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Molecular mechanics (MM) with MMFF94 and MMX force-fields and ab initio (RHF/6-31G*,RHF/6-311G** and B3LYP/6-311G** ) calculations are used with LIS to investigate the conformations of N-methyl-2-pyrrolidone 1, N-methyl-2-piperidone 2, e−caprolactam 3, γ-valerolactam (1,5-dimethyl-2-pyrrolidone) 4, 2-azetidinone 5, 4-methyl azetidinone 6, 4-phenyl azetidinone 7, and N-methyl-4-phenyl azetidinone 8. The Yb(fod)3 paramagnetic induced shifts of all the 1H and 13C nuclei are measured and the corresponding diamagnetic complexation shifts obtained by the addition of Lu(fod)3. The complexation model (two-, three- or four-site) used depends on the relative rates of the processes involved. The amide inversion is the same order as that of the five and six membered lactam rings and much faster than the lanthanide complexation and the inversion of the seven membered ring. Both MM and ab initio calculations give an envelope conformation for 1 with C-4 out of the ring plane in agreement with the LIS analysis. For the piperidone ring of 2 the half-chair is calculated as the most stable form. The LIS analysis confirms this but cannot exclude a small amount ( 1.5%). In 4-phenyl azetidinone 7 the MMFF94 geometry with 60% of the axial conformer gave Rcryst 1.2% but the other geometries Rcryst > 1.5%. In contrast the N-methyl-4-phenyl-2-azetidinone 8 gave good agreement for all the geometries. The butterfly conformation gave Rcryst 1.1% for 80% of the axial conformer and the planar geometries Rcryst 0.98%. The LIS results confirm the ab initio and MM optimised geometries but the conformer energies at times differ from the calculated values. They also differ considerably from the corresponding values for the lactones studied previously and possible reasons for this are discussed.

A refined Lanthanide-Induced-Shift Analysis (LISA) is used with molecular mechanics and ab initio calculations to investigate the conformations of benzamide (1), N-methylbenzamide (2), N,N-dimethylbenzamide (3) and the conformational equilibria of 2-fluoro (4), 2-chloro (5) and N-methyl-2-methoxy benzamide (6). The amino group in 1 is planar in the crystal but is calculated to be pyramidal with the CO/phenyl torsional angle (ω) of 20–25°. The LISA analysis gave acceptable agreement factors (Rcryst ≤ 1%) for the ab initio geometries when ω was decreased to 0°, the other geometries were not as good. In 2, the N-methyl is coplanar with the carbonyl group in all the geometries. Good agreement was obtained for the RHF geometries, with ω 25°, the other geometries were only acceptable with increased values of ω. In 3, good agreement for the RHF and PCModel geometries was found when ω was changed from the calculated values of 40° (RHF) and 90° (PCModel) to ca. 60°, the X-ray and B3LYP geometries were not as good. The two substituted compounds 4, 5 and 6 are interconverting between the cis (O,X) and trans (O,X) conformers. The more stable trans conformer is planar in 4 and 6 but the cis form non-planar. Both the cis and trans conformers of 5 are non-planar. There is an additional degree of freedom in 6 due to the 2-methoxy group, which can be either planar or orthogonal to the phenyl ring in both conformers. The conformer ratios were obtained from the LISA analysis to give Ecis-Etrans in 4 > 2.3 kcal/mol (CDCl3) and 1.7 kcal/mol (CD3CN), in 5 0.0 kcal/mol (CD3CN) and in 6 > 2.5 kcal/mol (CDCl3) and 2.0 kcal/mol (CD3CN). These values were used with the observed versus calculated 1H shifts to determine the conformer ratios and energies in DMSO solvent to give Ecis-Etrans 1.1, −0.1 and 1.8 kcal/mol for (4), (5) and (6). Comparison of the observed versus calculated conformer energies show that both the MM and ab initio calculations overestimate the NH..F hydrogen bond in (4) by ca. 2 kcal/mol. Copyright © 2015 John Wiley & Sons, Ltd.

The base-induced cyclization of ( E )-2-aryl-1-[2-(benzylsulfonyl)phenyl]-1-nitroethenes to polysubstituted thiochroman S , S -dioxides exhibits a diastereoselectivity that can be oriented towards a selected isomer by means of appropriate adjustments of the experimental conditions. The interest of such a result also rests on the promising pharmacological activity of the products, whose structure encompasses different well-acknowledged pharmacophores. A conformational 1 H NMR investigation, backed by molecular-mechanics calculations, has also been accomplished.

