Nucleophilicity and activation

Primary amino- and SH-groups are also nucleophiles and active for hydrolyses. Klotz et al.12S 127) investigated the activities of lauroyl-substituted polyethylenimine,... 

Scheme 8 Diketopiperazines by UDAC procedure. The simultaneous deprotection of BOC to liberate the amino nucleophile, and active amide (acylindole) formation is achieved with mild acid only...

A detailed discussion concerning this type of mechanism has been organized by Strukul in his book . In particular, kinetic studies concerning Pt hydroxo derivatives indicate that the metal plays two different roles activation of hydrogen peroxide by increasing its nucleophilicity and activation of the substrate toward nucleophilic attack by coordination to the metal center (Scheme 8). 

Promoted by copper iodide, a large array of 3-methylenetetrahydrofurans were synthesized from propargylic alkoxides as nucleophiles and activated alkenes as Michael acceptors. One of these reactions is shown below <02TL2609>. 

Michael addition is a facile reaction between nucleophiles and activated olefins and alkynes in which the nucleophile adds across a carbon-carbon multiple bond [25], For the preparation of hydrogels, the hydroxyl, thiol or amine functionalities have been reacted with vinyl sulfones [26-28], acrylates [29-31], acrylamides [32], and maleimides [33, 34] (Scheme 2). 

We began with our existing aminoadenosine and carbazolediimide structures, as both the carbazole portion of the receptor and the ribose portion of adenosine are well suited for synthetic elaboration. For the reciprocal system, each was outfitted with amine nucleophiles and active ester electrophiles for covalent coupling reactions [50]. Two amines and two p-nitrophenyl esters were prepared [(4), (45), (46) and (47), Figure 27], as well as the two templates (48) and (49) (Figure 28). Two reference templates (50) and... 

In addition, Svendsen [116] has studied the reaction of cyclic sulfites with various malonates and found that, in some cases, the substitution products could be obtained in good yields (Scheme 39). Unfortunately, the use of cyclic sulfites appears to be limited to a restricted number of nucleophiles and activated substrates. 

The two distinct mechanisms, based on activated nucleophile and activated electropbile, are summarized in Figure 39. According to the presence of mono or ditrihaloalanine analogues, two different reaction pathways could thus be followed. If two hydrogens are present on the /3-carbon, the olefinic terminus is not enough... 

Also piperylene can be used in telomerization however, so far only poor yields have been obtained [35]. Therefore, our investigations were focused on finding reactive nucleophiles and active catalyst systems which allow the telomerization of piperylene in high yields and selectivities [36]. We found that the three alcohols benzyl alcohol, furfuryl alcohol and 2,2,2-trifluoroethanol proved to be very reactive nucleophiles in the telomerization of piperylene. 

While NAS and EAS reactions make for interesting s mthesis problems, they are also good material for mechanism problems. Be sure to review the mechanisms of these two types of reactions, noting their similarities (both start and end with an aromatic molecule, and the rate of each reaction is dramatically affected by the presence and placement of EWG s or EDO s on the ring), and differences (in EAS the ring is nucleophilic and activated by ortho and para EDO s while in NAS the ring is electrophilic and activated by ortho and para EWO s). Note also that in EAS an electrophile substitutes for an aryl H, while in NAS a nucleophile substitutes for an aryl halogen. 

Two efficient syntheses of strained cyclophanes indicate the synthetic potential of allyl or benzyl sulfide intermediates, in which the combined nucleophilicity and redox activity of the sulfur atom can be used. The dibenzylic sulfides from xylylene dihalides and -dithiols can be methylated with dimethoxycarbenium tetrafiuoroborate (H. Meerwein, 1960 R.F. Borch, 1968, 1969 from trimethyl orthoformate and BFj, 3 4). The sulfonium salts are deprotonated and rearrange to methyl sulfides (Stevens rearrangement). Repeated methylation and Hofmann elimination yields double bonds (R.H. Mitchell, 1974). 

TT-Allylpalladium chloride (36) reacts with the nucleophiles, generating Pd(0). whereas tr-allylnickel chloride (37) and allylmagnesium bromide (38) reacts with electrophiles (carbonyl), generating Ni(II) and Mg(II). Therefore, it is understandable that the Grignard reaction cannot be carried out with a catalytic amount of Mg, whereas the catalytic reaction is possible with the regeneration of an active Pd(0) catalyst, Pd is a noble metal and Pd(0) is more stable than Pd(II). The carbon-metal bonds of some transition metals such as Ni and Co react with nucleophiles and their reactions can be carried out catalytic ally, but not always. In this respect, Pd is very unique. 

Typical nucleophiles known to react with coordinated alkenes are water, alcohols, carboxylic acids, ammonia, amines, enamines, and active methylene compounds 11.12]. The intramolecular version is particularly useful for syntheses of various heterocyclic compounds[l 3,14]. CO and aromatics also react with alkenes. The oxidation reactions of alkenes can be classified further based on these attacking species. Under certain conditions, especially in the presence of bases, the rr-alkene complex 4 is converted into the 7r-allylic complex 5. Various stoichiometric reactions of alkenes via 7r-allylic complex 5 are treated in Section 4. 

