Acyclic systems conformations

Careful conformational analysis of acyclic systems is needed. Hornoallylie Systems... 

Anions of small heterocyclics are little known. They seem to be involved in some elimination reactions of oxetan-2-ones (80JA3620). Anions of large heterocycles often resemble their acyclic counterparts. However, anion formation can adjust the number of electrons in suitable systems so as to make a system conform to the Hiickel rule, and render it aromatic if flat geometry can be attained. Examples are found in Chapter 5.20. Anion formation in selected large heterocycles can also initiate transannular reactions (see also Section 5.02.7 below). 

The anomeric effect is also present in acyclic systems and stabilizes conformations that allow antiperiplanar (ap) alignment of the C—X bond with a lone-pair orbital of the heteroatom. Anomeric effects are prominent in determining the conformation of acetals and a-alkoxyamines, as well as a-haloethers. MO calculations (4-3IG) have found 4kcal/mol as the difference between the two conformations shown below for methoxy-methyl chloride. ... 

In 1982 the present author discovered cyclic orbital interactions in acyclic conjugation, and showed that the orbital phase continuity controls acyclic systems as well as the cyclic systems [23]. The orbital phase theory has thus far expanded and is still expanding the scope of its applications. Among some typical examples are included relative stabilities of cross vs linear polyenes and conjugated diradicals in the singlet and triplet states, spin preference of diradicals, regioselectivities, conformational stabilities, acute coordination angle in metal complexes, and so on. 

In acyclic systems, the enolate conformation comes into play. p,(3-Disubstituted enolates prefer a conformation with the hydrogen eclipsed with the enolate double bond. In unfunctionalized enolates, alkylation usually takes place anti to the larger substituent, but with very modest stereoselectivity. 

A comparison of calculated and experimentally measured conformational energy differences for a small selection of singlerotor acyclic systems is provided in Table 8-1. The experimental data for some systems are subject to large uncertainties, and too much weight should not be placed on quantitative comparisons. 

SYBYL molecular mechanics is completely unsatisfactory for describing conformational energy differences in acyclic systems, and should not be employed for this purpose. On the other hand, the MMFF mechanics model provides a good account of all systems examined. In fact, the performance of MMFF is significantly better than any of the semi-empirical models, and in the same league as the best of the Hartree-Fock, local density, density functional and MP2 models (see discussion following). 

Surprisingly, the MP2/6-31G model is not as satisfactory as any of the density functional models, both insofar as mean absolute error and in terms of individual errors. Use of the 6-311+G basis set in place of 6-3IG leads to marked improvement, and the results are now of comparable quality to those of the best density functional models. Given the large difference in cost between density functional and MP2 models, and given the apparent need for basis sets larger than 6-3IG for the latter, it seems difficult to recommend use of MP2 models for the purpose of conformational analysis involving acyclic systems. 

MNDO, AMI and PM3 models are unsatisfactory for assignment of ground-state conformer and for calculation of conformational energy differences in acyclic systems. While this could have been anticipated, given the poor performance of semi-empirical models for other isodesmic processes (see discussion in Chapter 6), it is nevertheless disappointing. In many cases, semi-empirical models either yield the... 

As with acyclic systems, semi-empirical models provide a poor account of the ground-state conformation and conformational energy differences in cyclic systems. While all three models typically yield reasonable results for hydrocarbons, results for other systems are not acceptable. The performance of the PM3 model with regard to the... 

T1he conformational studies (I) on acyclic sugar derivatives and on aldopentopyranose derivatives that have been conducted in our laboratories during the last few years are surveyed, and some of our more recent results in each of these areas are introduced. For each aspect the sugar derivatives were examined in solution by proton magnetic resonance (PMR) spectroscopy, and the data obtained were used to provide conformational information. Acyclic systems will be treated first. 

During our further studies of ketone catalysts, ketone 16 was found to be highly enantioselective for a number of acyclic and cyclic d.s-olefins (Table 10.6).73-74 It is important to note that the epoxidation is stereospecific with no isomerization observed in the epoxidation of acyclic systems. Ketone 16 also provides encouragingly high ee s for certain terminal olefins, particularly styrenes.74-75 In general, ketones 1 and 16 have complementary substrate scopes. In our subsequent study of the conformational and electronic effects of ketone catalysts on epoxidation, ketone 17, a carbocyclic analog of 16, was found to be highly enantioselective for various styrenes (Table 10.7).76... 

The trouble is, in this conformation none of the oxygen lone pairs get the chance to donate into the C-O a orbitals. Although putting the bonds anti-periplanar to one another makes steric sense, electronically, the molecule much prefers to put the lone pairs anti-periplanar to the C-O bonds, so the bonds themselves end up gauche (synclinal) to one another. This is known as the gauche effect, but is really just another way in which the stereoelectronic effects that give rise to the anomeric effect turn up in acyclic systems. 

