Nucleophiles heteroatom

Two major resonance structures can be drawn for a protonated carbonyl compound (more if the carbonyl C is cr-bound to heteroatoms). In the second-best resonance structure, the O is neutral, and C is both formally positively charged and electron- 

Don t lose the forest for the trees The mechanism of substitution at the carbonyl group of esters or acids does not differ greatly depending on whether the conditions are acidic or basic. The mechanism always involves addition of a nucleophile to the carbonyl C, followed by elimination of the leaving group. Under acidic conditions, there are a lot of proton transfer steps, but the fundamental nature of the mechanism is not different under acidic and basic conditions. 

Amides and nitriles are hydrolyzed to carboxylic acids by a similar mechanism, the latter proceeding through an amide. These hydrolyses are irreversible under acidic conditions, though, because the product amine is protonated under the reaction conditions and is made nonnucleophilic. 

Problem 3.15. Draw mechanisms for the following carbonyl substitution reactions. In the second problem, think carefully about whence the O atoms in the product come. 

Ketones and aldehydes can be interconverted with acetals. (IUPAC now discourages the use of the word ketal.) Acetalizations are usually thermodynamically uphill, so the reaction is usually driven to completion by the removal of H2O from the reaction mixture by azeotropic distillation or by addition of a dehydrating agent like 4 A molecular sieves or triethyl orthoformate (HC(OEt)3). Hydrolyses of acetals are usually executed simply by dissolving the acetal in water and a cosolvent such as THF and adding a catalytic amount of acid. 

Just as there is no single measure of acidity and basicity, there is no single measure of nucleophilicity and electrophilicity—the rank order of nucleophiles changes when the reference electrophile changes. A hard nucleophile like a fluoride ion reacts fast with a silyl ether in an SN2 reaction at the silicon atom, which is relatively hard, but a soft nucleophile like triethylamine does not. In contrast, triethylamine reacts with methyl iodide in an SN2 reaction at a carbon atom, but fluoride ion does not. These examples, which are all equilibria, are governed by 

Another way of looking at the same problem uses the Salem-Klopman equation (Equation 3.4). Using only the HOMO of a nucleophile and the LUMO of an electrophile, Klopman simplified Equation 3.4 to Equation 4.2  

Nucleophile Effective HOMO El (eV) Electrophile Effective LUMO E (eV) 

Simply by adjusting the relative importance of the two terms of Equation 4.2, Klopman duplicated the otherwise puzzling changes of nucleophilicity as the electrophile changes. The proton is a hard electrophile because it is charged and small. Hence, a nucleophile can get close to it in the transition structure, and R in 

A scale of nucleophilicity, therefore, requires at least two parameters, and these were first provided empirically by Edwards with Equation 4.1.256 

As we have seen earlier, using only the frontier orbitals is a risky approximation because the interactions of the other orbitals will all have an effect, but they all have larger values of ET-ES and thus make a smaller contribution to the third term of Equation 3.13. 

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Conjugate Addition of Heteroatom Nucleophiles and Subsequent Nef Reaction... 

Aziridines bearing heteroatom substituents are best prepared through treatment of the corresponding azirines with heteroatom nucleophiles. Thus, azirine carbox-ylates (in this case prepared by thermal decomposition of the corresponding vinyl... 

Addition of heteroatomic nucleophiles to divinyl sulphoxides gives mono and bi-functionalized products as well as compounds resulting from their cyclization. For... 

ARYLATION OF HARD HETEROATOMIC NUCLEOPHILES USING BROMOARENES SUBSTRATES AND Cu, Ni, Pd-CATALYSTS... 

The arylation of different hard heteroatomic nucleophiles with arylbromides has been investigated using Pd, Ni or Cu-catalysts. 

The fundamental and pratical importance of arylation, particularly the arylation of heteroatomic nucleophiles, was several times emphasized in the last few years (refs. 1, 2) (eqn. 1). 

The Michael addition of heteroatom nucleophiles to nitroalkenes (Section 4.1.1) followed by denitration provides a useful method for the preparation of various natural products. 

Cationic Fp (olefin) complexes [Fp = f/5-C5H5Fe(CO)2] undergo regio-specific addition of heteroatomic nucleophiles.32 Subsequent ligand transfer (carbonyl insertion) occurs with retention of configuration at the migrating center (R—Fe—CO -> RCOFe).33 A combination of these processes has provided a novel stereospecific azetidinone synthesis which can also be applied to condensed systems.34... 

Ring-opening with heteroatomic nucleophiles is certainly among the most thoroughly studied behavior of epoxides, and this reaction continues to be a versatile workhorse of synthetic utility. This is exemplified in the recent literature by the examples of the p-cyclodextrin-catalyzed aminolysis of simple epoxides by aniline derivatives (i.e., 53 - 54) <00SL339> and the synthesis of oxa-azacrown ethers through the treatment of Ws-epoxides 55 with diamines 56. Yields in the latter synthesis are sensitive to the size of the macrocycle and substitution on the bis-epoxide <00TL1019>. 

A review of the reaction of nitroalkanes RNO2 with carbon and heteroatom nucleophiles X to yield RX has appeared438. The nucleophilic displacement of a nitro group in benzylic and tertiary nitroalkanes by a thiophenyl group is exemplified in equation 130439. 

The radical cation can alternatively react with a heteroatom nucleophile (Scheme lb) and after deprotonation lead to a radical bound to the nucleophile. This radical can be further oxidized to... 

The regio- and diastereoselective rhodium-catalyzed sequential process, involving allylic alkylation of a stabilized carbon or heteroatom nucleophile 51, followed by a PK reaction, utilizing a single catalyst was also described (Scheme 11.14). Alkylation of an allylic carbonate 53 was accomplished in a regioselective manner at 30 °C using a j-acidic rhodium(I) catalyst under 1 atm CO. The resulting product 54 was then subjected in situ to an elevated reaction temperature to facilitate the PK transformation. 

Pathway 2 of Scheme 9 corresponds to one of the most interesting developments in the Beckmann rearrangement chemistry. By trapping of the electrophilic intermediate with a nucleophile (Nu ) other than water, an imine derivative 227 is produced that may be used for further transformations. Carbon or heteroatom nucleophiles have been used to trap the nitrilium intermediate. Reducing agents promote the amine formation. More than one nucleophile may be added (for example, two different Grignard reagents can be introduced at the electrophilic carbon atom). Some of the most used transformations are condensed in Scheme 11. 

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