Carbinolamine formation

Oxidative attack on a carbon-hydrogen bond of an alkyl group a to a nitrogen atom is not restricted to saturated aliphatic amines. In fact X in an X-N-CH- structural subunit can be virtually any common atomic grouping that can be found in stable organic molecules. For example, w-carbon hydrogens of Aralkyl-substituted aromatic cyclic amines (119), aryl amines (120), amides (121), amidines (122), A-nitrosodialkylamines (123), etc. are all subject to oxidative attack, carbinolamine formation, and in most cases release of an aldehyde or ketone depending on the substitution pattern (1° or 2°)... 

Carbinolamine formation ammonia plus a carbonyl compound Nearing completion Manuscript in preparation... 

Carbinolamine formation arylamine plus a carbonyl compound Preliminary examination... 

Scheme After the initial carbinolamine formation, further base treatment is required... 

Fig. 7.7. Upper panel Energy profiles from G2 computations for (a) carbinolamine formation, (b) imine formation, and (c) iminium ion formation with zero, one, and two water molecules. Lower panel Transition structures for carbinolamine, imine, and iminium ion formation with zero, one, and two water molecules and showing selected bond lengths and angles. Reproduced from J. Phys. Chem. A, 102, 4930 (1998), by permission of die American Chemical Society.

The change in rate-determining step from carbinolamine dehydration to carbinol amine formation occurs as the pH decreases [5,8,9]. As shown in Fig. 1 for the hydrolysis of substituted benzylidene-l,l-dimethylethyl amines, the pH rate profiles vary dramatically at lower pH values. The high pH rates are due to attack of hydroxide ion on protonated imine, which is the reverse of the dehydration of carbinolamine. At lower pH values the term due to water addition to protonated imine becomes substantial for those imines with electron withdrawing substituents. At even lower pH values the rate drops because of the change in rate determining step to the decomposition of the carbinolamine intermediate, which is the reverse of carbinolamine formation. In those cases where the zwitterionic intermediate formed by amine addition to a carbonyl compound ( j in Scheme 1) is very unstable, the required proton-transfer steps (kh Scheme 1) may become rate-determining. This... 

STEP 1 Draw the three steps necessary for carbinolamine formation. 

Secondary amines (R2NH) have one hydrogen, and so carbinolamine formation is possible (Fig. 16.53). This reaction can be followed by protonation and water loss to give a resonance-stabilized cation, called an iininimn ion. An iminium ion has... 

FIGURE 16.53 For secondary amines (R2NH) carbinolamine formation is possible, then water is lost to give a resonance-stabilized iminium ion. There is no hydrogen remaining on nitrogen that can be lost to give an imine. 

The marked positive p value corresponds to the sign obtained when nitrogen bases react with a series of carbonyl compounds under conditions in which carbinolamine formation is rate limiting and contrasts with the near zero value of p obtained from the observed rate constants when carbinolamine dehydration is rate limiting. Thus we conclude that hydroxyhydrazine formation is rate linuting, and since it is evidently general acid catalyzed, it can be described by mechanism (52). This mechanism is analogous to mechanism (37) proposed... 

Figure 3. Logarithmic plot of the effect of substituents on benzaldehyde semicarbazone formation at neutral pH in 25% ethanol. (Equilibrium constant for carbinolamine formation, rate constant for carbinolamine dehydration, A2 rate constant for the overall reaction, Aovereu -)...

As the basicity of the amine is allowed to increase in a series of condensation reactions, there will be a gradual transition from mechanism (37) to mechanism (38). Reactions using amines of intermediate basicity are described by a combination of the two mechanisms. Also, a reaction that can be described by one of the mechanisms may require a combination of the two mechanisms for a description of its behavior under particular conditions. For example, mechanism (38) completely describes the course of oxime formation except when the reaction is carried out in strong acids. Under these conditions carbinolamine formation is acid catalyzed and a small contribution from mechanism (37) must be included in the description. It is of interest to note that the mechanism used to describe SchifF base formation depends on whether the amine used is aliphatic (mechanism 38) or aromatic (mechanism 37) . 

Rate constants have been measured for oxime formation in water for several substituted benzaldehydes and hydroxylamine, over a range of pH from 7 down to 2. Hammett plots have been constructed for carbinolamine formation and its dehydration. 

Formation of oxime (41) from 4-dimethylaminobenzaldehyde (X = NMc2) and 4-trimethylammoniobenzaldehyde (X = NMesP) has been interpreted in terms of a standard two-step mechanism initial carbinolamine formation, followed by dehydration. pH-rate profiles have been constructed for both compounds the amine shows evidence of a change in rate-determining step at low pH (and of the intervention of the reaction of the protonated amine), while the ammonium salt shows a change from acid-catalysed to uncatalysed carbinolamine formation. Equilibrium constants for oxime formation are also reported and discussed. 

---