A refined Lanthanide-Induced-Shift Analysis (LISA), in which both the paramagnetic and the diamagnetic lanthanide induced chemical shifts are normalised separately, is used with molecular mechanics (MMFF94) and ab initio (RHF/6-31G, RHF/6-311G** and B3LYP/6-311G**) calculations to investigate the conformations of methyl para-tolyl sulphoxide 1, sulphone 2 and sulphonate 3 and the conformational equilibria of methyl 2,4-dimethylphenyl sulphoxide 4 and sulphone 5. In 1 acceptable agreement factors (AFs) in the LISA analysis were only obtained when the SO/phenyl dihedral angle was increased from that (10–15°) of the computed geometries to 30–40°. The calculated geometries for 2 had the methyl group orthogonal to the phenyl ring and gave good AF in the LISA analysis. In both compounds, the AF were in the order MMFF94 ≤ B3LYP

3-Alkyl-3-chloro-4-chloromethyl-γ-lactones were synthesized in acceptable yields, exploiting the CuCl-N,N,N′,N″,N″-pentamethyldiethylenetriamine catalyzed atom transfer radical cyclization (ATRC) of O-allyl-2,2-dichlorohemiacetal acetates, starting materials easily prepared from 2,2-dichloroaldehydes. The oxidation of the intermediate dichloro-2-acetoxytetrahydrofurans was completed in a two-step, one-pot procedure: hydrolysis to γ-lactol and final oxidation to lactone with Jones' reagent.

(1 E ,3 Z )-1-Aryl-4-methanesulfonyl-2-nitro-1,3-butadienes ( 8 ), derived from the initial ring-opening of 3-nitrothiophene ( 5 ), have been found to undergo a facile base-induced cyclization leading to thiopyran S , S -dioxides ( 9 ), thus furnishing a further example of effective ring-enlargement from 5- to 6-membered sulfur heterocycles. Compounds 9 are obtained as single racemic mixtures in satisfactory yields; they still contain a nitrovinylic moiety, which can be exploited for further modifications targeted to new derivatives endowed with either synthetic or pharmacological potentialities e.g., in the field of L-type Ca 2+ -channel blockers.

With the goal of their exploitation for the synthesis of heterocycles, sulfides 10 and sulfones 11, derived from the initial ring-opening of 2-nitrothiophene (5) with pyrrolidine/AgNO3 in EtOH, were reacted with diazomethane. Interesting dichotomic behavior was found to yield pyrazolines 17 from 10 and isoxazolines 18 (as the main products) from 11. Intriguingly enough, in the latter case, an unexpected apparent C-C methylene insertion was also observed, leading to the homologous cyclopropanes 19 as secondary products.

[reaction: see text] In prosecution of previous work on the thermal cyclization of 1-aryl-4-methanesulfonyl-2-nitro-3-phenylsulfonyl-1,3-butadienes (7), the 3-unsubstituted derivatives 8, deriving from the initial ring opening of 3-nitrothiophene (2), have been likewise found herein to undergo cyclization, followed by aromatization, in analogous mild experimental conditions, leading to the ring-fused homo- or heteroaromatic nitro derivatives 10. The concerted electrocyclic nature of the process is strongly supported by the outcome of tests based on the variation of the polarity of the solvent or of the electron density on the aryl of 8. Thus, the successful application of the process to the non-phenylsulfonyl-activated 8 significantly widens the scope of a synthetically valuable overall ring-opening/ring-closing procedure from nitrothiophenes. Support to the recently renewed interest in thermal 6pi electrocyclizations as a tool for the construction of the benzene ring is furthermore provided.

Within an overall ring-opening/ring-forming protocol, the (E,E)-4-methylthio-2-nitro-3-phenylsulfonyl-1-pyrrolidino-1,3-butadiene (7) [derived from the initial opening of 3-nitro-4-(phenylsulfonyl)thiophene (6) with pyrrolidine and silver nitrate in EtOH] is revealed to be an excellent precursor of nitro(phenylsulfonyl) derivatives of ring-fused aromatic (naphthalene, phenanthrene) or heteroaromatic (benzothiophene) compounds whose substitution pattern cannot be easily achieved by conventional methods. The key step is represented by a thermal electrocyclic rearrangement of (E,E)-1-aryl-4-methylsulfonyl-2-nitro-3-phenylsulfonyl-1,3-butadienes (9), which, thanks to proper geometric and electronic factors, occurs in unprecedentedly mild conditions and is followed by an irreversible, concerted syn β-elimination of methanesulfinic acid to aromatize the newly formed cyclohexadienic ring.

