Intermolecular reactions carbon nucleophiles

Intramolecular reactions are favored by entropy. Recall that entropy is a measure of the disorder of a system. It costs energy to put order into a system—to decrease the entropy of that system. In the case of an intermolecular reaction, the nucleophile and the electrophile must first come together from their initial random positions. This requires an increase in the order of the system, an entropically unfavorable process. In the case of an intramolecular reaction, the nucleophile is held in proximity to the electrophile by the connecting carbon chain. It takes a much smaller increase in the order of the system to position the nucleophile for reaction. In other words, the nucleophile is much closer to the electrophile at all times, and attaining the proper orientation required for the reaction is much more probable. 

In the synthesis of molecules without functional groups the application of the usual polar synthetic reactions may be cumbersome, since the final elimination of hetero atoms can be difficult. Two solutions for this problem have been given in the previous sections, namely alkylation with nucleophilic carbanions and alkenylation with ylides. Another direct approach is to combine radical synthons in a non-polar reaction. Carbon radicals are. however, inherently short-lived and tend to undergo complex secondary reactions. Escheirmoser s principle (p. 34f) again provides a way out. If one connects both carbon atoms via a metal atom which (i) forms and stabilizes the carbon radicals and (ii) can be easily eliminated, the intermolecular reaction is made intramolecular, and good yields may be obtained. 

In the dihapto mode the pyridine ring can be protonated intermolecularly at nitrogen, or even intramolecularly deprotonated at carbon. The first evidence for metal C—N insertion is the reaction of the metallaaziridine complex (111) with homogeneity LiHBEt3 in THF at low temperature that yields (112) (Scheme 49).251-254 Experiments with carbon nucleophiles (RMgCl, MeLi) in place of LiHBEt3 have provided valuable information to allow discrimination between... 

Sargeson and his coworkers have developed an area of cobalt(III) coordination chemistry which has enabled the synthesis of complicated multidentate ligands directly around the metal. The basis for all of this chemistry is the high stability of cobalt(III) ammine complexes towards dissociation. Consequently, a coordinated ammonia molecule can be deprotonated with base to produce a coordinated amine anion (or amide anion) which functions as a powerful nucleophile. Such a species can attack carbonyl groups, either in intramolecular or intermolecular processes. Similar reactions can be performed by coordinated primary or secondary amines after deprotonation. The resulting imines coordinated to cobalt(III) show unusually high stability towards hydrolysis, but are reactive towards carbon nucleophiles. While the cobalt(III) ion produces some iminium character, it occupies the normal site of protonation and is attached to the nitrogen atom by a kinetically inert bond, and thus resists hydrolysis. 

Intramolecular nucleophilic attack at the double bond of an ally he system bearing an tt-leaving group has been extensively reviewed by Paquette and Stirling21. One of the key aspects of such reactions is the limitation of ring size on the trajectory of the nucleophile on the carbon double bond, although examples of 3,4,5 and 6 exo-trig reactions are known (for example see Scheme 3)29. The stereochemistry of these intramolecular reactions mirrors that of the intermolecular reactions in that the attack is usually, but not always, syn. 

Technically, the addition of carbon-centered radicals to C-N double bonds is as yet of little if any importance. In the free-radical chemistry of DNA it plays, however, a considerable role in the formation of the C(5 )-C(8) linkage between the sugar moiety and the purines (Chap. 10.5). Because of its importance, even an immune assay has been developed for the sensitive detection of this kind of damage in DNA (Chap. 13.2). The addition of the C(5 ) radical to the C(8) position of a purine is obviously facilitated for steric reasons (formation of a six-membered ring), but the same kind of reaction also occurs as an intermolecular reaction. Since alkyl radicals are nucleophilic, the rate of this reaction is noticeably increased upon protonation of the purine (Aravindakumar et al. 1994 for rate constants see Chap. 10.5). 

Carbopalladation occurs with soft carbon nucleophiles. The PdCl2 complex of COD (100) is difficult to dissolve in organic solvents. However, when a heterogeneous mixture of the complex, malonate and Na2C03 in ether is stirred at room temperature, the new complex 101 is formed. This reaction is the first example of C—C bond formation and carbopalladation in the history of organopalladium chemistry. The double bond becomes electron deficient by the coordination of Pd(II), and attack of the carbon nucleophile becomes possible. The Pd-carbon n-bond in complex 101 is stabilized by coordination of the remaining alkene. The carbanion is generated by treatment of 101 with a base, and the cyclopropane 102 is formed by intramolecular nucleophilic attack. Overall, the cyclopropanation occurs by attack of the carbanion twice on the alkenic bond activated by Pd(II). The bicyclo[3.3.0]octane 103 was obtained by intermolecular attack of malonate on the complex 101 [11]. 

