives are counted as three-dimensional (3D) structural isomers by the partial-cycle-index (PCI) method of the unit-subduced-cycle-index (USCI) approach (S. Fujita, Symmetry and Combinatorial Enumeration in Chemistry, Springer-Verlag, 1991; S. Fujita, Diagrammatical Approach to Molecular Symmetry and Enumeration of Stereoisomers, University of Kragujevac, Kragujevac, 2007), where the numbers of 3D structural isomers with given constitutional formulas are itemized with the subsymmetries of Oh. For this purpose, partial cycle indices with chirality fittingness (PCI-CFs) for respective subgroups of Oh are calculated by using unit subduced cycle indices with chirality fittingness (USCI-CFs) and an inverse matrix of the mark table of Oh. After introducing ligand-inventory functions into the PCI-CFs, expansions of the resulting equations provide us with generating functions for giving the numbers of 3D structural isomers. A Maple program source for counting cubane derivatives as 3D structural isomers is given as an example of practical calculation for listing the resulting data in tabular forms.

Symmetry-Itemized Enumeration of Cubane Derivatives as Three-Dimensional Entities by the Fixed-Point Matrix Method of the USCI Approach

Abstract Cubane derivatives with chiral and achiral proligands are counted as three-dimensional (3D) structural isomers by the fixed-point matrix method of the unit-subduced-cycle-index (USCI) approach (S. Fujita, “Symmetry and Combinatorial Enumeration in Chemistry,” Springer-Verlag, 1991). The numbers of such 3D structural isomers are itemized with respect to their point-group symmetries, which are subgroups of the point group Oh for a cubane skeleton. For this purpose, the full list of unit subduced cycle indices with chirality fittingness (USCI-CFs) of Oh is constructed in a tabular form. Fixed-point vectors or fixed-point matrices, which are calculated by starting from USCI-CFs, are used to count 3D structural isomers in the form of isomer-counting matrices. A Maple program source for counting cubane derivatives as 3D structural isomers is given as an example of practical calculation.

Theoretical Study on Thermodynamic and Detonation Properties of Polynitrocubanes

AbstractWe investigated the heat of formation (ΔfH) of polynitrocubanes using density functional theory B3LYP and HF methods with 6‐31G*, 6‐311+G**, and cc‐pVDZ basis sets. The results indicate that ΔfH firstly decreases (nitro number m=0–2) and then increases (m=4–8) with each additional nitro group being introduced to the cubane skeleton. ΔfH of octanitrocubane is predicted to be 808.08 kJ mol−1 at the B3LYP/6‐311+G** level. The Gibbs free energy of formation (ΔfG) increases by about 40–60 kJ mol−1 with each nitro group being added to the cubane when the substituent number is fewer than 4, then ΔfG increases by about 100–110 kJ mol−1 with each additional group being attached to the cubic skeleton. Both the detonation velocity and the pressure for polynitrocubanes increase as the number of substituents increases. Detonation velocity and pressure of octanitrocubane are substantially larger than the famous widely used explosive cyclotetramethylenetetranitramine (HMX).

Strain energies of cubane derivatives with different substituent groups

Homodesmotic reaction and isodesmotic reaction were designed for the computation of strain energies (SE) for a series of cubane derivatives. Total energies of the optimized geometric structures at the DFT-B3LYP/6-31G* level were used to derive the SE. The SE value of cubane is 169.13 kcal/mol for homodesmotic reaction, which is in good agreement with the experimental value. The variation of SE with respect to the number of substituents is similar for the homodesmotic reaction and isodesmotic reaction. The SE values of polynitrocubane and polydifluoroaminocubane increase slightly as up to four substituent groups being added to the cage skeleton. On contrary, the SE dramatically increases when the number of substituent groups m increases from 5 up to 8. For polynitratocubane, the SE decreases slightly at the beginning then increases as the number of group increases. For polyazidocubane, there are very small group effects on the SE. Among four types of substituent groups, the nitro group has greatest effect on the strain energy of caged cubane skeleton. The calculated SE value of octanitrocubane is 257.20 kcal/mol, while that of octaazidocubane is 166.48 kcal/mol via isodesmotic reaction. The azido group releases the strain energy of cubane skeleton when the number of azido groups is less than 7. The interactions among the substituted groups deviated from group additivity. The substituted groups withdraw electrons from the cubane, reducing the repulsion between C–C bonds and resulting the release the strain of the skeleton for isomers with fewer substituents. Group repulsions increase sharply with more and more nitro, nitrato and difluoroamino groups being attached to cubane, resulting large strains of the skeleton. The average negative charges of the substituted groups influence the strain energy of cubane derivatives.

