Periselectivity

The frontier orbitals, however, are clearly set up to make the longer conjugated system of the tropone more reactive than the shorter. The coefficients of the frontier orbitals of tropone were given in Fig. 6.33. The largest coefficients of the LUMO of tropone are at C-2 and C-7 (Fig. 6.56a), with the result that bonding to these sites lowers the energy more than bonding to C-2 and C-3 (Fig. 6.56b), when this frontier orbital is the 

However, carbenes react with dienes 6.457 to give vinylcyclopropanes 6.458, avoiding the symmetry-allowed [2 + 4] cycloaddition with a linear approach giving cyclopentenes 6.456. Almost the only exceptions to this pattern are the reaction of difluorocarbene with norbornadiene, where a [2 + 2 + 2] reaction is in competition with the [2 + 2],934 and the [2 + 4] pathway taking place in the opposite direction in the easy loss of carbon monoxide from strained cyclopentenones as in the decarbonylation 6.408 6.409. 

The reason why the C=C double bond of a ketene does not react as the 2S component of a [n2s+K4s] reaction, giving the adduct 6.460, is that the orbital localised on the C=C double bond is at right angles to the 

In open-chain and in some cyclic systems, therefore, reactions often take the path which uses the longest part of the conjugated system consistent with a symmetry-allowed reaction, but several other factors, spatial, entropic, steric, and so on, have obviously to be taken into account. Thus various sesquifulvalenes, with HOMO coefficients in the parent system 6.467, react in a variety of ways. The reaction giving the [8 + 2] adduct 6.468 finds the sites with the highest Zc2 value, but the three reactions with tetracyanoethylene giving the adducts 6.469-6.471 show different selectivities, for no obvious reason. These examples serve to emphasise the pitfalls of a too easy application of frontier orbital theory. 

More readily identifiable geometrical factors probably outweigh the contribution of the frontier orbitals in the remarkable reaction 6.47 between tetracyanoethylene and heptafulvalene giving the adduct 6.49 (see p. 261). The HOMO coefficients for heptafulvalene 6.420 (see p. 347) are highest at the central double bond, but a Diels-Alder reaction, with one bond forming at this site is impossible. The best reasonable possibility for a pericyclic cycloaddition, from the frontier orbital point of view, would be a Diels-Alder reaction across the 1,4-positions (HOMO coefficients of -0.199 and 0.253), but this evidently does not occur, probably because the carbon atoms are held too far apart. This is well-known to influence the rates of Diels-Alder reactions cyclopentadiene reacts much faster than cyclohexadiene, which reacts much faster than cycloheptatriene (see p. 302). The only remaining reaction is at the site which actually has the lowest frontier-orbital electron population, the antarafacial reaction across the 1, f-positions, which have HOMO coefficients of —0.199. 

However, carbenes react with dienes to give vinylcyclopropanes 6.302, avoiding the [2 + 4] cycloaddition with a linear approach giving cyclopentenes 6.299. We have seen that the cyclopropane-forming reaction is allowed when it uses a nonlinear approach 6.130, but we need to consider why the nonlinear approach is preferred when the linear approach giving a cyclopentene could profit from overlap to the atomic orbitals with the two large coefficients at the ends of the diene. 

One factor which must be quite important is the low probability that the diene is in the s-cis conformation 6.300 necessary for overlap to develop simultaneously at both ends. Since the cyclopropane-forming reaction can take place in any 

SCHEME 4.8 Indoles reacted with dienes demonstrate the high regioselectivity associated with ETC reactions. 

C-1 or C-4 of the diene allow for allylic conjugation and stabilization by substituents at C-1 or C-2 as shown in 31 and SI , respectively. 

In the cycloaddition of a conjugated system, there are three different situations to be considered (a) the entire conjugated array of electrons is involved, (b) a large part of the conjugated array of electrons is involved, and (c) only a small part of the 

The cycloaddition of 8 with dimethyl acetylene dicarboxylate 9 to generate 10 [2, 3], the electrocyclic ring closures 11 12 and 14 15 (8 electron conrotatory 

The exclusive acid-catalyzed transformations of hydrazobenzene 29 into 4,4 -diaminodiphenyl 30, A-phenyl-A -(2-thiazolyl)hydrazine 31 into 2-amino-5- 

It is important to understand whether indeed the above predominant selectivity arises solely on account of the FMO coefficients consideration or the thermodynamic factor, the thermodynamic stability of the product in particular, has any role in it. The species 6 and 15 are calculated to be more stable than the species 7 and 16 by 9.2 and 24.08 kcal mol-1, respectively, at the HF/6-31G level of theory. Further, the species 19 is more stable than the alternate species 22 and 23 by 13.8 and 2.53 kcal mol-1, respectively. From the observation that only the most stable products 6, 15, and 19 are formed, one may tend to infer that the thermodynamic factor may also have contributed to the observed selectivity. 

