Protonation intramolecular

Irradiation of some amines in the presence of 1,4-dicyanonaphthalene causes the formation of radical cations, which give iminium ions by loss of a proton. Intramolecular addition of a hydroxylic nucleophile yields aminals (equation 23). ... 

Sar-Gly)2,Cyclo-(Pro-Sar-Gly)2 takes a simpler conformation and includes more C2-symmetric conformation with two Gly-NH protons intramolecularly hydrogen-bonded. 

Finally, the conformation of Cyclo-(Pro-Gly-Gly)2, where two sarcosine residues of Cyclo- Sar-Gly-Gly)2 were replaced by proline residues, was analyzed. This cyclic hexapeptide has been investigated by Schwyzer etaL (25,117.120) and Pease et al. (116) and was shown to take a C2-tymmetric conformation with two Gly-NH protons intramolecularly hydrogen-bonded. Schwyzer et aL (117,120) and Pease etal. (116) investigated and NMR spectra of Cydo-(Pro-(3y-(3y)2 and... 

The model studies imply mechanistic paths in the enzyme that would accommodate much of the rate enhancement and are consistent with the observations above. These are displayed in Scheme 14. The phosphate ester binds to both Zn ions, which activates the P center to attack by the coordinated deprotonated serine nucleophile. Binding the serine hydroxyl to the metal ion enhances its deprotonation and gives an efficient intramolecular nucleophile, as we have seen from model studies. Such a process would also be assisted by an enzyme base to remove the proton intramolecularly and protonation of the alkoxide leaving group by an enzyme acid would be helpful. In addition, inversion of configuration would ensue at the P center. A coordinated water at the second Zn + ion could then be deprotonated to function as the intramolecular nucleophile which eliminates the serine alkoxide ion. Both aspects would be assisted by an enzyme base and acid, respectively. The stereochemistry of the processes would lead to inversion and therefore to net retention overall consistent with the expectation from the experiments by Jones et al. (89). 

The instability of RNA in alkali is due to its 2 -OH group. In the presence of OH the 2 -OH group of RNA is converted to an alkoxide ion (RO ) by removal of a proton. Intramolecular attack by the 2 -alkoxide on the phosphodiester in RNA gives a 2, 3 -cyclic nucleotide, cleaving the phosphodiester bond in the process. Further attack by OH on the 2, 3 -cyclic nucleotide produces a mixture of 2 and 3 -nucleotides. Note that the mechanism for ribonuclease action is quite similar (see Figure 9.18, p. 216). Since DNA lacks a 2 -OH group, it is quite stable in alkali. 

SCHEME 16.25. NHC-catalyzed homoenolate protonation/intramolecular aldol/acylation domino reaction. 

Notice that we first deprotonated to form an intermediate with no charge, and only then protonated. We specifically chose this order (first protonate, then deprotonate) to avoid having an intermediate with two positive charges. This is another important rule that you should make part of the way you think from now on. Avoid intermediates with two similar charges. Now, there are always some clever students who try to combine the two steps above into one step, by transferring a proton intramolecularly, like this ... 

While it might make sense, it actually doesn t occur that way because the oxygen atom and the proton are simply too far apart to transfer a proton intramolecularly. So, you must first remove a proton, and only then, do you protonate (and it is probably not going to be the same exact proton that was removed). 

Marzocchi M P, Mantini A R, Casu M and Smulevich G 1997 Intramolecular hydrogen bonding and excited state proton transfer in hydroxyanthraquinones as studied by electronic spectra, resonance Raman scattering, and transform analysis J. Chem. Phys. 108 1-16... 

Mavri, J., Berendsen, H.J.C., Van Gunsteren, W.F. Influence of solvent on intramolecular proton transfer in hydrogen malonate. Molecular dynamics study of tunneling by density matrix evolution and nonequilibrium solvation. J. Phys. Chem. 97 (1993) 13469-13476. 

Note that for 4.42, in which no intramolecular base catalysis is possible, the elimination side reaction is not observed. This result supports the mechanism suggested in Scheme 4.13. Moreover, at pH 2, where both amine groups of 4.44 are protonated, UV-vis measurements indicate that the elimination reaction is significantly retarded as compared to neutral conditions, where protonation is less extensive. Interestingy, addition of copper(II)nitrate also suppresses the elimination reaction to a significant extent. Unfortunately, elimination is still faster than the Diels-Alder reaction on the internal double bond of 4.44. 