Temperature-dependent 1 H- NMR experiments on the cyclic tetramers 1a, 1b, and 1c, obtained through reaction of the appropriate 3,5-disubstituted 4-hydroxybenzenesulfonyl chlorides and aliphatic tertiary amines in aprotic solvents, indicate that these cyclic compounds retain conformational flexibility. Free energies for the intra-annular rotation of the substituted benzene rings have been determined from the rate constants at the coalescence temperature. The influence of the nature of the ring substituents on the conformational barrier has been evaluated.

An improved LIS technique, using Yb(fod)3 to obtain the paramagnetic induced shifts of all the spin ½ nuclei in the molecule, together with complexation shifts obtained by the use of Lu(fod)3, has been used to investigate the conformations of a group of epoxides. These are cis (1) and trans (2) stilbene oxide, cyclopentene oxide (3), cyclohexene oxide (4), cycloheptene oxide (5), propene oxide (6) and styrene oxide (7).The LIRAS3 complexation model involving two symmetric lone pairs on the oxygen atom was used for the symmetric compounds but, for the unsymmetric compounds, a more complex unsymmetric complexation model (HARDER) was found to be necessary. The calculated LIS for styrene oxide and cis- and trans-stilbene oxide were in excellent agreement with the observed data for both the molecular mechanics (MM) and the ab initio geometries with the phenyl ring dihedral angles optimised.In styrene oxide and trans-stilbene oxide the phenyl rings are approximately perpendicular to the oxirane ring, in agreement with the conformation in the solid state and with the theoretical calculations. In cis-stilbene oxide steric repulsions between the phenyl rings splay them apart so that they are now exo to the oxirane ring. Again the LIS analysis is in good agreement with the theoretical calculations.Both the LIS data and the modelling studies agree that cyclopentene oxide is in a boat conformation with an angle of pucker of ca. 30° and that cyclohexene oxide is in a half-chair conformation with C4 and C5 displaced from the ring plane.The LIS analysis of cycloheptene oxide gave good agreement for two equilibrating chair conformations with an endo/exo ratio of 70∶30, in excellent agreement with low temperature NMR data.The accurate reproduction of the LIS data provides an unambiguous method of assigning the proton chemical shifts of the individual methylene protons in the cyclic epoxides, which are not easily available by any other technique.

An improved LIS technique, using Yb(fod)3to obtain the paramagnetic induced shifts of all the spin 1/2 nuclei in the molecule, together with complexation shifts obtained by the use of Lu(fod)3, has been used to investigate the conformations of several lactones. The appropriate complexation model was obtained by investigations on the planar well-defined structures of isocoumarin (1) and coumarin (2). This complexation model was then used to investigate the conformations and conformational equilibria in 3,4-dihydrocoumarin (3), β-butyrolactone (4), γ-valerolactone (5), δ-valerolactone (6) and Iµ-caprolactone (7).3,4-Dihydrocoumarin is puckered with both C2 and C3 displaced from the benzene ring plane. β-Butyrolactone is planar. γ-Valerolactone interconverts between the two envelope conformations with C4 out of the plane of the other ring atoms with 70% of the conformer with a pseudo-equatorial methyl group. For δ-valerolactone the two interconverting conformations are the half-chair and the boat form and analysis of the data suggests that there is ca. 20% of the boat form. In Iµ-caprolactone the LIS data gives a well-defined minimum for 100% of the chair form with no other significantly populated conformer. The LIS results agree with both the ab initio and MM optimised geometries and the observed and calculated conformer energies are in reasonable agreement to give ΔG (ax–eq) 0.6 kcal mol-1 for γ-valerolactone, ΔG (boat–half-chair) 0.9 kcal mol-1 for δ-valerolactone and ΔG (boat–chair) > 3.5 kcal mol-1 for Iµ-caprolactone.

The behaviour towards gas-phase protonation of a series of 2,6-dimethyl-4-X-acetophenones DM1 exhibits strong similarities with that of the corresponding 4-X-acetophenones 1 . A comparison with previous basicity data in solution and AM1 semiempirical calculations suggest that the X-dependent rotation of the probe group out of the plane of the aromatic ring caused by the two ortho methyls is of minor importance in influencing the substituent effect on the gas-phase basicity of DM1 ; on the contrary, it could heavily affect the solvatability and thus be responsible for the observed behaviour of DM1 in strongly acidic media.