On the contrary, the species 12 is less stable than 13 by 6.2 kcal mol 1 and yet 12 is formed predominantly. Likewise, 26 is less stable than 27 by 4.1 kcal mol 1 and yet the formation of 26 competes reasonably well with the formation of 27 so much so that both 26 and 27 are formed in about 1 2 ratio. It is equally noteworthy that 28 is more stable than both 26 and 27 by 4.6 and 0.53 kcal mol1, respectively, and yet none of 28 is formed. 

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Bis(tnfluoromethyl)-4,5-dihydrooxazin-6-ones [28] and their O-acetylated dcnvatives [96] are formed on treatment of acyl imines with acetyl chloride-hiethylamine at room temperature. The reaction was interpreted as a cycloaddition reaction involving a ketene [28] However, the periselectivity and regiochemistry of this reactwn-are not in agreement with results obtained from the reaction of... 

The azomethine imines exhibit the typical cycloaddition behavior expected of 1,3-dipolar species [fSJ] Numerous [3+2] cycloaddition reactions have been performed [201 204] Tetracyanoethylene adds to azomethine imines across the nitnle function instead of the C=C double bond This reaction is a rare example of this type of periselectivity [208] (equation 47)... 

In contrast, when ot,P-unsaturated multiple bond systems act as dienophiles in concerted [4+2] cycloaddition reactions, they react across the C=C double bond Periselectivity as well as regiochemistry are explained on the basis of the size of the orbital coefficients and the resonance integrals [25S]... 

Thermally allowed [6 + 4] cycloadditions offer the attractive features of high stereoselectivity and rapid increase of molecular complexity. The limiting feature of many higher-order processes, however, is a lack of periselectivity that translates directly into the relatively low chemical yields of the desired cycloadducts. 

The periselectivity of the tropone-diene cycloaddition is dependent on the reaction temperature. The exo [6 + 4] cycloadduct is considered to be the kinetic product, the endo [4 + 2] cycloadduct being the thermodynamic product291. 

Gandolfi and coworkers301 studied the periselectivity in the reactions of substituted cyclopentadienones with iV-aryl-8-azahcptafulvcncs. The reactions proved to produce mainly [6 + 4] cycloadducts, along with some [8 + 2] and [4 + 2] cycloadducts, as illustrated by the reaction between azaheptafulvene 488 and cyclopentadienone 489 which... 

An interesting problem of the periselectivity arises in the rearrangement involving an a-oxyallylic carbanion as the terminus. In this particular case, the [l,4]-shift may compete with the [1,2]-Wittig rearrangement (see Section n.C). For example, the rearrangement of 5 affords a mixture of the [l,4]-product 6 and the [l,2]-product 7 (equation 5) °. 

The isoxazole analogue 273 underwent a similar process via a completely periselective intramolecular reaction with the C=C of the isoxazole (Isox) (168). 

Such cycloadditions are dependent on the interactions of the azepine HOMO and the diene LUMO. Theoretical consideration of these orbitals reveals that bonding overlap is favourable for C-6—C-7 and C-4—C-5 additions and that, on the basis of secondary orbital interactions, the endo product is favored. Experimentally, however, it is found that additions are periselective and C-4—C-5 addition predominates in the cycloaddition of 1//-azepines with cyclopentadienones, isobenzofurans, tetra- and hexa-chlorocyclopentadienes, 1,2,4,5-tetrazines, a-pyrones and 3,4-diazacyclopentadienones (8lH(15)1569). 

Scheme 21). Fusion of a cyclohexyl ring at C2-C3 66 (n = 2) also led to the formation of pyrazoles 68, whereas the fusion of a cyclopentyl ring at C2-C3 66 (n = 1) led to a complete change in periselectivity, the benzodiazepines 67 being the only observed products (Scheme 22) [75JCS(P1)102]. 

