Oxidation of monosaccharides by N-metallo-N-haloarylsulfonamides a reviewW

Mechanism of oxidation of monosaccharides such as erythrose and threose series pentoses and hexoses, 6-deoxyhexoses, uranicacids and aminosugars arc studied with mild oxidizing agents such as Cl+, Br+ or J+ in detail. The product profile was confirmed by HPLC and GLC-MS dat:1. Based on the available data, general mechanism for the oxidation of monosac charides has been reported.


Introduction
Carbohydrates including sugars are one of the major groups of organic matter to occur naturally. Carbohydrates and its oxidative products play a key role as intermediates for the synthesis of many organic molecules. In this context, anumber of authors have developed many oxidation procedure '¥Dedicated to Professor Y. K. Gupta on his 80th birth anniversary.
for carbohydrates with various oxidants. Although the oxidation of monosaccharides were studied by several work-ers2·3·11, clear information or an overall view is lacking. In our laboratory we have studied extensively in detail and published several papers 5 · 12 -17 on the oxidation of varieties of monosaccharides. This prompted me to document an overall view on the oxidation of monosaccharides with various oxidants. Herein, report the oxidation of monosaccharides such as erythrose and threose series pentoses and hexoses, 6-deoxyhexoses, aminosugars and uronic acids with all avai I able N-metallo-N-haloarylsulfonamides in alkaline medium. The details of experimental procedure can be found from our previously pub!ished papers 5 · 12 . The product profile of the above monosaccharides are discussed. Based on these data, a general mechanisms for the oxidation of the monosaccharides have been proposed.

N-Metallo-N-haloarylsulfonamides (1) as oxidants :
The N-metallo-N-haloarylsulfonamides (1) are a class of compounds capable of producing halonium cations, hypohalites and N-anions which behave both as bases and as nucleophiles, depending on the reaction conditions. The subject has been extensively reviewed and well studied I-S. These oxidants contain a strongly polarized N-linked halogen which is in the+ I state (X = Cl or Br or I, bonded to nitrogen is positive). Since these oxidants react with a wide variety of functional groups, they are used as reagents in analytical chemistry5- 7 . We have demonstrated that these oxidants can be used as mild 5 , specific and selective oxidations can be carried out. Therefore, we employed these oxidants as effective and studied with several possibilities by changing Rand X in 1 to get the detailed information of the proposed studies. It is also noted that RNXis the active 1. Indian Chem. Soc., Vol. 81, December 2004 species under the present experimental conditions. The details regarding the active species can be found from the papers published elsewhere 8 -LO.

HPLC and GLC-MS analysis of products :
HPLC and GLC-MS analysis of the products indicated that o-mannose, D-glucose, o-fructose, L-arabinose and Dribose were oxidized to a mixture of aldonic acids consisting of arabinonic, ribonic, erythronic and glyceric acids. In the case of hexoses, besides these acids, small portions of hexonic acids were formed (Fig. 1). Incubation of sugars with alkali alone, under the reaction conditions, did not degrade the sugars to significant extent. The oxidation products of sugars were also analyzed at 0.5, 1, 2, 4, 8, 16 and 24 h. The relative proportions of various aldonic acids formed (see Fig. l and Table I) were similar at all time points analyzed (except in the case of hexoses, the formation of six-carbon aldonic acids was observed only after 4 h), revealing that the lower-carbon aldonic acids were not derived from the initially formed six-carbon aldonic acids. Consistent with these data, D-gluconic, D-mannonic, Dgalactonic, o-ribonic and D-arabinonic acids were not oxidized by 1.

Mechanism:
In the proposed mechanism (Scheme I) the anion Eof sugars (keto-isomer in the case of hexoses and aldo isomer in the case of pentoses) react with 1 to form intermediates X 1 -X 3 • In the case of anions (E-) froin hexoses, the loss of hydrogen occur at either C-1 or C-3 to form C-1-C-2 or C-2-C-3 enediols containing hal onium group at C-2 to form intermediates X I and x2. The formation of x2 accompanies epimerization at C-2 and C-3, X 1 and X 2 then can undergo cleavage of C-C bonds between C-1 and C-2, the former giving arabinonic acid and the later forming a mixture of arabinonic and ribonic acids. In the case of Efrom pentoses, hydrogen can be removed only from C-2 to form C-1-C-2 enediol anion, which in the presence of alkali forms intermediate X 3 with epimerization at C-2. Breakage of C-1-H bonds from X 3 gives a mixture of arabi nonic and Rangappa Oxtdallon ot mono~.lcchJI!dos by N-mct,dlo-N-It.tloatylsulton.umdes etc ubomc .lctds a<> m the case ot X, The clcJv,tgc ot C-C -~ bond<; between C-2 .1nd C-3 m X 1 ,md X 2 , .md the bteah.tng of C-C bonds between C-1 Jnd C-2 111 X.~ yteld .ddo-tett O'>c wtthout eptmettzallon at C-4 (hexoses) 01 at C-1 {pcmo<;cs) The a I do-tetrose further oxtdtLes to yteld et ytht omc .tud and a mtnm propm tton of threonrc .tcrd '('f,tble 1) The te-' actiOn can proceed further, wtth the cleavage of C-C bond<; between C-3 and C-4 of hexoses .1nd the brcJI-.mg ot C-C bonds between C 7 2 ancl C-3 of pentoses, to fot m glycertL actd 3. Oxidation of threo-.e -.cries pentoscs and hcxo..,cs by l in alkaline medium