An improved LIS technique, using, Yb(fod)3 to obtain the paramagnetic induced shifts of all the spin ½ nuclei in the molecule, together with complexation shifts obtained by the use of Lu(fod)3 has been used to investigate conformational isomerism in 2-fluorobenzaldehyde 1, 2-fluoroacetophenone 2, methyl 2-fluorobenzoate 3 and the corresponding 2-trifluoromethyl compounds 4, 5 and 6. The use of fluorine LIS in these molecules was first established by analysis of the LIS in 4-fluorobenzaldehyde 7 and 4-trifluoromethylbenzaldehyde 8 in which conformational isomerism is not possible and confirmed in subsequent analyses. It is shown that 19F LIS may be used with the same degree of confidence as the corresponding 1H and 13C LIS in theses molecules. Analysis of the LIS data was considered together with ab initio, modelling and solvation calculations to provide a comprehensive account of the conformer geometries and energies for these compounds in a variety of solvents. The 2-fluoro compounds are all planar, with the trans (CO···F) conformer always more stable, in 1 and 2 predominating in all but very polar solvents. In the corresponding 2-trifluoromethyl compounds both the cis and trans conformers of the aldehyde 4 are planar with the trans form predominating, but the ketone 5 is essentially in one orthogonal conformation and the ester 6 interconverting between two nonplanar conformations with the trans conformer predominant.

A 13C NMR study has been carried out in (CD3)2SO on the thiophene derivatives 5 and 7 and the related Meisenheimer adducts 6 and 8. The data obtained, and in particular the sums of the chemical-shift changes (ΣΔδ) at C-3, C-4 and C-5, accompanying the formation of the adducts, are compared with the corresponding data previously obtained for analogous substrates 1 and 3 and adducts 2 and 4. The four series of ΣΔδ values are then examined in the light of the already reported thermodynamic (Ke) and kinetic (k1) constants for the formation of the adducts. For a given X-substituent, log Ke values increase linearly as the corresponding absolute ΣΔδ values decrease. On these grounds, the smaller π-electron-density rearrangement accompanying the formation of gem-dimethoxy adducts emerges as an important factor, contributing to the larger observed Ke values. A further outcome is that, within a single series of adducts, a linear relationship of either log Ke or log k1 with Δδ holds only when excluding the terms with X = Ac or NO2. Such findings are interpreted on the basis of the two-component nature of the substituent –R effects: while for the nitro and the acetyl substituents the π-electron acceptor component is prevalent, the stabilizing effect of the other substituents is due mainly to a charge–dipole interaction. The analysis of some literature data for the benzene series fits the above conclusions.

An improved LIS technique, using Yb(fod)3to obtain the paramagnetic induced shifts of all the spin 1/2 nuclei in the molecule, together with complexation shifts obtained by the use of Lu(fod)3, has been used to investigate the conformations of several lactones. The appropriate complexation model was obtained by investigations on the planar well-defined structures of isocoumarin (1) and coumarin (2). This complexation model was then used to investigate the conformations and conformational equilibria in 3,4-dihydrocoumarin (3), β-butyrolactone (4), γ-valerolactone (5), δ-valerolactone (6) and Iµ-caprolactone (7).3,4-Dihydrocoumarin is puckered with both C2 and C3 displaced from the benzene ring plane. β-Butyrolactone is planar. γ-Valerolactone interconverts between the two envelope conformations with C4 out of the plane of the other ring atoms with 70% of the conformer with a pseudo-equatorial methyl group. For δ-valerolactone the two interconverting conformations are the half-chair and the boat form and analysis of the data suggests that there is ca. 20% of the boat form. In Iµ-caprolactone the LIS data gives a well-defined minimum for 100% of the chair form with no other significantly populated conformer. The LIS results agree with both the ab initio and MM optimised geometries and the observed and calculated conformer energies are in reasonable agreement to give ΔG (ax–eq) 0.6 kcal mol-1 for γ-valerolactone, ΔG (boat–half-chair) 0.9 kcal mol-1 for δ-valerolactone and ΔG (boat–chair) > 3.5 kcal mol-1 for Iµ-caprolactone.

