Aniline, basicity nucleophilicity

In this section, emphasis is placed on reactions which are characteristic of the ring systems present and do not depend on the presence of particular substituents. In addition, the well-known and widely applied behavior of morpholine as a basic and nucleophilic secondary amine is not covered and neither is the aniline-like nucleophilic and basic behavior of dihydrobenzoxazines save for a few special examples. 

Carbonates are clearly more versatile than acetates when nucleophiles are acidic. The general reaction is in Scheme 28 and the N-nucleophiles are listed in Table 2. When reactions are performed in more or less polar aprotic solvents, the comments on relative acidities of Sect. B should be taken into account. Nucleophiles are divided in Table 2 according to their p f, known or estimated, in DMSO. Basic nucleophiles such as aliphatic amines are less acidic than methanol or ethanol. Therefore, they are not deprotonated by alkoxide and they are nucleophilic as neutral species. Anilines are possibly on the borderline since aniline (pisfa (DMSO) = 30.6) is only slightly less acidic than methanol (DMSO) = 29.0).On the contrary, acidic nucleophiles require prior deprotonation by alkoxide. 

Diffusion-limited rate control at high basicity may set in. This is more eommonly seen in a true Br nsted plot. If the rate-determining step is a proton transfer, and if this is diffusion controlled, then variation in base strength will not affect the rate of reaction. Thus, 3 may be zero at high basicity, whereas at low basicity a dependence on pK may be seen. ° Yang and Jencks ° show an example in the nucleophilic attack of aniline on methyl formate catalyzed by oxygen bases. 

In spite of the potential complexity of the general problem, even when restricted to the reagent family of amines, the nucleophilicities of such series as meta- and pom-substituted pyridines and anilines appear to correlate very closely with the expected substituent effects and with the basicities. This has been verified in the following cases (i) The reaction of pyridines (R = H, m- andp-CHs) with 2-chloro-3-nitro-, 2-chloro-5-nitro-, and 4-chloro-3-nitro-pyridines. ... 

The rate of reaction of a series of nucleophiles with a single substrate is related to the basicity when the nucleophilic atom is the same and the nucleophiles are closely related in chemical type. Thus, although the rates parallel the basicities of anilines (Tables VII and VIII) as a class and of pyridine bases (Tables VII and VIII) as a class, the less basic anilines are much more reactive. This difference in reactivity is based on a lower energy of activation as is the reactivity sequence piperidine > ammonia > aniline. Further relationships among the nucleophiles found in this work are morpholine vs. piperidine (Table III) methoxide vs. 4-nitrophenoxide (Table II) and alkoxides vs. piperidine (Tables II, III, and VIII). Hydrogen bonding in the transition state and acid catalysis increase the rates of reaction of anilines. Reaction rates of the pyridine bases are decreased by steric hindrance between their alpha hydrogens and the substituents or... 

It would be ideal if the asymmetric addition could be done without a protecting group for ketone 36 and if the required amount of acetylene 37 would be closer to 1 equiv. Uthium acetylide is too basic for using the non-protected ketone 36, we need to reduce the nucleophile s basicity to accommodate the acidity of aniline protons in 36. At the same time, we started to understand the mechanism of lithium acetylide addition. As we will discuss in detail later, formation of the cubic dimer of the 1 1 complex of lithium cyclopropylacetylide and lithium alkoxide of the chiral modifier3 was the reason for the high enantiomeric excess. However, due to the nature of the stable and rigid dimeric complex, 2 equiv of lithium acetylide and 2 equiv of the lithium salt of chiral modifier were required for the high enantiomeric excess. Therefore, our requirements for a suitable metal were to provide (i) suitable nucleophilicity (ii) weaker basicity, which would be... 