Application of 7r-allylpalladium chemistry to organic synthesis has made remarkable progress[l]. As deseribed in Chapter 3, Seetion 3, Tt-allylpalladium complexes react with soft carbon nucleophiles such as maionates, /3-keto esters, and enamines in DMSO to form earbon-carbon bonds[2, 3], The characteristie feature of this reaction is that whereas organometallic reagents are eonsidered to be nucleophilic and react with electrophiles, typieally earbonyl eompounds, Tt-allylpalladium complexes are electrophilie and reaet with nucleophiles such as active methylene compounds, and Pd(0) is formed after the reaction. 

The N-oxide function has proved useful for the activation of the pyridine ring, directed toward both nucleophilic and electrophilic attack (see Amine oxides). However, pyridine N-oxides have not been used widely ia iadustrial practice, because reactions involving them almost iavariably produce at least some isomeric by-products, a dding to the cost of purification of the desired isomer. Frequently, attack takes place first at the O-substituent, with subsequent rearrangement iato the ring. For example, 3-picoline N-oxide [1003-73-2] (40) reacts with acetic anhydride to give a mixture of pyridone products ia equal amounts, 5-methyl-2-pyridone [1003-68-5] and 3-methyl-2-pyridone [1003-56-1] (11). 

Generally, isolated olefinic bonds will not escape attack by these reagents. However, in certain cases where the rate of hydroxyl oxidation is relatively fast, as with allylic alcohols, an isolated double bond will survive. Thepresence of other nucleophilic centers in the molecule, such as primary and secondary amines, sulfides, enol ethers and activated aromatic systems, will generate undesirable side reactions, but aldehydes, esters, ethers, ketals and acetals are generally stable under neutral or basic conditions. Halogenation of the product ketone can become but is not always a problem when base is not included in the reaction mixture. The generated acid can promote formation of an enol which in turn may compete favorably with the alcohol for the oxidant. 

Xenon difluoride [4, 5, 7, 8,10] is a white crystalline material obtained through the combination of fluorine and xenon m the presence of light The reagent is commercially available and possesses a relatively long shelf-life when stored cold (freezer) Xenon difluoride is very effective for small-scale fluormation of alkenes and activated nucleophilic substrates. The reactions are usually conducted between 0 °C and room temperature in chloroform or methylene chloride solutions Hydrogen fluoride catalysis is sometimes helpful Xenon difluoride reacts in a manner that usually involves some complexation between the substrate and reagent followed by the formation of radical and radical cation intermediates... 

The notion of concurrent SnI and Sn2 reactions has been invoked to account for kinetic observations in the presence of an added nucleophile and for heat capacities of activation,but the hypothesis is not strongly supported. Interpretations of borderline reactions in terms of one mechanism rather than two have been more widely accepted. Winstein et al. have proposed a classification of mechanisms according to the covalent participation by the solvent in the transition state of the rate-determining step. If such covalent interaction occurs, the reaction is assigned to the nucleophilic (N) class if covalent interaction is absent, the reaction is in the limiting (Lim) class. At their extremes these categories become equivalent to Sn and Sn , respectively, but the dividing line between Sn and Sn does not coincide with that between N and Lim. For example, a mass-law effect, which is evidence of an intermediate and therefore of the SnI mechanism, can be observed for some isopropyl compounds, but these appear to be in the N class in aqueous media. 

Numerous half-sandwich compounds of the type [M()7 -C5R5)L2], M = Rh, Ir R = H, Me L = CO, phosphine etc.) are known and are useful reagents. [Ir()7 -C5Me5)(CO)2] for instance is an excellent nucleophile and is also used in the photochemical activation of C-H in alkanes. It is particularly effective in the latter role when supercritical CO2 is the solvent. ... 

A large number of nucleophilic substitution reactions involving interconversions of pyridopyrimidines have been reported, the majority of which involve substituents in the pyrimidine ring. This subject has been reviewed previously in an earlier volume in this series which dealt with the theoretical aspects of nucleophilic re-activiti in azines, and so only a summary of the nucelophilic displacements of the substituent groups will be given here. In general, nucleophilic substitutions occur most readily at the 4-position of pyrido-... 

When a positively charged substituent such as the trimethylam-monio group is anywhere on the ring, but most effectively when it is ortho to the leaving group, it can favorably affect the entropy of activation with anionic nucleophiles and accelerate reaction. A recent example of reagent-substituent interaction is the electrophilic substitution of 2-carboxybiphenyl, nitration (non-polar solvent) of which occurs only at the 2 -position and not the 4 -position and has been postulated to be due to the interaction of the nitronium ion with the carboxyl group. 

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