Following a previous experiment, an original heteropolycyclic structure 4 was obtained by a reaction of chloroacetyl chloride with compound 3 bearing a conjugated double bond system. The condensation develops with an initial NH-chloroacetylation and ring closure by quaternarization of the pyridine nitrogen. This is achieved through an 1,4-cycloaddition of chloroketene to make a pyranone ring.

The synthetically useful nucleophilic attack on nitrobenzo-[b]thiophenes, a starting point for ring-opening/ring-closure pathways to different heterocyclic systems, has been investigated in detail. 3-Nitrobenzo[b]thiophene (9) and 2-nitrob-enzo[b]thiophene (10) react with sodium methoxide in either DMSO or methanol to give the relevant "Meisenheimer-type" adducts 9' and 10', identified by NMR spectroscopy. A UV study indicated that the equilibrium constants for the formation of 9' at 293 K are 10.1 and 40700 L mol -1 in methanol and in DMSO, respectively. Competition reactions showed that the stability constant of 10' is lower than that of 9': accordingly, DFT [B3LYP/6-31+G(d,p)] calculations indicate that the formation of 9' is thermodynamically more favoured than that of 10' both in the gas phase and in DMSO. The reason for the opposite sequence in the stability constants previously found for the corresponding gem-dimethoxy Meisenheimer adducts 7' and 8' was therefore investigated in depth and appears to be a consequence of different steric interactions in the starting compounds, 2-methoxy-3-nitro-(7) and 3-methoxy-2-nitrobenzo[b]thiophene (8), respectively. A study of 13 C NMR chemical shift changes accompanying the formation of adducts 9' and 10' confirms that the formation of the adduct exhibiting the larger stability constant is accompanied by a smaller π electron density redistribution, as we have previously found in other cases all governed by electronic effects. The opposite behaviour is observed in the formation of the gem-dimethoxy adducts 7' and 8', which is a consequence of the predominance of steric effects. Further outcomes of more general interest deal with the aromatic character of benzo[b]thiophenes. NMR spectroscopic data and calculated bond lengths show that in the studied reactions the benzene ring, unlike the thiophene one, is scarcely affected by methoxide addition, retaining its nearly "full" aromatic character. Benzocondensation increases the stability constants of σ-adducts mainly because of a marked reduction in the aromatic character of the thiophene ring in the substrates.

A LIS analysis of 2-isopropyl-1,3-dioxane (1) and 2-methyl-2-phenyl-1,3-dioxane (2) is reported. The monodentate complexing model gives good agreement with the observed shifts in both compounds, whereas the bidentate model (lanthanum binding to both oxygens) does not give an acceptable solution. In 1 the lanthanide complexes almost exclusively (90%) with the axial lone pair of the oxygen atom. The four-site binding model gives excellent agreement with the observed shifts (Rx 3.5%). In 2 a similar lanthanide binding is found, and the analysis of the LIS allows both the deduction of the molecular conformation (C-2-methyl equatorial, C-2-phenyl axial) and also the orientation of the phenyl group (perpendicular).

A facile stereoselective synthesis of Knoevenagel-type compounds 8 and 9 was accomplished through a one-pot two-step procedure. The reaction of ethylenethiourea ( 1) and ethyleneurea ( 2) with benzoyl chloride- N, N-dimethylformamide complex in N, N-dimethylformamide gave the corresponding isolable ternary N-methyleniminium chlorides 3 and 4, along with benzoic acid ( 5) as a byproduct. Hydrolysis of salts 3 and 4 yielded the N-formyl derivatives 6 and 7, thus confirming the N-methyleniminium structure. Salts 3 and 4 condensed in situ at 120 °C with a variety of acyclic active methylene reagents Y-CH 2 -Z (Y = or ≠ Z), in the presence of 5 (Procedure A) or of 5 and triethylamine (1.5 equiv) (Procedure B), afforded α,β-unsaturated compounds 8 and 9. The overall yields ranged from poor to good. Mechanistic hypotheses concerning the formation of 3 and 4 and the origin of the stereoselectivity are also discussed.

4-Alkyl-2-nitrothiophenes [10: R = CH3, CH(OH)CH3, CH(OCH3)CH3] react with secondary aliphatic amines, in the presence of AgNO3, to give 3-alkyl-2-amino-5-nitrothiophenes (12) through an oxidative nucleophilic substitution of hydrogen (ONSH) of synthetic interest. This behavior is in striking contrast with that of the parent 2-nitrothiophene (6), which was found to undergo ring-opening in analogous reaction conditions. A possible rationale for the crucial effect of alkyl groups is suggested, grounded also on a study of the corresponding Meisenheimer-like adducts.