Intermolecular addition of carbon nucleophiles to the ri2-pyrrolium complexes has shown limited success because of the decreased reactivity of the iminium moiety coupled with the acidity (pKa 18-20) of the ammine ligands on the osmium, the latter of which prohibits the use of robust nucleophiles. Addition of cyanide ion to the l-methyl-2//-pyr-rolium complex 32 occurs to give the 2-cyano-substituted 3-pyrroline complex 75 as one diastereomer (Figure 15). In contrast, the 1-methyl-3//-pyrrolium species 28, which possesses an acidic C-3-proton in an anti orientation, results in a significant (-30%) amount of deprotonation in addition to the 2-pyrroline complex 78 under the same reaction conditions. Uncharacteristically, 78 is isolated as a 3 2 ratio of isomers, presumably via epimerization at C-2.17 Other potential nucleophiles such as the conjugate base of malononitrile, potassium acetoacetate, and the silyl ketene acetal 2-methoxy-l-methyl-2-(trimethylsiloxy)-l-propene either do not react or result in deprotonation under ambient conditions. 

In this sense Organ and coworkers [80] have developed intriguing syntheses of polysubstituted olefins based upon consecutive intermolecular reactions such as allylic and allylic-vinylic halide coupling sequences. Therefore, l-acetoxy-4-chloro but-2-ene can be readily submitted as a template for Pd-catalyzed allylic substitutions with two different carbon or nitrogen nucleophiles, leading to unsymmetrically substituted butene derivatives 66-70 in good yields (Scheme 22). Mechanistically, the chloro substituent is replaced... 

The C-Sn a orbital also interacts with a neighboring nonbonding p orbital of heteroatoms, and this interaction decreases the oxidation potential significantly [128,129]. It should be noted that the oxidation potentials of a-heteroatom-substituted tetraorganos-tannanes are less positive than those of carbon nucleophiles such as allylsilanes and enol sily ethers. Consequently, such carbon nucleophiles can be used for the electrochemical oxidation of a -heteroatom-substituted tetraorganostannanes to achieve the carbon-carbon bond formation. In fact, various intermolecular carbon-carbon bond formation reactions have been developed using a-heteroatom-substituted tetraorganostannanes [130-132]. 

An intermolecular reaction, again with overall syn Sn substitution, was successfully applied in a synthesis of the carbocyclic nucleoside analog aristeromycin to introduce the nitrogen base stereoselectively (equation 21), although with heteronucleophiles, unlike the case of carbon nucleophiles, a lower propensity for attack distal to oxygen to give the 1,4-product with vinyloxiranes exists. 

Intramolecular reactions are faster and cleaner than intermolecular reactions. When we want to make a C-N bond in a ring, therefore, we no longer have to take any special precautions and we can use a nitrogen nucleophile and any carbon electrophile. Two useful disconnections are ... 

Secondary alkyl chloride with good nucleophile (Et2N) can participate in the formation of an aziridinium intermediate that is attacked by HO in Sj 2 mode to give an amino-alcohol (Scheme 2.42). The CH2 carbon has less steric crowing than the CHMe carbon. Intramolecular reactions, including participation, that give three-, five-, or six-membered rings are usually faster than intermolecular reactions. 

This reaction has been extended to the translocation of the acyl group for indole derivatives. In addition, a chiral planar DMAP derivative has been developed and applied for the enantioselective rearrangement of 0-acylated azlactone and the same catalyst recently has been used for an intermolecular reaction to form 1,3-diketones. Moreover, 3-(2,2,2-triphenyl-1 -acetoxyethyl)-4-(dimethylamino) pyridine (TADMAP) has been applied as a chiral nucleophilic catalyst to catalyze the carboxyl migration of oxazolyl, furanyl, and benzofuranyl enol carbonates with good to excellent levels of enantioselec-tivity. The rearrangement for oxazole derivatives are particularly efficient for giving chiral lactams and lactones. ... 

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