Heteroatom lone pair reactivity

The unexpected heteroatom lone pair reactivity exposed during the failed 2nd approach to agelastatin A mandated that sufficient attention be directed to the cyclization options of 64. As with carbene intermediate... 

Many different types of 1,3-dipoles have been described [Ij however, those most commonly formed using transition metal catalysis are the carbonyl ylides and associated mesoionic species such as isomiinchnones. Additional examples include the thiocar-bonyl, azomethine, oxonium, ammonium, and nitrile ylides, which have also been generated using rhodium(II) catalysis [8]. The mechanism of dipole formation most often involves the interaction of an electrophilic metal carbenoid with a heteroatom lone pair. In some cases, however, dipoles can be generated via the rearrangement of a reactive species, such as another dipole [40], or the thermolysis of a three-membered het-erocycHc ring [41]. 

The chemoselectivity of the dioxirane oxyfunctionalization usually follows the reactivity sequence heteroatom (lone-pair electrons) oxidation > JT-bond epoxida-tion > C-H insertion, as expected of an electrophilic oxidant. Because of this chemoselectivity order, heteroatoms in a substrate will be selectively oxidized in the presence of C-H bonds and even C-C double bonds. In allylic alcohols, however, C-H oxidation of the allylic C-H bond to a,/ -unsaturated ketones may compete efficaciously with epoxidation, especially when steric factors hinder the dioxirane attack on the Jt bond. To circumvent the preferred heteroatom oxidation and thereby alter the chemoselectivity order in favor of the C-H insertion, tedious protection methodology must be used. For example, amines may be protected in the form of amides [46], ammonium salts [50], or BF3 complexes [51] however, much work must still be expended on the development of effective procedures which avoid the oxidation of heteroatoms and C-C multiple bonds. 

All tervalent phosphorus acid derivatives have a lone pair on phosphorus and are therefore nucleophiles, but their reactivity depends on the electronegativity of the group(s) bound to phosphorus. Aminophosphines are the most reactive and chlorophosphines the least reactive, with the phosphinites, phosphonites and thio analogues in between. In principle they are ambident nucleophiles because there are lone pairs both on the heteroatoms and on phosphorus, but apart from the thio analogues these heteroatom lone pairs do not participate in the common reactions discussed below. 

Electrocyclization of 1,4-dienes is an efficient process when a heteroatom with a lone pair of electrons is placed in the 3-position, as in 77 (Scheme 20)38. Photoexcitation of these systems generally results in efficient formation of a C—C bond via 6e conrotatory cyclization to afford the ylide 78. These reactive intermediates can undergo a variety of processes, including H-transfer (via a suprafacial 1,4-H transfer) to 79 or oxidation to 80. In a spectacular example of reaction, and the potential it holds for complex molecule synthesis, Dittami and coworkers found that the zwitterion formed by photolysis of divinyl ether 81 could be efficiently trapped in an intramolecular [3 + 2] cycloaddition by the... 

Since dioxiranes are electrophilic oxidants, heteroatom functionalities with lone pair electrons are among the most reactive substrates towards oxidation. Among such nucleophilic heteroatom-type substrates, those that contain a nitrogen, sulfur or phosphorus atom, or a C=X functionality (where X is N or S), have been most extensively employed, mainly in view of the usefulness of the resulting oxidation products. Some less studied heteroatoms include oxygen, selenium, halogen and the metal centers in organometallic compounds. These transformations are summarized in Scheme 10. We shall present the substrate classes separately, since the heteroatom oxidation is quite substrate-dependent. 

These compounds are reasonably stable and surprisingly easy to prepare and to handle. Conjugation between the double bond of the thiocarbonyl group and the lone pair on the a heteroatom leads to a good balance between stability and reactivity for these functional groups. 

Determination of electron configurations can provide insight into reactivity. Calculations <1996JA6317> of the percentage of t character of lone pairs at the heteroatom revealed that there was a dramatic increase in s character upon going from pyridine (%s= 29.1) to phosphinine (%s 83.8), correlated with a lower basicity of the heteroatom... 

The reactivity sequence furan > selenophene > thiophene > benzene has also been observed in the nucleophilic substitutions of the halogenonitro derivatives of these rings.21,22 This shows that the observed trend does not depend on the effectiveness of lone-pair conjugation of the heteroatoms NH, O, Se, and S and the 77-electron density at the carbon atoms. It is interesting to note that a good correlation is observed between molecular ionization potentials (determined from electron impact measurements) and reactivity data in electrophilic substitution, in that higher reactivities correspond to lower ionization potentials182 pyrrole furan < selenophene < thiophene benzene (see Table VII). This is expected in view of a... 

The basis and extent of their aromaticity is discussed in Chapter 1. In summary, the capacity for the lone pair on a particular heteroatom to be delocalised is inversely related to the electronegativity of the heteroatom. For instance, furan is the least aromatic of the trio because oxygen has the greatest electronegativity and hence mesomeric representations 2.4b-e make relatively less of a contribution to the electronic structure of furan than they do in the cases of pyrrole and thiophene. The order of aromaticity is furan < pyrrole < thiophene. We shall see later how this variation in aromaticity affects the reactivities of these three related heterocycles. 

The 2-position in azoles with 1,3-heteroatoms should be more reactive than the 5-position of azoles with 1,2-heteroatoms, but for reactions of the free base this turns out not to be the case because of the adjacent lone pair effect illustrated by the relative reaction rates in Scheme 7.3. Thus the 2-position of thiazole is 7 times less reactive than the 5-position of isothiazole. The same reasoning accounts for the 3-position of isothiazole being less reactive than the 4-position of thiazole. The former should be the more reactive since the electron-withdrawing effect of nitrogen should be greater across the bond of higher order, and the fact that it is not more reactive suggests that the effect of the adjacent lone pair is more severe across the shorter C-3—N bond in isothiazole. For reaction of the azol-... 

Carbene attack is followed by proton transfer to generate a neutral molecule from the first formed zwitterion (or ylid ). However, if the heteroatom does not carry a hydrogen, attack on its lone pair generates an ylid that cannot rearrange in this way. Reaction of a carbene with a neutral nucleophile forms an ylid. This type of reaction is, in fact, a very useful way of making reactive ylids that are inaccessible by other means. 

Secondly, the ring fixes the orientation of the heteroatom—and, in particular, the orientation of its lone pairs—relative to the atoms around it. This has consequences for the reactivity and conformation of the heterocycle which can be explained using the concept of stereoelectronics. 

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