Aldehyde or Ketone and Ring-carbon

Addition of Alcohols to Form Hemiacetals (Section 16.7B) Hemiacetals are only minor components of an equilibrium mixture of aldehyde or ketone and alcohol, except where the —OH and the C—O are parts of the same molecule and a five- or six-mem-bered ring can form. The reaction is catalyzed by acid or base. The mechanism involves protonation of the carbonyl oxygen atom that facilitates attack by an alcohol at the carbonyl carbon followed by loss of a proton to give the hemiacetal. 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

Routes to dihydro-1,4-thiazines are more diverse (B-78MI22701). For example, ring expansion of the thiazolidine (273) by heating with elemental sulfur and n-butylamine affords a 3 1 mixture of the isomers (276) and (277) and it appears likely that these products are derived from their tautomers (274) and (275) respectively which are the initial reaction products (Scheme 118) (70LA(739)32). Thiazolidines also accompany dihydrothiazines as products when aldehydes or ketones are reacted with aziridines in the presence of sulfur and DMF or potassium carbonate and it seems certain that a similar mechanistic sequence is involved (79M425). 

Hydrazide groups directly react with aldehyde and ketone functional groups to form relatively stable hydrazone linkages (Chapter 2, Section 5.1). Two fluorescein derivatives are commonly available that contain hydrazide groups off their No. 5 carbons on the lower ring structure. Both may be used to label fluorescently aldehyde- or ketone-... 

Another hydrazine derivative of fluorescein, 5-(((2-(Carbohydrazino)methyl)thio)-acetyl)-aminofluorescein, contains a longer spacer arm off its No. 5 carbon atom of its lower ring than fluorescein-5-thiosemicarbazide, described previously (Molecular Probes). The reagent can be used to react spontaneously with aldehyde- or ketone-containing molecules forming a hydrazone linkage (Fig. 209). It also can be used to label cytosine residues in DNA or RNA by use of the bisulfite activation procedure (Chapter 17, Section 2.1). The resulting fluorescent derivative exhibits a maximal excitation at 490 nm and a maximal luminescence emission peak at 516 nm when dissolved in buffer at pH 8. In the same buffered environment, the compound has an extinction coefficient of approximately 75,000 M-1cm 1 at 490 nm. 

BODIPY 530/550 C3 hydrazide is 4,4-difluoro-5,7-diphenyl-4-bora-3a,4a-diaza-s-indacene-3-propionyl hydrazide, a derivative of the basic BODIPY structure, which contains two phenyl rings off the No. 5 and 7 carbon atoms and a propionic acid hydrazide group on the No. 3 carbon atom (Molecular Probes). The hydrazide functional group reacts with aldehyde- or ketone-containing molecules to form hydrazone linkages (Fig. 229). The compound may be used to label glycoproteins or other carbohydrate-containing molecules after oxidation of their polysaccharide portions with sodium periodate to yield aldehyde residues. 

Many heterocyclic rings are made by the formation of a carbon-heteroatom bond and it is important when planning this to get the oxidation level of the carbon electrophile right. If we disconnected either C-N bond of the pyrrole 8, we get back to a ketone and an amine 9. If we disconnected the imine in imidazole 10 we should also get back to a ketone and an amine 11. Both 9 and 11 are unstable and neither is likely to be a real intermediate but the point is worth making. These carbon electrophiles are at the aldehyde or ketone oxidation level. 

All monosaccharides and their derivatives that possess aldehyde or ketone groups (that is, excepting derivatives such as alditols and aldonic acids) will have reducing properties. Moreover, those with the appropriate number of carbon atoms can form rings occurring in two forms (anomers) and in which the potential reducing carbon is called the anomeric carbon. 

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