Substituent effects on heats of formation, group interactions, and detonation properties of polyazidocubanes

We have calculated the heats of formation (HOFs) for a series of polyazidocubanes by using the density functional theory (DFT), Hartree-Fock, and MP2 methods with 6-31G* basis set as well as semiempirical methods. The cubane skeleton was chosen for a reference compound, that is, the cubane skeleton was not broken in the process of designing isodesmic reactions. There exists group additivity for the HOF with respect to the azido group. The semiempirical AM1 method also produced reliable results for the HOFs of the title compounds, but the semiempirical MINDO3 did not. The relationship between HOFs and molecular structures was discussed. It was found that the HOF increases 330-360 kJ/mol for each additional number of the azido group being added to the cubane skeleton. The distance between azido groups slightly influences the values of HOFs. The interacting energies of neighbor azido groups in polyazidocubanes are in the range of 2.3 approximately 6.6 kJ/mol, which are so small and less related to the substituent numbers. The average interaction energy between nearest neighbor --N3 groups in the most stable conformer of octaazidocubane is 2.29 kJ/mol at the B3LYP/6-31G* level. The relative stability related to the number of azido groups of the title compounds was assessed based on the calculated HOFs, the energy gaps between the frontier orbitals, and the bond orders of the C--N3 and C--C bonds. The predicted detonation velocity of hepta- and octa-derivatives is over 9 km/s, and the detonation pressure of them is ca. 40 GPa or over.

Theoretical Studies on the Heats of Formation and the Interactions among the Difluoroamino Groups in Polydifluoroaminocubanes

The heats of formation (HOFs) were calculated for a series of polydifluoroaminocubanes by using density functional theory (DFT), Hartree-Fock, and MP2 method with 6-31G basis set as well as semiempirical methods. The cubane skeleton was not broken in the process of designing isodesmic reactions; i.e., the cubane skeleton was chosen for a reference compound. The contribution of difluoroamino group to the heat of formation deviates from group additivity. The semiempirical MO (MNDO, AM1, and PM3) methods did not produce accurate and reliable results for the HOFs of the title compounds. The relationship between HOFs and molecular structures was discussed. It was found that the HOFs decreased dramatically initially and then gradually with each difluoroamino group attached to the cubane skeleton. The distance between difluoroamino groups influences the values of HOFs. The interacting energies of polydifluoroaminocubanes are in the range 14-20 kJ/mol. The interaction of neighbor difluoroamino groups discords with the group additivity. The average interaction energy between the nearest-neighbor NF(2) group in the most stable conformer of octadifluoroaminocubane is 13.94 kJ/mol at the B3LYP/6-31G level. The NF(2) group can rotate freely around the C-N bond. The relative stability of the title compounds was accessed on the basis of the calculated HOFs, the energy gaps between the frontier orbitals, and the bond order of C-NF(2). These results provide basic information for the molecular design of novel high energetic density materials.

