Addition, electrophilic cyclic intermediates

In the case of electrophiles like Br", which can form cyclic intermediates, both 1,2-and 1,4-addition products can be rationalized as stemming from an intermediate like 17. Direct nucleophilic attack by W would give the 1,2 product, while the 1,4 product could be formed by attack at the 4 position, by an Sn2 type mechanism (see p. 422). Intermediates like 18 have been postulated but ruled out for Br and Cl by the observation that chlorination or bromination of butadiene gives trans 1,4... 

Halogenation ofbutadiene has also attracted alot of interest. Both 1,2- and 1,4-isomers are formed. Since the trans- y-4-isomer was observed from the 1,4-addition product, researchers postulate that the the electrophilic X+ forms a 1,2-cyclic intermediate and not a 1,4-cyclic intermediate that would form the cis- 1,4-addition product (51,52). 

To account for the stereospecificity of bromine addition to alkenes, it has been suggested that in the initial electrophilic attack of bromine a cyclic intermediate is formed that has bromine bonded to both carbons of the double bond. Such a bridged ion is called a bromonium ion because the bromine formally carries the positive charge ... 

The cyclic intermediate, called an osmate ester, is not isolated instead, the osmium-oxygen bonds are cleaved by using a reagent such as sodium sulfite, Na2S03, resulting in the formation of a 1,2-diol. (The mechanistic details of the cleavage step need not concern us.) Because both the electrophilic and nucleophilic oxygens are attached to the same metal atom, both are delivered from the same side of the plane of the double bond—the reaction is a syn addition. 

If the electrophile has an unshared pair of electrons, the reaction is one from Table 11.3 and proceeds through a three-membered cyclic intermediate, which is formed by syn addition. If the cyclic intermediate is neutral, the reaction stops here. If the intermediate is chained, the nucleophile adds with inversion (borderline SN2 mechanism), resulting in overall anti addition. 

Seven-membered cyclic ethers 736 have been prepared by palladium(0)-catalyzed ring expansion of the adducts resulting from the addition of the intermediate 719 to 4,4-dialkylisochromanones 7351061. However, when isochromanones 737 were used as electrophiles, the resulting adducts afforded the corresponding eight-membered cyclic ethers... 

The choice of the solvent and of the electrophile is very important since the reaction can be carried out under kinetic or thermodynamic control. The possibility of equilibrating a cyclic intermediate strongly influences the regio- and stereochemistry of the reaction. The presence of a base in an aqueous medium generally results in kinetic control of the cyclization process18, while reversible conditions are favored by iodine in acetonitrile19. In addition, A -iodosuccin-imide in chloroform, iodine in chloroform and iodine in tetrahydrofuran/pyridine are considered to give cyclizations under kinetic control. On the other hand, the use of AT-bromosuccin-imide or bromine affords lower selectivity. 

This analysis of the simple addition of an electrophilic bromine molecule to a symmetrical alkene or alkyne has highlighted many points. First, there is the induction of a temporary dipole of the soft electrophile by the n electrons of the carbon/carbon double bond. Second, there is the heterolytic fission of the bromine molecule, and the subsequent formation of the cyclic bromonium ion. Third, this cyclic intermediate places certain restrictions on the potential line of attack for the second reagent, and so controls the structural and stereochemical consequences for the product. 

A TMSOTf-initiated cyclization of the dicarbonyl substrate was invoked to explain the reactivity pattern [79]. Selective complexation of the less hindered carbonyl group activates it toward intramolecular nucleophilic attack by the more hindered carbonyl which leads to an oxocarbenium species. Subsequent attack by the enol ether results in addition to the more hindered carbonyl group. The formation of this cyclic intermediate also explains the high stereochemical induction by existing asymmetric centers in the substrates, as demonstrated by Eq. 52, where the stereochemistry at four centers is controlled. A similar reactivity pattern was observed for the bis-silyl enol ethers of / -diketones. The method is also efficient for the synthesis of oxabicyclo[3.3.1] substrates via 1.5-dicarbonyl compounds, as shown in Eq. 53. Rapid entry into more complex polycyclic annulation products is possible starting from cyclic dicarbonyl electrophiles [80]. 

