ORGANIC - CLUTCH CH CARBOHYDRATES.

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2 CONCEPT: INTRODUCTION TO CARBOHYDRATE MONOSACCHARIDES Sugars or saccharides are also referred to as carbo-hydrates, implying that carbon has been combined with Monosaccharides are the most basic units of sugars All unmodified monosaccharides have the same general formula:, where n 3 Monosaccharides can be represented as straight chains OR rings One oxygen attached to each and every carbon atom, and 1 IHD regardless of form Monosaccharides begin as either or Aldehyde sugar = Ketone sugar = General Features: Monosaccharides can be described by both generic names and specific names. Generic naming involves: Carbonyl type (i.e. aldo ) Carbon Chain Length (Pre-IUPAC) with ose ending (i.e. triose, -tetrose, pentose, -hexose, etc) The total number of stereoisomers possible is described by Epimers are stereoisomers of monosaccharaides differing at only one chiral carbon EXAMPLE: Epimers of aldohexose Page 2

3 PRACTICE: Provide the generic name for the following monosaccharide. PRACTICE: How many possible stereoisomers AND epimers exist for the following aldopentose? Draw all of the possible epimers. Page 3

4 PRACTICE: Identify and label all of the possible stereoisomers of aldotetrose as enantiomers, diastereomers or epimers of each other. Page 4

5 CONCEPT: MONOSACCHARIDES D and L-ISOMERISM All monosaccharides come in dextrorotary (D) and levorotary (L) forms. These are enantiomers of each other. Monosaccharide stereochemistry is determined by the penultimate carbon or chiral carbon NOTE: This carbon (C-5) will be used as a later in this chapter D = - configuration (-OH pointing RIGHT) L = - configuration (-OH pointing LEFT) PRACTICE: Provide the generic name, including stereochemistry, for the following monosaccharides: Page 5

6 CONCEPT: MONOSACCHARIDES DRAWING FISCHER PROJECTIONS In 1891, Emil Fischer devised a representation known as Fischer Projections specifically to depict carbohydrates. The most atom is always represented on It is necessary to learn how to convert Bondline to Fischer and Fischer to Bondline Bondline to Fischer: Similar to our lessons in Orgo 1, we can use the caterpillar method to convert Bondline to Fischer Alternatively we can just swap the stereochemistry of all downward facing alcohols Fischer to Bondline: Reverse caterpillar is the most reliable method. Two possible answers Page 6

7 PRACTICE: Convert the following monosaccharide into its Fischer representation. Is it a D or L-isomer? PRACTICE: Convert the following monosaccharide into a bondline representation. Page 7

8 CONCEPT: MONOSACCHARIDES COMMON STRUCTURES Pentoses and hexoses are highly prevalent in biological systems. You probably only need to know a few of these. Biological systems tend to recognize D-monosaccharides more than L- monosaccharides The other important monosaccharides can all be related back to these basic structures. Page 8

9 CONCEPT: MONOSACCHARIDES FORMING CYCLIC HEMIACETALS By definition, monosaccharides contain at least one carbonyl group and multiple alcohols. The nucleophilic addition of 1 eq. alcohol produces hemiacetals. A second equivalent produces acetals Recall that the only stable hemiacetals are cyclic (5 and 6-membered rings) Thus many monosaccharides can undergo reversible intramolecular, ring-forming hemiacetal mechanism EXAMPLE: D-Glucose undergoes nucleophilic addition to form a cyclic, 6-membered hemiacetal. Page 9

10 PRACTICE: Provide the mechanism for the cyclic hemiacetal formation of the following hydroxycarbonyl. Page 10

11 CONCEPT: MONOSACCHARIDES CYCLIZATION In aqueous solutions, monosaccharides are most stable in a cyclic form. Furanose = -carbon cyclic sugar Pyranose = -carbon cyclic sugar Nucleophilic addition of the penultimate alcohol to the electrophilic carbonyl carbon leads to cyclization The carbonyl carbon is, so it can be attacked from either the top or bottom When monosaccharides cyclize, two different C-1 epimers are possible. These are known as anomers - The α-anomer = anomeric oxygen is with the stereodescriptor (C-5) carbon - The β-anomer = anomeric oxygen is with the stereodescriptor (C-5) carbon The OH s on the in the straight chain point in the ring The OH s on the in the straight chain point in the ring - D-Sugars: Stereodescriptor (C-5) faces on the ring PRACTICE: Draw the β-anomer predicted through the cyclization of D-mannose. Page 11