Nitration of Cubane‐1,4‐dicarboxylic Acid Dimethyl Ester by Dinitrogen Tetraoxide.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The structure of nitrocubane: the last in the series of nitrocubanes

The structure of nitrocubane, C8H7NO2, 1, reported herein, is the last to be reported in a series of nitrocubanes, ranging from mono- to octanitrocubane. Compound 1 crystallizes in the orthorhombic space group Pnma with cell dimensions a = 17.507(5), b = 6.584(2), and c = 5.832(2) A and Z = 4. Thus the nitrocubane molecule possesses a crystallographically imposed mirror plane. Since the nitro group is in the mirror plane, it is coplanar with the C1–C6 bond in the cubane skeleton. As has been found previously, the C1–C6 bond in the cubane skeleton that is coplanar to its attached nitro groups is shortened (1.533(4) compared to an average value of 1.543(2) A for all other cubane C–C bonds). In addition the single substitution of the nitro group into the cubane skeleton causes a tetrahedral distortion which is exhibited by alternating C–C–C angles which are greater than and less than 90°.

Nitration of cubane-1,4-dicarboxylic acid dimethyl ester by dinitrogen tetraoxide

A first direct nitration of C—H bond of cubane-1,4-dicarboxylic acid dimethyl ester by dinitrogen tetraoxide at ∼20 °C has been carried out. During the nitration no rearrangement of cubane skeleton has been observed.

Halogenation of cubane under phase-transfer conditions: single and double C-H-bond substitution with conservation of the cage structure.

The first highly selective C-H chlorination, bromination, and iodination of cubane (1) utilizing polyhalomethanes as halogen sources under phase-transfer (PT) conditions is described. Isomeric dihalocubanes with all possible combinations of chlorine, bromine, and iodine in ortho, meta, and para positions were also prepared by this method; m-dihalo products form preferentially. Ab initio and density functional theory (DFT) computations were used to rationalize the pronounced differences in the reactions of 1 with halogen (Hal(*)) vs carbon-centered trihalomethyl (Hal(3)C(*)) radicals (Hal = Cl, Br). For Hal(3)C radicals the C-H abstraction pathway is less unfavorable (DeltaG(double dagger)(298) = 21.6 kcal/mol for Cl(3)C(*) and 19.4 kcal/mol for Br(3)C(*) at B3LYP/6-311+G//B3LYP/6-31G) than the fragmentation of the cubane skeleton via S(H)2-attack on one of the carbon atoms of 1 (DeltaG(double dagger)(298) = 33.8 and 35.1 kcal/mol, respectively). In stark contrast, the reaction of 1 with halogen atoms preferentially follows the fragmentation pathway (DeltaG(double dagger)(298) = 2.1 and 7.5 kcal/mol) and C-H abstraction is more unfavorable (DeltaG(double dagger)(298) = 4.6 and 12.0 kcal/mol). Our computational results nicely agree with the behavior of 1 under PT halogenation conditions (where Hal(3)C(*) is involved in the activation step) and under free-radical photohalogenation with Hal(2) (Della, E. W., et al. J. Am. Chem. Soc. 1992, 114, 10730). The incorporation of a second halogen atom preferentially in the meta position of halocubanes demonstrates the control of the regioselectivity by molecular orbital symmetry.

The Cubane Cage – A Sensitive Probe for Assessing Substituent Effects on a Four-Membered Ring, Part II

The crystal structures of methyl 4-methoxycubane-1-carboxylate (1), 1-acetamido-4-fluorocubane (2), methyl 4-acetoxycubane-1-carboxylate (3), 1,4-difluorocubane (4), 1,4-dichlorocubane (5), and N,N-diisopropylcubane-1,4-dicarboxamide (6) have been investigated by means of X-ray diffraction analysis. Fluorine and chlorine substituents cause a shortening of the vicinal bonds, as is seen in the 4-halocubane-1-carboxylates. The cage bonds vicinal to the ester substituent, with a favorable orientation with regard to the π-acceptor influence of this group become longer than the CH–CH bonds. Furthermore, the influence on bond length with respect to the orientation of this group relative to bonds within the cubane skeleton has been investigated experimentally. The effect of the methoxy group has also been found to depend on the orientation. The cage bond antiperiplanar to the methyl group is shortened, while the cage bonds in gauche orientation to this group are lengthened. As seen in the case of the halogen-substituted derivatives, the bonds bearing the acetoxy substituent are shortened due to the σ-acceptor property of this group. Ab initio calculations on compounds 1, 2, 4, and 5 performed at the 6-31G* level confirm the experimental results.

