Imine formation proton transfer

Another type of bifunctional catalysis has been noted with a,cn-diamines in which one of the amino groups is primary and the other tertiary. These substituted diamines are from several times to as much as 100 times more reactive toward imine formation than similar monofunctional amines. This is attributed to a catalytic intramolecular proton transfer. 

The TS proposed for these proline-catalyzed reactions is very similar to that for the proline-catalyzed aldol addition (see p. 132). In the case of imines, however, the aldehyde substituent is directed toward the enamine double bond because of the dominant steric effect of the (V-aryl substituent. This leads to formation of syn isomers, whereas the aldol reaction leads to anti isomers. This is the TS found to be the most stable by B3LYP/6-31G computations.199 The proton transfer is essentially complete at the TS. As with the aldol addition TS, the enamine is oriented anti to the proline carboxy group in the most stable TS. 

Noyori and coworkers reported well-defined ruthenium(II) catalyst systems of the type RuH( 76-arene)(NH2CHPhCHPhNTs) for the asymmetric transfer hydrogenation of ketones and imines [94]. These also act via an outer-sphere hydride transfer mechanism shown in Scheme 3.12. The hydride transfer from ruthenium and proton transfer from the amino group to the C=0 bond of a ketone or C=N bond of an imine produces the alcohol or amine product, respectively. The amido complex that is produced is unreactive to H2 (except at high pressures), but readily reacts with iPrOH or formate to regenerate the hydride catalyst. 

Scheme 6.104 Key intermediates of the proposed catalytic cycle for the 100-catalyzed Michael addition of a,a-disubstituted aldehydes to aliphatic and aromatic nitroalkenes Formation of imine (A) and F-enamine (B), double hydrogen-bonding activation of the nitroalkene and nucleophilic enamine attack (C), zwitterionic structure (D), product-forming proton transfer, and hydrolysis.

C-C bond formation occurs at the re-face of the enamine intermediate. This facial selection is controlled by proton-transfer from the carboxylic acid to the imine nitrogen. 

The mechanism for formation of the hydrazone is the same as the mechanism for imine formation (Key Mechanism 18-5 in Section 18-15). The actual reduction step involves two tautomeric proton transfers from nitrogen to carbon (Mechanism 18-7). In this strongly basic solution, we expect a proton transfer from N to C to occur by loss of a proton from nitrogen, followed by reprotonation on carbon. A second deprotonation sets up the intermediate for loss of nitrogen to form a carbanion. This carbanion is quickly reprotonated to give the product. 

Whereas the proton transfer does not effect the stochiometry of the final PI when water is eliminated in the imidization reaction (fig. 3F), addition of an excess ODA molecule to polyamic acid could lead to the imine type crosslink formation schematically shown in figure 3G. This would lead to a deficiency of carbonyl oxygen atoms for vapor deposited polyimide and is consistent with our analysis. Mack et al. [16] proposed imine crosslink formation from their Raman spectroscopic studies for vapor deposited polyimides with excess ODA. In accordance with this model we attribute the low binding energy shoulder in the polyimide Nls line (figure 4c) to double bonded nitrogen species. However, the model gives no explanation for the carbonyl deficiency found in spin deposited polyamic acid and polyimide. In this case no excess of ODA is observed and only a very weak shoulder has been reported for the Nls line [4,11]. 

The steps involved in imine formation (1) dehydration, (2) nucleophilic addition of the amino group of the amino acid, (3) proton transfer, and (4) loss of water. 

The mechanism of the alkylation of imines with electrophilic alkenes has been discussed by D Angelo and coworkers S who conclude that reaction occurs via an aza-ene reaction-like transition state 206 involving concerted proton transfer from the nitrogen and carbon-carbon bond formation (Scheme 206). ITiey further propose that the remarkable regiocontrol observed in these reactions originates from this crucial internal proton transfer which would not be possible in a conformation such as 207 of the less substituted enamine tautomer, since the N—H bond would be anti to the enamine double bond. However, although this seems probable, it is by no means proven. Inconsistencies in the argument and the evidence presented cast some doubt on the validity of these conclusions. For example ... 

The same scaffold was used to design catalysts for pyridoxal phosphate-dependent deamination of aspartic acid to form oxaloacetate, one half of the transamination reaction [8], and oxaloacetate decarboxylation [14]. Catalysis was due to binding of pyridoxal phosphate in close proximity to His residues capable of rate limiting 1,3 proton transfer. A two-residue catalytic site containing one Arg and one Lys residue was found to be the most efficient decarboxylation agent, more efficient per residue than the Benner catalyst, most likely due to a combination of efficient imine formation, pK depression and transition state stabilization. 

Bovine serum amine oxidase (BSAO) is a copper-containing amine oxidase which utilizes a covalently bound 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor in the two-electron oxidation of a broad spectrum of primary amines [99]. The oxidation is thought to proceed via the formation of an iminium complex between the oxidized form of the cofactor and the primary amine (1 in Scheme 10.4). The substrate imine undergoes deprotonation to form product imine, which, after hydrolysis, releases aldehyde product and reduced cofactor [100]. Proton transfer is either partially or largely rate-limiting for the oxidation of benzylamines, as evidenced by a large deuterium isotope effect at the methylene adjacent to the amino group [36, 101, 102]. 

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... 

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