12 CONCEPT: MONOSACCHARIDES HAWORTH PROJECTIONS Simplified drawings of sugars in their cyclic form, imagining that the ringed structure is planar. NOTE: The anomeric carbon is always drawn at the far in Haworth Projections This is true for both pyranose and furanose rings PRACTICE: Properly number the following Haworth Projections. Identify each anomer and predict anomeric equilibrium. PRACTICE: Draw the Haworth Projection that would be expected from cyclization of D-Fructose into α-d-fructofuranose. Page 12

13 CONCEPT: MONOSACCHARIDES MUTOROTATION Pyranose and furanose rings are constantly hydrolyzing back and forth between cyclic and straight-chain forms. Mutorotation: The process by which the anomeric position interconverts between α and β forms Anomers always differ in optical activity. e.g. α-d-glucopyranose = ; β-d-glucopyranose = They are NOT enantiomers of each other. Hence the unrelated activities In solution, any D-glucopyranose will always equilibrate to +52.5, indicating mutorotation Acid-Catalyzed Mechanism: Page 13

14 CONCEPT: MONOSACCHARIDES EPIMERIZATION In basic conditions, monosaccharides will undergo a multitude of tautomerizations and isomerizations. The most straightforward of these is epimerization. Monosaccharides will readily epimerize the position Several possible mechanisms exist. Can proceed through and enolate or enediol intermediate General Reaction: Enolate Mechanism: Enediol Mechanism: Page 14

15 CONCEPT: MONOSACCHARIDES ALDOSE-KETOSE REARRANGEMENT In basic conditions, monosaccharides will undergo a multitude of tautomerizations and isomerizations. The most profound of these is the ability of aldoses and ketoses to reversibly rearrange Also known as the Enediol Rearrangement or Lobry de Bruijn van Ekenstein Reaction Proceeds through an enediol intermediate General Reaction: Mechanism: Page 15

16 CONCEPT: MONOSACCHARIDES ALKYLATION Monosaccharides have the ability to react at the O position in several different ways. The simplest of these is called exhaustive alkylation to form 4 and an Reactions resemble Williamson Ether Synthesis, and utilize similar reagents Potential alkylation reagents include 1. RX / base 2. ROSO3R / base or 3. RX / Ag2O General Reaction: Base-Promoted Mechanism: Silver-Oxide Catalyzed Mechanism: Page 16

17 CONCEPT: MONOSACCHARIDES ACYLATION Monosaccharides have the ability to react at the O position in several different ways. Base-promoted reactions with or form polyester derivatives Pyridine is the most commonly used base. Acetyl (OAc) groups are the most common carbonyls added General Reaction: Mechanism: Page 17

18 CONCEPT: MONOSACCHARIDES O-GLYCOSIDES Monosaccharides have the ability to react at the O position in several different ways. In acidic conditions, monosaccharides can alkylate at the anomeric position to produce o-glycosides Also known as Fischer Glyocosidation. Proceeds through a reversible oxocarbenium intermediate General Reaction: Why does alkylation only occur on the anomeric carbon? Mechanism: Page 18

19 CONCEPT: MONOSACCHARIDES N-GLYCOSIDES Monosaccharides have the ability to react at the O position in several different ways. In acidic conditions, monosaccharides can substitute selectively at the anomeric position to produce glycosides When nucleophiles are used, the substitution is product is called an N-glycoside or glycosylsamine General Reaction: An N-glycoside that specifically contains a ribose monosaccharide + heterocyclic base is called a ribonucleoside (RNA) Page 19

20 PRACTICE: Propose an acid-catalyzed mechanism by which cytosine can form a β-1 N-linkage with 2-deoxy-β-Dribofuranose to produce a deoxynucleoside (DNA) called deoxycytidine. Page 20

21 CONCEPT: MONOSACCHARIDES REDUCTION (ALDITOLS) As polyols with carbonyls, monosaccharides can undergo a series of oxidation and reduction reactions. Reduction of a monosaccharides produces polyols known as alditols or sugar alcohols Alditols are used industrially as sugar substitutes, food thickeners, and in medicine mostly as laxatives Whereas reduction of aldoses produces one product, reduction of ketoses forms products due to C2 racemization General Mechanism: NaBH4 acts as a hydride donor and attacks the carbonyl via nucleophilic addition, then protonation occurs. Page 21

22 PRACTICE: Determine the structure of the alditol formed when b-d-xylofuranose is treated with NaBH4 and then water. Explain how NaBH4 can reduce the hemiacetal group of the furanose. Page 22