Organoplatinum compounds: VI . Trimethylplatinum thiomethylate and trimethylplatinum iodide. The crystal structures of [(CH 3) 3PtS(CH 3)] 4 and [(CH 3) 3PtI] 4·0.5CH 3I

During the course of our platinum cluster investigations [(CH 3) 3PtS(CH 3)] 4 ( 1) was synthesized according to Hall et al. (J.R. Hall, D.A. Hirons, G.A. Swile, J. Organomet. Chem. 174 (1979) 355) [1]from [(CH 3) 3Pt(H 2O) 3] 2+SO 4 2- and SCH 3 - ions in aqueous solution; [(CH 3) 3PtI] 4·0.5CH 3I ( 2) was obtained as the first logically derived product from the oxidative addition of CH 3I to CODPt(CH 3) 2 in pure CH 3I solution as transparent yellow crystals (COD=1,5-cyclooctadiene). Compound ( 1) crystallizes in space group P 3 c1 and ( 2) in space group R 3 . Compound ( 1) is isostructural with tetrakis(trimethylplatinum azide) {(a) M. Atam, U. Müller, J. Organomet. Chem. 71 (1974) 435 and (b) K.-H. von Dahlen, J. Lorberth, J. Organomet. Chem. 65 (1974) 267} [2]; both the iodine and azide compounds have four tetramers in the unit cell. The unit cell dimensions of ( 1) are: a= b=1044(2) and c=3208(2) pm. For ( 2) we observe 12 tetramers in the unit cell and disordered solvent CH 3I in a 2:1 ratio resulting in a huge cell volume extremely extended along the c-axis with >90 Å: a= b=1021.39(4) and c=9055.5(8) pm. X-ray diffraction data refinements converged at R=0.048 and Rw=0.039 for [(CH 3) 3PtS(CH 3)] 4 and at R=0.0599 and wR 2=0.1013 for [(CH 3) 3PtI] 4·0.5CH 3I. A distorted ‘cubane skeleton’ is found for [(CH 3) 3PtS(CH 3)] 4 with octahedrally coordinated platinum atoms and tetrahedrally coordinated sulfur atoms. In ( 2) we have a similar skeleton but with two independent tetrameric molecules in the unit cell.

A new class of flexible energetic salts, part 2: The crystal structures of the cubane-1,4-diammonium dinitramide and cubane-1,2,4,7-tetraammonium dinitramide salts

The crystal structures of cubane-1,4-diammonium dinitramide, 1, and cubane-1,2,4,7-tetraammonium dinitramide, 2, have been determined. 1 crystallizes in the space group P21/c with cell dimensions a = 6.018(2), b = 11.642(3), c = 9.754(3) A, β = 107.24(2), while 2 crystallizes in the space group P21/c with cell dimensions a = 9.401(4), b = 9.603(3), c = 12.603(4) A, β 111.08(3). In these structures the ammonium substituents are symmetrically attached with respect to the cubane skeleton and have neither low lying empty orbitals nor available lone pairs of electrons thus they have a minimal effect on the metrical parameters of the cubane skeleton. All C–C bond lengths are close to the overall average C–C bond length for all reported cubanes of 1.559 A. The conformations adopted by the dinitramide ions in both structures are quite different, with the bend, twist, and torsion angles for the dinitramide ion in 1 being significantly larger than those found for the dinitramide ions in 2, due to the different types of hydrogen bonding found in the two structures. In 2, the conformation adopted by the adjacent ammonium ions allows two of the three protons from each ammonium cation to form hydrogen bonds in such a manner that they span either the syn or the anti oxygen atoms of a single dinitramide anion. The dinitramide anion is thus constrained by these interactions and is less free to twist and bend. These results provide further confirmation that the metrical parameters of both the cubane and dinitramide moieties are flexible and reflect their local environment.