Evaluation of the only appropriate Fukui function is required for investigating an intramolecular reaction, as local softness is merely scaling of Fukui function (as shown in Equation 12.7), and does not alter the intramolecular reactivity trend. For this type, one needs to evaluate the proper Fukui functions (/+ or / ) for the different potential sites of the substrate. For example, the Fukui function values for the C and O atoms of H2CO, shown above, predicts that O atom should be the preferred site for an electrophilic attack, whereas C atom will be open to a nucleophilic attack. Atomic Fukui function for electrophilic attack (fc ) for the ring carbon atoms has been used to study the directing ability of substituents in electrophilic substitution reaction of monosubstituted benzene [23]. In some cases, it was shown that relative electrophilicity (f+/f ) or nucleophilicity (/ /f+) indices provide better intramolecular reactivity trend [23]. For example, basicity of substituted anilines could be explained successfully using relative nucleophilicity index ( / /f 1) [23]. Note however that these parameters are not able to differentiate the preferred site of protonation in benzene derivatives, determined from the absolute proton affinities [24],... 

Catalysis by DABCO in the reactions of FDNB with piperidine, r-butylamine, aniline, p-anisidine and m-anisidine (usually interpreted as base catalysis as in Section B) was also assumed to occur by the formation of a complex between DABCO and the substrate14913. The high (negative) p-value of —4.88 was deemed inappropriate for the usually accepted mechanism of the base-catalysed step (reaction 1). For the reactions with p-chloroaniline, m- and p-anisidines and toluidines in benzene in the presence of DABCO a p-value of —2.86 was found for the observed catalysis by DABCO (fc3DABC0). The results were taken to imply that the transition state of the step catalysed by DABCO and that of the step catalysed by the nucleophile have similar requirements, and in both the nucleophilic (or basicity) power of the nucleophile is involved. This conclusion is in disagreement with the usual interpretation of the base-catalysed step. 

Unsubstituted thiadiazole is unstable under basic conditions, and will decompose. 2-Amino-thiadiazole derivatives (45) react with amines to yield triazolinethiones (46). 2-Amino-5-halo-thia-diazole reacts with hydrazine to give a mixture of (47) and (48). 2,5-Dihalo and 2,5-dithio-thiadiazoles yield only (48) under the same conditions. Even a weaker nucleophile such as aniline... 

One of the earlier second-generation quinolones indeed includes fluorine at the 6 position and a basic function at the 7 position, characteristic of the more potent drugs that also feature a broader spectmm of antibacterial activity. The starting material (39-3) for one of these agents is prepared by application of the same scheme as above to the substituted aniline (39-1). Nucleophilic aromatic displacement with A-methylpiperazine (39-4) proceeds at the 7 position due to activation by the carbonyl group para to the chlorine (39-5). Saponification of the displacement product leads to pefloxacin (39-6) [46]. 

Anilines are generally less basic and nucleophilic than aliphatic amines, but can still be alkylated with alkyl halides under relatively mild reaction conditions under which, for instance, aliphatic alcohols will not undergo alkylation (Scheme 6.7). Monoalkylations of primary anilines with highly reactive alkylating agents can be difficult, and usually require use of excess of aniline and/or careful optimization of the reaction conditions [31-33]. 

Scheme 6.11). Reactions of this type will only proceed well with electron-rich, nucleophilic anilines, but fail with electron-deficient anilines. Yields will usually be low if the reaction is conducted under basic conditions [35]. 

The nucleophilic substitution (SN) of aromatic compounds is one of the fundamental organic reactions in the condensed phase. For example, it is known that aniline can be produced from chlorobenzene under a severe basic condition such as in liquid ammonia (Pine et al. 1980). This bimolecular reaction depends strongly on the solvent. In this respect, the SN reaction in the gas phase may be inefficient due to the absence of solvent molecules assisting the attack, by the nucleophilic agent, on the aromatic ring. However, the situation is completely different for molecular complexes where the nucleophile can be directly bound to the aromatic ring and then can attack the positively charged carbon atom (Mayeama and Mikami 1988). 

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