CHEM 203

Topics Discussed on Dec. 4

Hydrolysis of a complex (disaccharide, trisaccharide, ..., polysaccharide) to simpler carbohydrates with dilute aqueous acid; e.g.:

OH HO O HO OH HO OH HO O O OH HO OH O dil. aq. HO O HO + OH OH H2SO4 HO sucrose OH HO D-glucopyranose HO D-fructofuranose

OH OH OH OH OH O OH dil. aq. O HO O O + HO O HO HO HO OH HO H2SO4 HO OH HO HO OH D-galactopyranose D-glucopyranose

OH OH O HO O OH dil. aq. HO O 2 HO HO O OH HO HO H2SO4 HO cellobiose HO OH D-glucopyranose

Important reactions of monosaccharides: formation of ethers by Williamson reactions

Principle: a reducing sugar is a generally poor substrate for a traditional Williamson reaction, and it must be first converted into a glycoside; e.g.:

NaH, CH I; or OH OH 3 OCH3 CH OH (e.g.) NaH, (CH3O)2SO2 O HO O 3 HO O H3CO HO HO H3CO cat. HCl or NaOH, (CH3O)2SO2 OCH HO OH HO OCH3 H3CO 3 α- or β-D-glucopyranose α- or β-methyl-D-glucopyranoside

Reasons for the above: basic conditions induce undesirable reactions of (CHEM 213)

Mild modification of the Williamson reaction: alkylation of an alcohol with MeI / Ag2O:

OH OCH3 O Ag O, CH I O HO 2 3 H3CO HO H3CO HO OH H CO OCH3 α- or β-D-glucopyranose 3 Lecture of Dec 4 p. 2

Complete methylation ("permethylation") of polysaccharides, followed by hydrolysis, as a means of structural elucidation; e.g., with cellobiose, a typical disaccharide:

OH OCH3 O OH HO Ag O CH O O OCH3 O 2 3 O HO O CH3O O HO HO CH3I CH3O CH3O HO OH OCH cellobiose CH3O 3

OCH3 A OCH3 O O dil. aq. CH3O + HO CH3O CH3O OH H2SO4 CH3O B OH CH3O

the structures of the simple carbohydrates thus obtained indicates that, in the original disaccharide, OH group A must have been connected to the anomeric carbon B

Important reactions of monosaccharides: oxidation of to aldonic acids and aldaric acids (no mechanisms):

Monosaccharides react with aqueous Br2 to produce aldonic acids and with nitric acid to form aldaric acids (complex reactions – no mechanism). Example with :

COOH CHO COOH H OH H OH H OH HNO3 Br2 HO H HO H HO H

H OH H2O H OH H2O H OH H OH H OH H OH COOH OH OH

D-glucaric acid: D-glucose D-gluconic acid: an aldaric acid an

Important redox reactions of monosaccharides: reduction to alditols

Possible nucleophilic additions of hydride ion (H:–) to the C=O group of aldehydes or ketones:

a nucleophilic form R1 R1 an alkoxide of hydride ion ΔpKa ≈ –23 H– O H O pKa ≈ 17 (pKa ≈ 40) O–H ΔG << 0 H–H R2 2 weaker base strong driving force stronger base R

Metal hydrides: compounds possessing a metal – H bond: Mt–H (Mt = any metal)

Principle: the nature of the metal influences the reactivity of the hydride ion carried by a Mt–H. Thus, certain metal hydrides carry a basic form of H– (= an H– that exhibits affinity for protons; e.g. NaH), while others carry a nucleophilic form of H– (an H– that exhibits affinity for carbon)

Sodium borohydride (NaBH4): a reagent that carries a nucleophilic form of hydride ion: Lecture of Dec 4 p. 3

H sodium borohydride Na H B H H

Sodium borohydride (NaBH4) as a carrier of a nucleophilic form of hydride that adds easily to the C=O group of aldehydes and ketones

H Na H B H Na H H mild H R2 C O R2 C O R2 C OH R1 + R1 H3O R1 R1 = H; R2 = alkyl: 1 2 a sodium alkoxide R = H; R = alkyl: primary alcohol R1, R2 = alkyl: ketone 1 2 R , R = alkyl: secondary alcohol