[reaction: see text] In prosecution of previous work on the thermal cyclization of 1-aryl-4-methanesulfonyl-2-nitro-3-phenylsulfonyl-1,3-butadienes (7), the 3-unsubstituted derivatives 8, deriving from the initial ring opening of 3-nitrothiophene (2), have been likewise found herein to undergo cyclization, followed by aromatization, in analogous mild experimental conditions, leading to the ring-fused homo- or heteroaromatic nitro derivatives 10. The concerted electrocyclic nature of the process is strongly supported by the outcome of tests based on the variation of the polarity of the solvent or of the electron density on the aryl of 8. Thus, the successful application of the process to the non-phenylsulfonyl-activated 8 significantly widens the scope of a synthetically valuable overall ring-opening/ring-closing procedure from nitrothiophenes. Support to the recently renewed interest in thermal 6pi electrocyclizations as a tool for the construction of the benzene ring is furthermore provided.

1-(Methyl-p-tolyl-amino)-3-phenoxy-2-azetidinones 4-COX and 4-R substituted (COX: X=Me, Et, Ph, NMe2, NEt2, OBut; R=Me, Et, Ph) were smoothly prepared from the corresponding α-(methyl-p-tolyl)hydrazonylated ketones, amides and esters via [2+2] cycloaddition with phenoxyketene. The reaction was generally high-yielding and diastereoselective, leading to β-lactams with a cis relationship between the PhO and the COX moieties, except for R=Ph, where an opposite stereoselectivity was instead observed. The azetidinones represent interesting intermediates which couple protection at N(1) and functionalization at position 4 of the ring. Deprotection of N(1) can be easily attained by oxidative N–N cleavage with magnesium monoperoxyphthalate.

The (E)-2-aryl-1-[2-(methylthio)phenyl]-1-nitroethylenes 5 can easily be oxidized to the relevant sulfones 6 and effectively subjected to cyclization via an intramolecular Michael addition after metallation with lithium bis(trimethylsilyl)amide in THF. After quenching with ammonium chloride the 3-aryl-4-nitrothiochroman S,S-dioxides 2 are obtained as diastereomeric mixtures in good to excellent yields. Both yields and stereochemistry of the ring-closure step appear to be influenced by steric effects of the 3-aryl moiety. As sulfides 5 derive from an initial ring opening of 3-nitrobenzo[b]thiophene ( 1 ), the overall 1 to 2 process can be considered as an effective 5 to 6 ring enlargement of the sulfur heterocycle. A conformational 1H NMR and molecular-mechanics investigation on the isolated diastereomeric 2 has also been accomplished.

Within an overall ring-opening/ring-forming protocol, the (E,E)-4-methylthio-2-nitro-3-phenylsulfonyl-1-pyrrolidino-1,3-butadiene (7) [derived from the initial opening of 3-nitro-4-(phenylsulfonyl)thiophene (6) with pyrrolidine and silver nitrate in EtOH] is revealed to be an excellent precursor of nitro(phenylsulfonyl) derivatives of ring-fused aromatic (naphthalene, phenanthrene) or heteroaromatic (benzothiophene) compounds whose substitution pattern cannot be easily achieved by conventional methods. The key step is represented by a thermal electrocyclic rearrangement of (E,E)-1-aryl-4-methylsulfonyl-2-nitro-3-phenylsulfonyl-1,3-butadienes (9), which, thanks to proper geometric and electronic factors, occurs in unprecedentedly mild conditions and is followed by an irreversible, concerted syn beta-elimination of methanesulfinic acid to aromatize the newly formed cyclohexadienic ring.

By means of an iodide-catalyzed nitrocyclopropane to 4,5-dihydroisoxazoline 2-oxide isomerization, the 1,1'-dinitro-(1,1')bi(cyclopropyl)s 5, deriving from an initial ring-opening of 3,4-dinitrothiophene 1, can be stereospecifically converted into the bisnitronates 6. From these, successive N-oxide reduction (P(OMe)3/dioxane) and aromatization (DDQ/toluene) provide convenient access to the interesting 4,5,4'5'-tetrahydro(3,3')bi-isoxazolyls 7, and (3,3')bi- isoxazolyls 8, respectively.