Ligands such as phosphoramidite (3) and TADDOLs (4) have proven to be remarkably discriminating in their reactions of cyclic cases. Due to interconversion between s-cis and s-trans conformers, acyclic systems have been far more challenging. Here, optically pure peptidic phosphines (e.g. 5) deliver products of 1,4-additions in good yields and high enantioselectivities (equation 9). 

In acyclic systems, Claisen rearrangements show a well-established prefoence for chair-like transition states. With crotyl propenyl ether, the chair selectivity amounts to 97-98% at 142 C, which corresponds to an approx. 3 kcal mol difference between the fiee energy of activation (AAG ) of chair and boat TS (equation 26). The preference for a chair-like geometry in the TS is even more pronounced in the Cope reaiT ement 99.7% of the 3,4-dimethylhexa-1,5-diene rearranges at 225 C via a chair-like TS, corresponding to a AAG chair-boat of -5.7 kcal mol" . - The latter result closely parallels the difference in energy of the chair and boat conformations of cyclohexane (5-6 kcal mol" ). ... 

Nucleophilic additions to cyclic carbonyl compounds differ greatly from those of acyclic systems. In acyclic systems, only the configuration at an adjacent (1,2-asymmetric induction) or nea y center (remote asymmetric induction) is usually considered in predicting the outcome of nucleophilic attack. In cyclic systems, the conformation of the entire molecule (which is in part determined by the individual substituents) must be considered when predicting the mode of nucleophilic attack. Furthermore, a number of other factors such as torsional and electronic effects also play a role in the stereochemical course of additions to cyclic substrates. The relative importance of all of these effects (as well as others) has been the subject of considerable debate in the literature, and has not as yet been adequately resolved. ... 

Diastereofacial selection in nucleophilic additions to acyclic aldehydes and ketones is of major importance in synthetic organic chemistry." The greater conformational freedom of acyclic systems makes predictions as to the stereochemical outcome of such reactions more difficult than when the carbonyl group is contained within a cyclic framework. 

An instructive example of a 7i-facial, homoallylic OH-directed stereoselective epoxidation in an acyclic system, used for the construction of the natural product monensin, is depicted belowC As expected, the more electron-rich trisubstituted double bond in A would be more susceptible to epoxidation than the terminal double bond. To minimize allylic 1,3-strain between the ethyl group and the CH2CH=CH2 appendage, A should preferentially adopt the conformation B, in which the smallest substituent H (hydrogen) is now in the same plane as the ethyl group. This places the hydroxymethyl moiety (CH2OH) in proximity to the P-face of the double bond, leading, after treatment with mCPBA, to the formation of epoxide diastereomer C. 

In acyclic systems the Claisen-lreland rearrangement proceeds via a chairlike transition state (TS). However, iri cyclic systems conformational constraints can override the inherent preference for chairlike TS and the boatlike TS becomes dominant. One explanation for the preference of boatlike transition states in cyclic systems is the destabilizing steric interactions of the silyloxy substituent and the ring atoms in a chairlike TS. ... 

Because of the number of conformations that need to be considered for acyclic systems, cyclohexanones are somewhat simpler for analysis. However, even for these systems the situation is not easily amenable to isolating specific components of selectivity. Several explanations have been proposed over the years to account for the preference of axial attack of cyclohexanones by sterically unhindered nucleophiles (L1A1H4, NaBH4, AIH3) [9]. Equatorial attack is favoured for sterically hindered cyclohexanones or reducing agents (Fig. 6-7). 

AG <5 kcal/mole, AG 2 >10 kcal/mole). If the rate of reaction is fast with respect to conformational equilibration the relative populations of the conformers will be of major importance (Fig. 6b). This situation is often encountered with conformationally rigid systems (e.g., polycyclic compounds). Obviously, conformational control can also be brought about by increasing the rate of reaction. We have seen (Section 3) that some 1,2 shifts in carbocations are extremely fast (AG <5 kcal/mole). We expect, therefore, that rearrangements of carbocations may be competitive, at least, with conformational equilibration even in acyclic systems. 

The rearrangements of the 2-norbornyl cation are unexceptional. All 1,2-alkyl shifts, even those in acyclic systems (Section 7.6.1) conform to essentially the same pattern. Individual differences exist in the rates of alkyl shift, relative to the rates of capture by solvent. In that respect the 2-norbornyl cation is superior to acyclic analogs because it can approach the geometry of corner-protonated nortricyclene with only small distortions of the nuclear positions. (A more sophisticated treatment in terms of relaxation theory has been published548. ) Other bicyclic and polycyclic systems provide similarly favorable conditions for 1,2-alkyl shifts. Some of them will be discussed in the following Sections. 

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