Mechanism :
In the proposed mechanism (Scheme 2), the keto-enolic anions (E-) of sugars react with 1 to form intennediates X 1 -X 3 • For threose-series hexoses, the anions (E-) intenne-diatc~ are predominantly the keto-enolic forms. However, for pcntoses, the major reacting species are aldo-enolic an-ion<>: probably minor proportions of keto-isomer may also be involveu. In the case of anions (E-) from hexoses, the loss of hydrogen can occur at either C-1 or C-3 to form C-1-C-2 or C-2-C-3 enediols containing a hypochlorite group at C-2. Since epimerization at C-3 was limited, as   evidenced by the formation of only very minor proportions of epimeric pen tonic acids from hexoses, it ca11 be concluded that cleavage of the C-1-H bond occurs preferentially as compared with cleavage of the C-3-H bonds to form C-1-C-2 enediols. The enediols thus formed contain polarized double bonds to which hydroxide ion can add at C-2 to form intermediates X 1 (major) and X 2 (minor). X 1 and X 2 then can undergo cleavage of C-C bonds between C-1 and C-2, the former giving lyxonic acid and the latter forming a mixture of lyxonic and xylonic acids.
In the case of aldo-enolic anions from pentoses, hydrogen can be removed only from C-2 to form the C-1-C-2 enediol-anion, which in the presence of l and alkali forms intermediate X 3 with epimerization at C-2. The cleavage of C-1-H bonds from X 3 gives a mixture of lyxonic ami xylonic acids. The cleavage of C-C bonds between C-2 and C-3 in X 1 and X 2 , and the breaking of C-C bonds between C-1 and C-2 in X 3 yield aldo-tetrose without epimerization at C-4 (hexoses) or at C-3 (pentoses). The aldo-tetrose further oxidizes to yield threonic acid and a minor proportion of erythronic acid ( Table 2). The reaction can proceed further. with the cleavage of C-C bonds between C-3 and C-4 of hexoses and the breaking of C-C bonds between C-2 and C-3 of pentoses, to form glyceric acid. Minor proportions of threonic and glyceric acids could also be formed by the cleavage of C-1-C-2 and C-2-C-3 bonds, respectively, from the keto-enolic form of pentoses through the reaction sequences similar to those outlined for keto-hexoses in Scheme 2.

HPLC and GLC-MS analysis of products:
H PLC analysis of products of L-rhamnose, L-fucose and o-fucosc indicated a mixture of aldonic acids in varying proportions. The products were identified by comparison of their HPLC retention times with retention times of the saturated aldonic acids. Oxidation of both o-fucose and Lfucosc yielded identical products namely, 5-deoxy lyxonic acid, 5-cleoxy xylonic acid and 4-deoxy erythronic acid while for L-rhamnose, the oxidation products were 5-deoxy arabinonic acid, 5-deoxy ribonic acid and 4-deoxy erythronic acids. Besides these products, small amounts of 2-hydroxy propanonic acid and 6-deoxy hexonic acids are formed (Fig. 3, Table 3). The oxidation products of 6-deoxy hexoses were also analyzed at 0.5, 1, 2, 4, 8, 16 and 24 h. The relative proportions of various aldonic acids formed (Fig. 3, Table 3) were similar at all time points analyzed. However, the formation of six-carbon aldonic acids was observed only after 4 h, revealing that the lower carbon aldonic acids were not derived from the initially formed six-carbon aldonic acids.

Mechanism :
A probable mechanistic picture of the oxidation of Lrhamose is shown in Scheme 3. In alkaline solutions, the enediol anion cs-) of the sugar reacts with the oxidant in the rate determining step to form an intermediate X.
Here the cleavage of C-C bonds between C I and C2 with epimerization at C3 forms mixture of 5-dcoxy pentonic acids. L-Rhamnose gives a mixture of (L-) 5-dcoxy arabinonic and (L-) 5-deoxy ribonic acid. The cleavage of C-C bonds between C2 and C3 in X, of 6-deoxy hexose yield (L-) 4-deoxy tetronic acid with no significant epimerization at C4 of the sugars. This explains the formation of (L-) 4-deoxy erythronic acid. The reaction can proceed further with the cleavage of C-C bond between C2 and C3 of (L-) 5-deoxy arabinose to form (L-) 2-hydroxy 5. Oxidation of amino sugars by N-metallo-N-haloarylsulfonamidcs in alkaline medium