Substituent effects on 1 J CO,C1 in methyl 4-X-benzoates 1 and 2,6-dimethyl-4-X-benzoates 2 appear to be related with chemical-shift variations at the two involved carbon nuclei rather than with π-bond-order changes

The protonation of the title compounds has been studied in aqueous sulphuric acid at 25 °C. Relevant pKBH+ values have been calculated according to both modified Hammett and excess-acidity methods. The data obtained show that the para substituents exert practically the same electronic effects in the two series of amides in spite of the much larger torsion of the carbamoyl group out of the aromatic plane in the 2,6-dimethyl derivatives. The observed behaviour can be related to the internal conjugation of the carbamoyl group which strongly reduces that between the same group and the ring.

The rate and equilibrium constants for the formation of the Meisenheimer-type adducts [(6) and (8)] from some 4-nitro-2-X-(5) or some 2-nitro-4-X-thiophenes (7) and sodium methoxide have been measured at 25 °C in methanol or methanol–dimethyl suiphoxide mixtures. The observed stability and reactivity patterns have been interpreted in the light of the hyper-ortho relation in the thiophene ring and the special ability of the nitro group to stabilize effectively the adducts from a para-like position also.

Following a previous experiment, an original heteropolycyclic structure 4 was obtained by a reaction of chloroacetyl chloride with compound 3 bearing a conjugated double bond system. The condensation develops with an initial NH-chloroacetylation and ring closure by quaternarization of the pyridine nitrogen. This is achieved through an 1,4-cycloaddition of chloroketene to make a pyranone ring.

The protonation equilibria of some 4-X-acetophenones (1c–h, j–l) and their 2,6-dimethyl derivatives (2c, d, f–h, l) have been investigated in sulfuric acid at 298.0 K. Correlations of the pKBH+ values with the para-substituent constants evidence a markedly different sensitivity of the base strength of 1 and 2 to substituent effects [ρ+(1)= 1.20 ± 0.09, ρ(2)= 5.3 ± 0.5]. Solvation plays a major role in determining an attenuation (in 1) or an exaltation (in 2) of the substituent effect as suggested by the excellent correlation with gas phase basicities for the series 1 and by the behaviour of m* whose values are essentially constant for 1c–h, j–l(0.57 ± 0.03) but increase, in the series 2, as the base strength decreases (m* 0.48 for X = OMe, 1.08 for X = NO2). In 2 the steric inhibition of through-conjugation between the 4-X substituent and the carbonyl group also contributes to the observed trends. The 17O NMR chemical shifts for 1a–l and 2a–d, f–i, l in CDCl3 have also been collected: in 1 they appear to be related to the pKBH+ values and then to the carbonyl oxygen electron densities, whereas in 2 they are strongly influenced by the spatial location of the oxygen atom and/or of the relevant p-orbitals.

The possible use of Lu(fod)3vs. La(fod)3 in probing diamagnetic complexation contributions to the shifts induced Yb(fod)3 on the 1H and 13C NMR signals of aromatic ketones has been investigated. For all the compounds examined the patterns of the shifts caused by the two diamagnetic reagents are qualitatively similar, reflecting predominantly π-electron-density transmission. For the less activated substrates fluoren-9-one 1 and 2,6-dimethyl-4 nitroacetophenone 3 the use of either La(fod)3 or Lu(fod)3 yielded very similar sets of data, indicating in 3 a ca. 90° torsion angle between the acetyl and the ring. More interstingly, in the case of acetophenone 2, 2-acetylnaphthalene 4,3-methoxyacetophenone 5 and 2-methylacetophenone 6 the use of Lu(fod)3 gave a markedly improved definition of essentially the same solutions. These are a planer conformation for 2 a prevalence(ca. 68%) of the E conformer for 4 and of the Z conformer for 5 and 6(ca. 63% and 92%, respectively). In the case of 6 the geometries of the two conformers to be submitted to LIS analysis have been obtained through an ab initio RHF 6-13G* full-optimization process, indicating a planar structure for the Z and a 35°-rotated structure for the E conformer. In conclusion the analysis using Lu(fod)3, while supporting the results obtained with its lanthanum analogue, appears to reproduce better the diamagnetic contribution to induced shifts in strongly coordinating substrates. With the unhindred substrates 2, 4 and 5, where very reliable starting geometries could be adopted, solutions obtained through the use of Lu(fod)3 have been particularly good (Rcryst 0.2–0.4%), as pseudoconatact shifts ranging up to 130–150 ppm could be reproduced with an average absolute error of ±0.1 ppm. This shows how accurate the LIS method can be in the absence of additional problems and leaves little doubt about the accuracy of its theoretical background.

