Double Hydrogen Bonding

3 Intermolecular Hydrogen Bonding 1.3.1 Double Hydrogen Bonding 

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Kelly and colleagues91 explored the use of bisphenylenediol 103 as a catalyst in Diels-Alder reactions of a,/i-unsaturated carbonyl compounds. Activation of the dieno-phile occurred through double hydrogen bonding of the two hydroxyl functions on 103 to the carbonyl group on the dienophile. The reaction of cyclopentadiene with methyl vinyl ketone (equation 31) at ambient temperature showed, after a reaction time of 10 minutes, 3% of product formation in the absence of 103 against 90% of product formation in the presence of 0.4 equivalents of 103. 

The two more stable structures jomo and ietero are characterized by a double hydrogen bond between Ej and Pj or P. The Ej molecule acts as proton donor towards the nitrogen of prolinol, and as acceptor towards the alcoholic proton of P . In the two less stable structure IIhomo and Utetero. the prolinol maintains an intramolecular H-bond between the alcoholic oxygen and nitrogen and, thus, only one hydrogen bond with the Ej molecule is possible, in which the oxygen of Pr/s accepts a proton. 

The other two hydroxyls in each POi, group of the chain link it with water or some other proton acceptor molecules in the solution. In a diluted PA there are less direct P0i,-H-P0h connections, with more water molecules inserted between POit groups, which means that dilution hinders the formation of long PA chains. In a more concentrated PA double hydrogen bonds between POi, groups appear (17) leaving less free hydroxyls for the side linkages of PA chain with other molecules in the solution. 

Fig. 2 Double hydrogen bonding enamine catalysts developed by Gong and Singh...

Activation of carbonyl compounds by double hydrogen bonding an emerging tool in asymmetric catalysis (P. M. Pihko, 2004) [lb]. 

For organizational reasons, several catalytic systems possessing multiple hydrogen bond donating functionalities have been included in this section which may not be classified as BBAs. For example, the bistrifylamide Mikami catalyst could perhaps be classified as a double-hydrogen bond donor catalyst akin to thiourea catalysis. 

Scheme 6.1 Active sites of enzymes employing a double hydrogen-bonding motif for substrate coordination and activation in various biochemical transformations Haloalcohol dehalogenase (1), formate dehydrogenase (2), and serine protease (3).

Figure 6.1 Chronological order of milestone achievements toward catalytically active (thio)urea organocatalysts utilizing explicit double hydrogen-bonding interactions for substrate activation.

Key Publications for the development of explicit (double) hydrogen-bonding (thio)urea organocatalysts and numiser of publications on this research field per year... 

Wittkopp and Schreiner introduced the simple electron-deficient N,N -bis [3,5-(trif-luoromethyl)phenyl]thiourea 9 (Figure 6.3) as an efficient double hydrogen-bonding organocatalyst in a series of Diels-Alder reactions and 1,3-dipolar cycloadditions of... 

As demonstrated in a series of kinetic experiments by Wittkopp and Schreiner, nitrone N-benzylideneanihne N-oxide can be activated for 1,3-dipolar cycloadditions through double hydrogen-bonding 9 [Ij. Takemoto and co-workers, in 2003, published the nucleophilic addition of TMSCN and ketene silyl acetals to nitrones and aldehydes proceeding in the presence of thiourea organocatalyst 9 (Figure 6.4) [147]. 

Figure 6.4 Proposed double hydrogen-bonding activation of nitrones through thiourea derivative 9.

In Nature, epoxide ring-opening is catalyzed by enzymes by employing the (double) hydrogen-bonding motif (Scheme 6.1) for epoxide activation toward... 

These experimental results suggested a hydrogen-bonding mediated cooperative Bronsted acid catalysis mechanism (Scheme 6.28). Thiourea cocatalyst 9 is viewed to coordinate to mandelic acid 20 through double hydrogen-bonding, stabilizes the acid in the chelate-hke cis-hydroxy conformation, and acidifies the a-OH proton via an... 

Urea 32, the bis-(mono-trifluoromethyl)phenyl derivative of urea catalyst 16 [178], was reported to operate as double hydrogen-bonding organocatalyst in the diastereoselective synthesis of y-butenolide products substituted at the y-position... 

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