Double proton-relay

Figure 6.1 Double proton-relay in the dimers 2-hydroxy pyridine (1) to 2-pyridone (2) and lH,3X-pyrazole (3) to 2H,3X-pyrazole (4).

In a very important paper, Tsuchida and Yamabe [26] proposed a tautomeriza-tion mechanism applicable for solutes in the solution of nonprotic solvents. The basic idea was presented by the example showing the dimeric 2-OH pyridine (1) (Figure 6.1), where each solute has a N-C-O-H substructure. Through a double proton-relay within an eight-member ring, the H-N-C=0 moiety can come into existence in both solute molecules, corresponding to the dimer of the 2-pyridone (2) tautomer. However, the mechanism in the presented form works only if the dimerization is feasible in the given solvent and the two polar sites are sterically close within the molecule or if the sites involved in the proton-relays can get close to each other at least in the dimer. 

Figure 6.6 Direct double proton-relay in the natural guanine-cytosine pair G- -C resulting in the formation of a rare complex (G- ). ...

As mentioned above, the appearance of the so-called rare tautomers of the nucleobases may cause severe health problems. A number of theoretical papers [70-73] investigate the thermodynamic conditions for their formations. Intramolecular proton migrations are unlikely in the gas phase. However, hydrogen-bonded pairs can be formed in DNA and RNA. The rare form can come into existence through a double proton-relay. Whether the process is concerted or sequential, it is a matter of debate and could depend also on the system (A-T/U... 

Especially interesting are the computational results of Ceron-Carrasco et al. [72] who investigated the double proton-relay for the G-C complex with three intermolecular hydrogen bonds (Figure 6.6). The water molecules reside on the periphery of the complex and therefore cannot directly participate in the proton transfer for the middle hydrogen bond. The authors conclude that the double proton-relay process is sequential thus the above first proton-relay necessarily leads to the formation of a zwitterionic structure. 

In the aromatic series, Nagy and Takacs-Novak [49] pointed out both theoretically and experimentally that the 3- and 4-COOH pyridine carboxylic acids (nicotinic and isonicotinic acids) form the zwitterionic species in aqueous solution. The distances of the -COOH groups from the pyridine nitrogens prevent the formation of a favorable dimeric form (except for the 3-COOH isomer with and anti carboxylic conformation) where a double-proton-relay... 

FIGURE 7.2. Two alternative mechanisms for the catalytic reaction of serine proteases. Route a corresponds to the electrostatic catalysis mechanism while route b corresponds to the double proton transfer (or the charge relay mechanism), gs ts and ti denote ground state, transition state and tetrahedral intermediate, respectively. 

Double proton transfer mechanism, see Serine proteases, charge-relay mechanism... 

Interpretation of early X-ray and NMR spectroscopic results lead to the hypothesis that the serine hydroxyl is activated via a charge-relay mechanism including proton removal from serine to the buried aspartate anion via the neighbouring histidine (cf. Fig. 4 b). This double proton transfer would yield neutral aspartic acid and an alkoxide anion with enhanced nucleophilicity. Later this was questioned on the basis of more precise NMR and neutron diffraction studies (cf. [241] for references). At variance with earlier quantum chemical calculations [246, 247] predicting the aspartate as the ultimate proton acceptor, we stressed the importance of the electrostatic effect of the environment including the protein dipoles, surrounding water molecules and a counter ion, and concluded that, while the Asp-His couple exists in a neutral form in vacuo, the ion-pair form is stabilized by the environment [239, 241]. These results have been confirmed by recent sophisticated calculations [218]. 

We first present the overall featme of an example of the dynamics in water-assisted proton transfer in Fig. 7.11. Panel (a) indicates that the distance of the proton Hoo from Op becomes longer than that from Ow at time about 2 fs, while panel (b) shows that the proton Hqn leaves from the site of Ow and arrives at the vicinity of N at about 5 fe. Thus the first transfer took place in the site of Op — Ow and that of Op — N followed in this particular example of proton relay. This is not always the case, though. That is, proton transfer in the site of Ow — N can precede that of Op — Ow- The tt bond-order displayed in panel (c) claims the double bond has shifted from C — N to Op — C at time about 7 fe. Since the tautomerization is completed in this way, we may judge that the present proton-relay has been achieved successfully along this path. 

An immediate suggestion from the above study is that the rotation along the axis of C — N in polypeptide becomes far more difficult by the presence of water molecules for two reasons They may stabilize the zwitter ionic structure as a solvent effect. Besides, water molecules may cause proton relay transfer in the reverse manner of the present state, that is, from keto form (peptide) to enol form, which results in creation of a strong double bond in C — N. Thus the presence of water molecules around polypeptide can make the dramatic difference from gas phase reaction. Although the extent of possibility of free rotation around the C - N bond in polypeptide is well-known as one of the classic issues in protein science [244], one should... 

In 1969 it was suggested that the proton from the catalytic histidine may be transferred to the buried aspartate during catalysis and this charge-relay mechanism vastly increases the nucleophilicity of the active serine through its ionization. This process, outlined in many textbooks, is called the double proton-transfer or charge-relay mechanism. Later on, the hypothesis was questioned on the basis of experimental studies, - molecular orbital - and semimacroscopic calculations. All the above studies supported the early proposal by Polgar and Bender who stated that the buried aspartate remains ionized throughout the catalytic process and its role is mainly to increase the stability of the ion pair formed by the tetrahedral intermediate and protonated histidine. 

The presence of an ionized aspartic acid next to histidine raises its basicity and facilitates proton transfer from Ser-195 in the direction of His-57. If the proton resides on histidine, this side chain is positively charged. The charge is stabilized by the neighboring Asp-102, which may also stabilize the conformation of His-57. In some earlier proposals for SP mechanisms, it was assumed that a "double PT" or "charge relay" system is operating between the catalytic triad residues, and two PTs, the second being from His to Asp, take place. 

The individual proton spin systems for each sugar residue were delineated by homonuclear and heteronuclear correlations as detected from COSY and multistep homonuclear relayed coherence transfer (RCT) experiments [9], In this way triple relayed correlations were detected from anomeric protons (Hi) to H5 via the intervening H2 ( direct coupling), H3 (single relayed coherence transfer) and H4 (double relayed coherence transfer). Thus, beginning from the anomeric proton (5 6.13, Glc Hi 5.68, Rha. Hi 4.89, Glc . Hi 4.70, Ara . Hi 4.68, Ara. Hi ), all 2-position protons of sugar moieties were easily located in the... 

Figure 2 (a) Single RCT spectrum of 1. Labelled peaks indicate the relayed coherence transfers between anomeric protons of sugar residues with their respective 3-position protons, (b) Double RCT Sj tnim of 1. Labelled peaks indicate the relayed coherence transfers between ancmieric protons with their respective 4-position protons, and the coherence transfer between Rha.Hi with Rha.H3. 

In 2013, Terada and Toda reported a relay catalysis for a ternary reaction sequence composed of double bond isomerisation, protonation of the double bond, and enantioselective Pictet-Spengler-type cyclisation, which was accomplished using a binary catalytic system consisting of a ruthenium hydride complex and a chiral phosphoric acid. As shown in Scheme 7.47, the intramolecular reaction of allylamides led to the corresponding chiral tetrahydroisoquinoline derivatives in moderate to good yields and insufficient enantioselectivities of 18 to 53% ee. 

Figure 5.88. Pulse sequence for recording two-dimensional double-quantum 2QT NMR spectra. This results in cross peaks between directly coupled protons (i.e., protons on the a-carbons) as well as more remote protons (on the j5-carbon atoms) by a relayed effect.

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