The behaviour of some benzoic acids both as bases (pKBH+) and acids (pKa*)has been compared with that of their 2,6-dimethyl derivatives. In particular the protonation equilibria, while assigning (through the value of the m* parameter of the excess-acidity method) a significant role to solvation as a stabilising effect on the cations, seem to further assess a major contribution of π-polarisation to the resonance effect of para-substituents, although some through-conjugation with electron-donating groups cannot be excluded, possibly enforced by the strong requirement for stabilisation of the positive charge in the protonated forms.

1,4-Dimethyl-2,3-dinitronaphthalene (1) reacts with sodium arenethiolates in DMSO to give 2-arylthio-1, 4-dimethyl-3-nitronaphthalene (3) [normal substitution product (NSP)] and 1-arylthiomethyl-4-methyl-3-nitronaphthalene (5) [tele-substitution product (TSP)]. The percentage of TSP is found to increase with the enhancement of the reaction temperature, the presence of electron-withdrawing substituents in the arenethiolate; the increase of steric hindrance in the nucleophile, and the substitution of two Et for two Me groups in 1. A mechanism, involving a partial tautomerization of 1 into 2,3-dinitro-4-methyl-1-methylene-1,2-dihydronaphthalene (7) followed by attack of the nucleophile on this tautomeric form, is suggested to account for the formation of TSP. The analogous reactions on 1,4-dimethyl-2,3-dinitrobenzene and 5,8-dimethyl- and 5,8-diethyl-6,7-dinitro-1,2,3,4-tetrahydronaphthalene yield only NSPs. Some double bonds localization together with steric compression in the congested naphthalene derivative are suggested to play an important role in driving the reaction along the tele-substitution pathway.

Interpretation of 1 H and 13 C lanthanide-induced N.M.R. shifts on adamantanone depends critically on the model chosen for lanthanide ion binding.

A rigorous error analysis of LIS is described which avoids the use of any normalising atom. This analysis is used to investigate the LIS of benzaldehyde and thiophen- and furan-2-aldehyde. The non pseudo-contact components of theYb(fod)3 induced shifts are isolated and found to be appreciable at the carbonyl carbon and the ortho and para carbons. Estimation of the diamagnetic contribution to these shifts withLa(fod)3 allows a precise analysis of the1H and13C LiS of these aldehydes without the need to invoke any contact shifts. The lanthanide-complex geometry found is essentially one-site, i.e. 100% population on the unhindered exo side of the carbonyl. The lanthanide is in the molecular plane of the aldehydes with Ln O and Ln.O.C. parameters ofca 2.5A˚and 140°, respectively. This procedure also gives the percent population of the O-cis conformer of furfural asca 70–75% in CDCl3 solution.

The solution conformation of bicyclo [3.1.0] hexan-3-one has been obtained by the use of the shifts induced in its 1H and 13C NMR by Yb(fod)3. Refinement of the angle of pucker, ∝, of the 5-membered ring indicates that the molecule adopts a flattened boat conformation with ∝ = 195°. This prediction is supported by ab initio, STO-3G, calculations on the isolated molecule. Use of a two- or four-site model for lanthanide-substrate complexing adequately reproduces the experimental data whereas a one-site binding model is unsatisfactory. The importance of multi-site binding is further emphasised by results for the C2v-symmetric ketone, adamantanone, where only a four-site model gives satisfactory agreement between observed and calculated lanthanide-induced shifts.

An L.I.S. N.M.R. investigation of conformational isomerism in meta-nitrobenzaldehyde and furan- and thiophene-3-aldehydes, and of the conformation of acetophenone has been carried out. With the diamagnetic (complexation) contributions to the observed shifts removed by means of experiments with La (fod)3 and the application of our previously-described lanthanide ion complexing model, the pseudo-contact shifts have been used to obtain the precise conformational preferences of the aldehydes. They exist to the extent of 45%, 100% and 80% respectively in the O - trans conformation, findings which are good agreement with the previously-reported values. The L.I.S.'s for acetophenone are in best agreement with a planar molecule, although the definition is not as good in this case. These examples suggest that the L.I.S. technique is of general applicability in the determination of conformer populations and the conformations of aromatic aldehydes and ketones.