Nucleophilic Attack on Hydrogen Attached to Carbon

This section treats the lithiation of 1,2,3-triazines by lithium 2,2,6,6-tetramethylpiperidide (LTMP). The theoretical aspects of H/Li-exchange, especially for alkoxytriazines, have been discussed in Section 9.01.2.13, and the option to bypass the reluctance of 1,2,3-triazines to undergo electrophilic substitution by lithiation, followed by quenching with electrophiles, has been pointed out in Section 9.01.5.3. 

Method A (accumulation of lithiated tria dne attempted). The triazine was treated with 4 equiv of LTMP in THE at — 100°C for 20 min, followed by reaction with an arenealdehyde at —100 °C for 1 h and subsequent aqueous acidic workup. Method B (shift of equilibrium to the lithio derivative attempted). The triazine was treated with a mixture of LTMP and TMSCl at — 100°C for 2h and subsequent aqueous acidic workup. 

Starting triazine Method applied Electrophile Products and yields i%) 

Many silylated products (from GC-MS) none isolated or identified 

All of the products, 123-128, were characterized fully spectroscopically and, in the case of (iJ, J )-123, also by a single crystal X-ray structure analysis. It was demonstrated that the starting triazines had been degraded with the loss of two N-atoms and that, from the number of residues introduced by reaction with electrophiles, 2equiv of LTMP had been used. N-atoms alone may support lithiation but do not stabilize the lithiated species satisfactorily 2003TH1 . 

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Nucleophilic Attack on Hydrogen Attached to Carbon Deprotonation 830... 

Nucleophilic Attack on Hydrogen Attached to Carbon Reactions with Radicals and Electron-deficient Species. 8.1 Homolytic substitution. 8.2 Reaction with carbenes... 

You see in Chapter 10 that aldehydes and ketones contain a carbonyl group attached to carbon or hydrogen atoms. In the case of carboxylic acids and their derivatives, a carbonyl group is attached to an electronegative element such as oxygen, chlorine, or nitrogen. The presence of these elements tends to increase the 5+ charge on the carbonyl carbon, which makes the carbon atom more susceptible to nucleophilic attack. 

Alternatives to the oxocarbenium ion mechanism are the direct attack of water on the substrate, and the nucleophilic attack of Asp-52 on the C-1 carbon to give an ester intermediate. The single-displacement reaction has been ruled out by showing that the reaction proceeds with retention of configuration (Chapter 7, section C3 Chapter 8, section C2).212-214 The oxocarbenium ion or SN1 mechanism has been substantiated by secondary isotope effects, using substrates containing either deuterium or tritium instead of hydrogen attached to the C-1 carbon 215 216 For example, kK/kD for structures 16.42 is 1.11,... 

Pyridine compounds in which phosphorus is directly attached to a ring carbon are relatively rare. Phosphorus nucleophiles are not able to replace ring hydrogen atoms in pyridines and pyridine 1-oxides. Some time ago it was found that pyridine yields a zwitterion (170) when it is heated under reflux in the presence of tetraphosphorus decasulfide (Scheme 105) (68MI20500). Recently, a product that contains a C—P bond was isolated after extended heating under the same conditions followed by treatment with hydrochloric acid (81 JCR(S)285). However, it is uncertain whether free pyridine undergoes reaction in this case. Attack by phosphorus nucleophiles on salts is well established. Af-Methylacridinium methosulfate affords a stable isolable 9,10-dihydro adduct (171) that readily forms a... 

Addition involves nucleophilic attack by bisulfite ion on carbonyl carbon, followed by attachment of a hydrogen ion to carbonyl oxygen ... 

We can understand the regioselectivity —why the electrophile (Br+) ends up attached to the sp carbon bonded to the most hydrogens— if we examine the two possible transition states. They show that the C—Br bond has broken to a greater extent than the C—O bond has formed. As a result, there is a partial positive charge on the carbon that is attacked by the nucleophile. 

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