The first step in the mercuric-ion-catalyzed hydration of an alkyne is formation of a cyclic mercurinium ion. (Two of the electrons in mercury s filled 5d atomic orbital are shown.) This should remind you of the cyclic bromonium and mercurinium ions formed as intermediates in electrophilic addition reactions of alkenes (Sections 4.7 and 4.8). In the second step of the reaction, water attacks the most substituted carbon of the cyclic intermediate (Section 4.8). Oxygen loses a proton to form a mercuric enol, which immediately rearranges to a mercuric ketone. Loss of the mercuric ion forms an enol, which rearranges to a ketone. Notice that the overall addition of water follows both the general rule for electrophilic addition reactions and Markovnikov s rule The electrophile (H in the case of Markovnikov s rule) adds to the sp carbon bonded to the greater number of hydrogens. 

This is an example of electrophilic addition of Cl to an alkene. The mechanism of this reaction involves the following steps. In the first step, the ethylene reacts with chlorine to form the cyclic ethylene chloronium ion (intermediate) and chloride ion. Note that in this cyclic intermediate, the chlorine has a positive charge. This step is followed by the nucleophilic attack by chloride ion on the chloronium ion. The reaction is enhanced by electron-donating substituents such as alkyl groups on the carbon-carbon double bond, since such groups can further stabilize the formation of the transition state which results in the formation of the chloronium ion. Halogen addition is usually an anti addition process. 

Mechanistic studies have been most complete with the sulfenyl halides.The reaction shows moderate sensitivity to alkene structure with electron-releasing groups accelerating the reaction. The addition can occur in the Markownikoff or anti-Markownikoff sense depending upon the structure of the alkene and the electrophile. These results can be understood by focusing attention on the addition intermediate, which may range from a sulfonium intermediate to a less electrophilic cyclic chlorosulfurane ... 

The combination of reactions of rhodium carbenoids with polyether-macrocycle synthesis offered interesting procednres for the synthesis of this important class of compounds. One elegant example is the Rh-catalyzed four-component reaction of two a-diazo- 3-keto esters and two cyclic ethers, such as tetrahydrofuran or 1,4-dioxane, to yield functionalized 16- to 18-membered macrocycles 65 (Scheme 5.44) [42]. The process involves the generation of electrophilic rhodium carbenoid A, the addition of cyclic ether to this intermediate, as well as the formation and dimerization of the oxonium ylide intermediate B. Another example is the Rh-catalyzed macrocyclization of oxetanes with a-diazocarbonyls (Scheme 5.45) [43]. In this case, three oxetanes and one rhodium carbenoid intermediate condense in a one-step process. It is noteworthy that these macrocyclizations could proceed under high-concentration conditions (1M). 

In the first step an S03 molecule is inserted into the ester binding and a mixed anhydride of the sulfuric acid (I) is formed. The anhydride is in a very fast equilibrium with its cyclic enol form (II), whose double bonding is attacked by a second molecule of sulfur trioxide in a fast electrophilic addition (III and IV). In the second slower step, the a-sulfonated anhydride is rearranged into the ester sulfonate and releases one molecule of S03, which in turn sulfonates a new molecule of the fatty acid ester. The real sulfonation agent of the acid ester is not the sulfur trioxide but the initially formed sulfonated anhydride. In their detailed analysis of the different steps and intermediates of the sulfonation reaction, Schmid et al. showed that the mechanism presented by Smith and Stirton [31] is the correct one. 

Addition to conjugated systems can also be accomplished by any of the other three mechanisms. In each case, there is competition between 1,2 and 1,4 addition. In the case of nucleophilic or free-radical attack, the intermediates are resonance hybrids and behave like the intermediate from electrophilic attack. Dienes can give 1,4 addition by a cyclic mechanism in this way ... 

Yet another intermediate, a cyclic bromonium ion, 15, is involved in the electrophilic addition of bromine to 3-hexyne, 1 -hexyne (32,33), and other alkylacetylenes (44). In these reactions, only trans dibromides have been... 

In contrast to a, -ethylenic ketones or even a, -ethylenic sulfones, a, ) -ethylenic sulfoxides generally are not sufficiently electrophilic to undergo successful nucleophilic j8-addition . a-Carbonyl-a, j8-ethylenic sulfoxides, however, are potent, doubly activated alkenes which undergo rapid and complete -addition of various types of nucleophiles even at — 78 °C. A brief account summarizing this area is available . The stereochemical outcome of such asymmetric conjugate additions to enantiomerically pure 2-sulfmyl 2-cycloalkenones and 2-sulfinyl-2-alkenolides has been rationalized in terms of a metal-chelated intermediate in which a metal ion locks the -carbonyl sulfoxide into a rigid conformation (36 cf. 33). In this fixed conformation, one diastereoface of the cyclic n... 

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