This difference in periselectivity was rationalized in terms of greater separation of the termini in the cyclopentyl fused compound 69, requiring a greater distortion of the diazo group to achieve cyclization. This distortion has a large energy barrier and so the 1,7- becomes preferable to 1,5-electrocyclization. The 1,5-ring closure also leads to a more strained product, a 5,5-fused system, than that formed from the cyclohexyl fused compound 70, which also has a smaller separation between the termini of the 77 system. 

It is frequent but not invariable that where a longer conjugated system has a geometrically accessible and symmetry-allowed transition structure like that in 5.90, the longer system is used. Thus, the [8+2] and [6+4] cycloadditions on pp. 15 16, and the [14+2] cycloaddition on p. 44 take place rather than perfectly reasonable Diels Alder reactions, and the 8-electron electrocyclic reactions of 4.51 and 4.54 takes place rather than disrotatory hexatriene-to-cyclohexadiene reactions. This kind of selectivity is called periselectivity. 

Dramatic changeover is observed not only in the ene/HDA product ratio, but also in the absolute stereochemistry upon changing the central metal from Ti to Al. Thus, Jprgensen et al. reported the HDA-selective reaction of ethyl glyoxylate with 2,3-dimethyl-1,3-butadiene catalyzed by a BINOL-derived Al complex [25], where the HAD product was obtained with up to 89% periselectivity and high enantiopurity (Scheme 8C.9). The absolute configuration was opposite to that observed by using BINOL-Ti catalyst. 

Acenaphthylene, indene, and styrene undergo periselective 4 + 2-cycloaddition with 3-ethoxycarbonyl-2//-cyclohepta[Z>]furan-2-one in high yield.152... 

Abstract The main computational studies on the formation of (3-lactams through [2+2] cycloadditions published during 1992-2008 are reported with special emphasis on the mechanistic and selectivity aspects of these reactions. Disconnection of the N1-C2 and C3-C4 bonds of the azetidin-2-one ring leads to the reaction between ketenes and imines. Computational and experimental results point to a stepwise mechanism for this reaction. The first step consists of a nucleophilic attack of the iminic nitrogen on the sp-hybridized carbon atom of the ketene. The zwitterionic intermediate thus formed yields the corresponding (3-1 actant by means of a four-electron conrotatoty electrocyclization. The steroecontrol and the periselectivity of the reaction support this two-step mechanism. The [2+2] cycloaddition between isocyanates and alkenes takes place via a concerted (but asynchronous) mechanism that can be interpreted in terms of a [n2s + (n2s + n2s)] interaction between both reactants. Both the regio and the stereochemistry observed are compatible with this computational model. However, the combination of solvent and substituent effects can result in a stepwise mechanism. 

Scheme 5 [2+2] and [4+2] periselectivity in the reaction between ketenes and a,(3-unsaturated imines... 

Figure 4 shows the main geometric features of the transition structures associated with the [n4c] and [n6d] steps in the reaction between ketene and prop-2-en-l-imine. Experimental and computational studies [42, 43] showed that the periselectivity of this reaction is very sensitive to substituent effects. Thus, in general disubstituted ketenes and/or imines possessing bulky substituents at the (3-position favor the formation of [2+2] cycloadducts because of severe steric... 

Intramolecular Diels-Alder reaction (with high periselectivity and good yields) of conjugated carbodiimides, catalyzed by Lewis acids, affords a simple procedure for the construction of pyrido[2,3-h]indole and indolo[2,3-ft]quinoline ring systems (equation 176)631. This procedure is superior to the often mixed reactions that occur in the absence of the Lewis acid632-635. It is interesting to note that Lewis acids also improve yields and selectivity in intermolecular reactions of this type636. 

Herndon and co-workers4 developed a model for predicting regioselectivity which has been adapted to periselectivity problems by Paddon-Row.64 It makes two assumptions (a) the two reaction partners approach in parallel planes and (b) the distance between these planes is the same in all reactions. The second is a serious constraint, which explains a success rate of 14 correct predictions out of 17 cases (82%). The model is more reasonable when applied to regioselectivity, where two different orientations of the same cycloaddition are compared (122 correct predicttions in 133 cases, i.e. 91.7%).5 Nonetheless, to the best of our knowledge, FO theory provides the only simple way to study periselectivity available at present. 

Condition (3) is often poorly satisfied for periselectivity, where the difficulties associated with rules 2 and 3 are often combined. Furthermore, whereas regioselectivity can be treated qualitatively, periselectivity requires a quantitative approach, so assumptions concerning transition state geometries must also be made. 

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