HPLC and GLC-MS analysis of products:
The oxidation products analyzed by HPLC and GC-MS indicated that the alkoxy anion cs-) of the hexosamine formed in a base catalyzed reaction at C-l carbon is subjected to an electrophilic rate limiting attack by x+ (1, CI+ or Br+ or r+) of the oxidant. The hexonic acid formed is decarboxylated with loss of ammonia to form the respective pcntoses, which is further converted into the corresponding pcntonic acid. The breaking of the bond between C-I and C-2 carbons in pentosc yield tetronic acids ( Fig. 4 and Table 4 ). with the oxidant to form o-arabinose through dec at boxylation followed by deamination tn the form of NH 1 via hydrolysis of mtermediate imine. The pentose i ~ fut ther oxidized to arabinonic acid and its epimer ribontc acid. The former predominates over its epimer. 'Thr~ t' > pos<>tbly due to stabilization of transition state, as the preceedtng intermediate has hydrogen bonding invo[ving hydroxyl hydrogen on C-5 with oxygen on C-2. T,he-C-C bond scisston between C-l and C-2 on pentose yield the tetronic actds.

Mechanism
Tbc H and OH groups on C-3 are not significantly isomer-Ized. TillS explains the formattot~ "br erythronic acid. Further/ bond breaking. between C-2 and C~j results in the for-mati011 ·of glycet·ic acid.-, A srt)1ilar mechanism can be drawn for the oxidation of o-galactosamine by I into a mixture of o-lyxonic acid, Dthreonic actd and o-glyccric acids'ft(al~ll~e medium. 6. Oxidation of uronic acids by N-metallo-N-haloarylsulfonamides 1 in alkaline medium

HPLC and GLC-MS analysis of products:
The oxidation of D-glucuronic acid and o-galacturonic acid by 1 leads to the conesponding dicarboxylic acids, namely o-glucaric and o-galactaric acids. In this case also the oxidation was found to be smooth in the presence of NaOH at the C-1 carbon without affecting the C-6 carboxyl group, leading to the formation of the products.

Mechanism:
A possible mode of oxidation of the uronic acids as illustrated by o-glucuronic to D-glucaric acid is shown in Scheme 5. The sugar reacts in the pyranose form to give the anion which is frequently attack ll1e positive halogen of the RNX-.

Rate studies and Conclusion
(i) The observed oxidation rate is lower when R = CH 3 C 6 H 4 S02 compared toR= C 6 H 5 S02 in 1. The ratio of kobs(C 6 H 5 S02)/k 0 bs(CH 3 C 6 H 4 S02) > I, indicating the participation of -CH 3 group in the oxidant, which exerts a strong inductive effect pushing up the electron density at the polar N-X bond, thus reducing the electrophilicity of the X atom and hence the observed rate constants (Tables 5 and 6).
(ii) From the Tables 5 and 6 it is seen that, the kobs J+ > kobs Br+ > kobs et+. This may be due to the difference in electrophilicities of iodine, bromine and chlorine.
In these reactions electronegativity of halogens play an important role. Iodine has the least electronegativity of 2.2; bromine has a higher electronegativity of 2.7 and chlorine still higher electronegativity of 2.8. As the electronegativity increases, the electropositive nature decreases. Since the positive halogen atoms are the reactive species in these oxidation reactions and the electropositive nature is in the order I > Br > Cl. Therefore, reactivity of N-metallo-Nhaloarylsulfonamides is in the order lAB> BAB >CAB in the case of benzene analogues of 1. Similarly in the case of toluene analogues of 1, the reactivity is in the order IAT > BAT> CAT. From the above observation it can be generalized that iodamines are strong oxidising agents than bromamines and chloramines, and bromamines are strong oxidising agents compared to chloramines for the oxidation of monosaccharides.

Conclusion :
The present studies report a detailed investigation on the oxidation of varieties of sugars such as erythrose, threose series pentoses and hexoses, 6-deoxyhexoses, amino sug-1036 Comparison of observed rate constants for oxidation of monosaccharides by N-metallo-N-haloarylsulfonamides in alkaline medium ars and uronic acids with different oxidizing species namely et+, Br+ or r+ (1) to ascertain the mechanism involved in this type of redox systems. Furthermore, the product pro-file has been examined thoroughly. The observed rate constants (kobs) for all the sugars are given in Tables 5 and 6 and the rate of oxidation is carefully observed. With the available data, such as, kobs values, stoichiometry and product profile(%), a common mechanism in each category of sugar is operating in these molecules. The products of oxidation of all these sugars (monosaccharides) lead to the corresponding acids. In the present studies, it is observed that the change of oxidants from CJ+ tor+ did not alter the product profile(%). However, it has been noted that, the oxidation is generally faster with the iodine analogues of 1 than that of bromine or chlorine fkobs (I)> kobs (Br) > kobs (CI)].
This has been rationalized in terms of the differences in electrophilicity of halonium cations, CJ+, Br+ or J+ which are generally the reactive species in these reactions. Also, it is partly due to the moderate differences in the Van der Waal's radii of iodine, bromine and chlorine.