The addition of hydride ion to a as a reduction (the oxidation state of the carbonyl carbon becomes more negative):

NaBH4 O then OH [ + 1 ] [ –1 ] a 2-electron reduction C C R H R H has occurred generic aldehyde mild H + H3O

NaBH4 O then OH [ + 2 ] [ 0 ] C C a 2-electron reduction R R' mild R R' has occurred H generic ketone + H3O

Conversion of aldoses to alditols by treatment with NaBH4; e.g.:

CHO OH OH OH H OH H OH O NaBH HO HO OH HO H 4 HO H HO HO CHO H OH H OH HO OH HO H OH H OH free aldehyde α- or β-D-glucopyranose OH OH D-glucitol, a.k.a. D-sorbitol (noncaloric sweetener)

CHO OH OH OH OH OH HO H HO H O NaBH HO HO OH HO H 4 HO H HO HO CHO OH H OH H OH H OH H OH free aldehyde α- or β-D-mannopyranose OH OH D-mannitol Lecture of Dec 4 p. 4

Conversion of ketoses to a mixture of two diastereomeric alditots by treatment with NaBH4; e.g.:

OH OH OH HO HO H OH HO H OH OH OH O O OHOH NaBH HO H 4 HO H HO H + OH O H OH H OH H OH HO HO H OH H OH H OH α- or β-D-fructofuranose free ketone OH OH OH D-glucitol D-mannitol (D-sorbitol)

the formation of two diastereomeric products is easily rationalized by considering that NaBH4 may deliver hydride ion to either face of the carbonyl group:

OH H B—H 3 H OH H mild HO H HO HO O H OH D-glucitol rest of the rest of the H O+ molecule molecule O 3 H OH OH OH HO H O mild HO HO HO H O D-mannitol rest of the rest of the H O+ H OH molecule molecule H 3 H OH OH H3B—H

Acid-catalyzed reaction of aldehydes and ketones with primary amines: formation of imines (= Schiff bases: the nitrogen analogs of carbonyl systems):

3 1 R1 H2N–R R O N + H2O 2 R2 cat. Z–H R R3 aldehyde Z–H = generic an imine, also termed or ketone Bronsted acid a Schiff base

Presumed mechanism of the above reaction:

H–Z H–Z 1 1 Z Z 1 OH R R R1 OH R O OH H 2 NH R2 R2 R2 N H R 3 R3 aldehyde 3 R H2N–R or ketone Lecture of Dec 4 p. 5

H Z Z 1 R1 H R 1 O H N R N + H2O R2 3 3 R2 3 R R2 NH–R R

Enormous importance of Schiff bases (= imines) in biological chemistry (enzymatic reactions, aminoacid metabolism, biosynthetic pathways, etc.)

Important reactions of monosaccharides: formation of glycosylamines

OH OH Schiff OH OH aq. OH base OH HO O HO HO HO O HO HO H HO H NH form. HO OH 3 HO HO NH2 HO O NH HO D-glucopyranose glucosylamine: a glycosylamine O aq. O HO OH HO NH2 likewise: NH3 HO OH HO OH D-ribofuranose ribosylamine: a glycosylamine

Pyrimidine and purine

N N N N N N H pyrimidine purine

Important pyrimidine and purine N-glycosides ("nucleosides"): building blocks of nucleic acids

NH O O 2 N NH2 N NH NH N HO HO N N N O O N N O O H N N H adenosine uracil HO OH HO OH uridine adenine Lecture of Dec 4 p. 6

O NH NH 2 N 2 O NH N HO N N N HO NH O N NH2 N O N O O N H N NH2 cytidine H HO OH guanosine cytosine guanine HO OH

(components of RNA)

O O

NH NH HO N O N O O H thymine NH2 HO 2-desoxythymine O NH2 N N N N NH HO HO N N HO N O N O O N NH2 O

HO 2-desoxyadenosine HO 2-desoxyguanosine HO 2-desoxycytidine

(components of DNA)