Hydroxamic acids hydrogen bonding

In the crystal structures, the inhibitors coordinate to the active site zinc and make a series of hydrogen bonds via their hydroxamic acid moiety. The hydroxamic acids are linked by a flexible spacer with bulky cap groups. The aromatic or aliphatic spacer participates in van der Waals interactions throughout the long charmel, whereas the terminal part of the inhibitor interacts with residues at the rim of HDAC. In general, the binding mode of the cocrystallized inhibitors TSA and SAHA is conserved among the different species and subtypes [35]. 

As points of reference, we will take two well-established hydrogen-bond donor/ acceptors, H2O and NH3. Their computed gas-phase Vs,max and Vs,mm are in Table 5, along with the same data for all of the molecules that have been discussed hydroxylamine (5), dimethylhydroxylamine (6), acetoxime (7), acetohydroxamic acid (8), and the isomeric pairs of oximes examined in the last section. Finally, we included an additional hydroxamic acid, 11, to see the effects of the strongly electron-withdrawing cyano group. 

In Table 2 are listed the hydroxylamines, oximes and hydroxamic acids for which we have determined the gas phase structures. We tried to select a representative group in each category. There are two types of oximes, as indicated, aldoximes and ketoximes. Due to restricted rotation around the C=N double bond, these can exist in two isomeric forms (except when R = H for an aldoxime and R = R" for a ketoxime). We have investigated both isomers in nearly every instance. For aldoximes, they are generally labeled syn when the H and OH are on the same side of the double bond and anti when on opposite sides. Note that the ketoximes in Table 2 contain one pair of isomers in which the >C=NOH group is not bonded to two carbons instead one bond is to a chlorine. One of these isomers wiU be of interest in Section B.D in the context of hydrogen bonding vi lone pair—lone pair repulsion. 

The hydroxamic acids also all have very similar O—H bond distances, but they are slightly longer, 0.981 to 0.984 A. This can be attributed to the intramolecular hydrogen... 

The hydrogen bonding in hydroxamic acids produces, in effect, five-membered rings (as in 1) and thus it should not be expected to be linear. For the hydroxamic acids in Table 2, the O—H---0 angles are between 118° and 122°. 

The N—O—H angles for the 55 molecules in Table 2 do not require a histogram, because they range only between 100° and 103°, except for the hydroxylamine having R = H and R" = NO2, for which the angle is 104°. This remarkable uniformity is all the more noteworthy because the molecules encompass a variety of structural features, such as the C=N double bonds in the oximes and the intramolecular hydrogen bonding in the hydroxamic acids. 

The structures of these molecules show the effects of intramolecular electrostatic interactions. Two examples are the lone pair—lone pair repulsion that is an important determinant of hydroxylamine and oxime conformations, and the intramolecular hydrogen bonding in hydroxamic acids that promotes the near-planarities of their —C(=0)—NO frameworks. 

The low value for oS30 undoubtedly arises from intramolecular hydrogen bonding stabilizing the neutral form of the acid (4), a circumstance also occurring in the pyridine-2-carboxylic and -2-hydroxamic acids as well as 2-hydroxypyridine. 

Chlorination of aldoximes. NCS converts aryl aldoximes to hydroxamic acid chlorides without significant chlorination of the aryl group. This reaction has been used for a novel synthesis of nitrile oxides. Thus reaction of salicylaldoxime (1) with NCS followed by dehydrochlorination with pyridine generates a nitrile oxide, which is trapped by styrene to give the isoxazoline 2. The N-O bond can be cleaved by catalytic hydrogenation to 3, which is converted into the chalcone 4 on elimination of water. This product can be converted by classical methods to the flavanone 5 and the flavone 6. An analogous route can be used to synthesize 2-... 

A careful 11 NMR study, together with the results of the accompanying molecular modeling calculations, predicted the most stable conformation of piperazine-l,4-bis(N-methylaceto-hydroxamic acid) 123 (cf. Scheme 44) (97JCS(P2)1977) the hydroxamate moities of the side chains interact with the nearby amino function via hydrogen bonded six-membered ring structures, tilted upward and downward . 

A type 2 intramolecular /V-acylnitroso Diels-Alder reaction of hydroxamic acid 177 followed by catalytic hydrogenation of the double bond was employed for the synthesis of substituted bridged bicyclic derivative 178, as a single diastereomer (Scheme 75 <2002OL2637>). Cleavage of the N-O bond was performed by reduction with Na(Hg) amalgam and provided m-3,7-disubstituted azocane 9, as a single isomer in 80% yield. 

Brief reports of cycloadditions with chiral acyl nitroso dienophiles have recently appeared. - In one study, acyl nitroso compound (101) derived from the corresponding hydroxamic acid was added to cy-clohexadiene to afford a 3.5 1 mixture of diastereomeric adducts (102) and (103). It was proposed that dienophile (101) reacts in the cyclic chelated form shown, since the related methyl ether which cannot internally hydrogen bond shows much lower diastereoselectivity. ... 

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