Carbanions stabilized by phosphorus and acyl substituents have also been frequently used in sophisticated cyclization reactions under mild reaction conditions. Perhaps the most spectacular case is the formation of an ylide from the >S-lactam given below using polymeric Hflnig base (diisopropylaminomethylated polystyrene) for removal of protons. The phosphorus ylide in hot toluene then underwent an intramolecular Wlttig reaction with an acetyl-thio group to yield the extremely acid-sensitive penicillin analogue (a penem I. Ernest, 1979). 

The synthesis described met some difficulties. D-Valyl-L-prolyl resin was found to undergo intramolecular aminoiysis during the coupling step with DCC. 70< o of the dipeptide was cleaved from the polymer, and the diketopiperazine of D-valyl-L-proline was excreted into solution. The reaction was catalyzed by small amounts of acetic acid and inhibited by a higher concentration (protonation of amine). This side-reaction can be suppressed by adding the DCC prior to the carboxyl component. In this way, the carboxyl component is "consumed immediately to form the DCC adduct and cannot catalyze the cyclization. 

The mechanism of these reactions involves the rapid and reversible addition of a proton to the aromatic ring, followed by 1,2-intramolecular methyl shifts (10) ... 

Maleic and fiimaric acids have physical properties that differ due to the cis and trans configurations about the double bond. Aqueous dissociation constants and solubiUties of the two acids show variations attributable to geometric isomer effects. X-ray diffraction results for maleic acid (16) reveal an intramolecular hydrogen bond that accounts for both the ease of removal of the first carboxyl proton and the smaller dissociation constant for maleic acid compared to fumaric acid. Maleic acid isomerizes to fumaric acid with a derived heat of isomerization of —22.7 kJ/mol (—5.43 kcal/mol) (10). The activation energy for the conversion of maleic to fumaric acid is 66.1 kJ/mol (15.8 kcal/mol) (24). 

Another successhil strategy for derivatization of erythromycin employed modification of functional groups involved in intramolecular cyclizations. The C-9 ketone, C-6 hydroxyl group, C-8 proton, and/or C-ll,12-diol of erythromycin were converted into functional groups which participate poorly, if at all, in intramolecular cyclizations. Some derivatives which have been extensively evaluated in preclinical and clinical trials exhibit such desirable properties as better stabiUty under acidic conditions, greater oral bioavadabihty, and higher and more prolonged concentrations of antibiotic in semm and tissues. 

Other approaches to inhibiting intramolecular cycli2ations of erythromycin have also proven successhil. Erom a series of O-alkyl derivatives of erythromycin, clarithromycin (6-0-methylerythromycin) (37) was selected for clinical development (146,147). Another approach replaced the C-8 proton of erythromycin with duorine, which was accompHshed by both chemical and bioconversion methods to yield durithromycin (38) (148). 

Protonated pyridazine is attacked by nucleophilic acyl radicals at positions 4 and 5 to give 4,5-diacylpyridazines. When acyl radicals with a hydrogen atom at the a-position to the carbonyl group are used, the diacylpyridazines are mainly converted into cyclo-penta[ f]pyridazines by intramolecular aldol reactions (Scheme 43). 

The acid-catalyzed rearrangements of substituted pyrroles and thiophenes consequent on ipso protonation have been referred to previously (Section 3.02.2.4.2). There is some evidence that these rearrangements are intramolecular in nature since in the case of acid-induced rearrangement of 2-acylpyrroles to 3-acylpyrroles no intermolecular acylation of suitable substrates could be demonstrated (Scheme 10) (8UOC839). 

DFT STUDY OF 8-MERCAPTOQUINOLINE INTRAMOLECULAR HYDROGEN BOND, SINGLE PROTON TRANSFER AND WATER-ASSISTED TAUTOMERIZATION... 

In an attempt to metalate a MEM-protected phenol with BuLi, the methoxy group was eliminated, forming the vinyloxymethyl ether. This was attributed to intramolecular proton abstraction. ... 

The situation presented in fig. 29 corresponds to the sudden limit, as we have already explained in the previous subsection. Having reached a bend point at the expense of the low-frequency vibration, the particle then cuts straight across the angle between the reactant and product valley, tunneling along the Q-direction. The sudden approximation holds when the vibration frequency (2 is less than the characteristic instanton frequency, which is of the order of In particular, the reactions of proton transfer (see fig. 2), characterised by high intramolecular vibration frequency, are being usually studied in this approximation [Ovchinnikova 1979 Babamov and Marcus 1981]. 

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