23 CONCEPT: MONOSACCHARIDES WEAK OXIDATION (ALDONIC ACID) As polyols with carbonyls, monosaccharides can undergo a series of oxidation and reduction reactions. Selective oxidation of monosaccharide to is known as weak oxidation Can be used as a method to differentiate between aldoses and ketoses. The mechanism is not fully known General Reaction: PRACTICE: Predict the product of the following reaction. Page 23

24 CONCEPT: MONOSACCHARIDES REDUCING SUGARS Bromine water provides high yields of aldonic acid, but does not undergo a transformation. Tollens, Benedict s and Fehling s Tests also transform reducing sugars into aldonic acid, while providing visual cues. Tests any sugar capable of forming straight-chain aldoses or ketoses Definition of Reducing Sugars: Any straight-chain monosaccharide Any cyclic monosaccharide, disaccharide or sugar derivative with cyclic hemiacetal groups Hemiacetal groups can be to straight-chain saccharides. Acetals cannot. EXAMPLE: Identify the following sugars as reducing sugars (RS) or non-reducing sugars (NS) Page 24

25 PRACTICE: Identify the following sugars as reducing sugars (RS) or non-reducing sugars (NS) a. b. c. d. Page 25

26 CONCEPT: MONOSACCHARIDES STRONG OXIDATION (ALDARIC ACID) When exposed to nitric acid, monosaccharides can be oxidized to derivatives called aldaric acids Due to symmetry of the dicarboxylic acids, different monosaccharides can lead to the same aldaric acid product EXAMPLE: First, circle the two monosaccharides that would produce identical aldaric acids upon treatment with nitric acid. Then label the products of these oxidations as optically active (chiral) or optically inactive (achiral). Page 26

27 CONCEPT: MONOSACCHARIDES OXIDATIVE CLEAVAGE (PERIODIC ACID) Periodic acid has the ability to vicinal diols. Sugars contain multiple diols that can potentially be cleaved. General mechanism is identical to oxidative cleavage of diols with periodic acid Monosaccharide Oxidation Products: There are 4 cleavage patterns of monosaccharides you should memorize EXAMPLE: Predict the products of the following oxidative cleavage. Page 27

28 PRACTICE: In aqueous base, D-glucose has the ability to epimerize into small amounts of D-mannopyranose and rearrange into D-fructofuranose. Fischer Glycosidation can then transform these saccharides into O-glycosides. a. Predict the structure of the glycoside products after treatment with acid and methanol b. How could treatment of those O-glycosides with periodic acid distinguish if epimerization or rearrangement is more favored? Page 28

29 CONCEPT: MONOSACCHARIDES OSAZONES Aldose aldehydes are susceptible to the same nucleophilic addition reactions that we learned in carbonyl chemistry When exposed to derivatives in acid, aldoses can transform into imine derivatives When phenylhydrazine is the imine derivative used, the product is referred to as a phenylhydrazone. Surprisingly, when exposed to additional eq. phenylhydrazine, the imine derivative continues to tautomerize and react The resulting product is a C1-C2 diphenylhydrazone derivative known as an osazone In 1888, Emil Fischer used osazones to prove that glucose and mannose were epimers Page 29

30 CONCEPT: MONOSACCHARIDES MODERN KILIANI-FISCHER SYNTHESIS Aldose aldehydes are susceptible to the same nucleophilic addition reactions that we learned in carbonyl chemistry When exposed to, aldoses can reversibly transform into cyanohydrins. The cyano group can then be reduced and hydrolyzed to form a new, chain-lengthened aldehyde Synthesis can be repeated multiple times, however a mixture of C2 epimers are created at every cycle Modern vs. Classical Method: The original Kiliani-Fischer synthesis required two additional steps after cyanohydrin addition, and resulted in poor yields An improved reducing agent was developed which was poisoned to form imines instead of amines In aqueous solution, imines rapidly hydrolyze into carbonyls. Same mechanism as imine hydrolysis. Page 30

31 PRACTICE: Predict the product(s) for the following reaction. Provide the mechanism of the imine hydrolysis step if required. Page 31

32 CONCEPT: MONOSACCHARIDES WOHL DEGRADATION Aldose aldehydes are susceptible to the same nucleophilic addition reactions that we learned in carbonyl chemistry Opposite to Kiliani-Fischer, aldehydes are transformed into to be reversibly removed in base Chain is shortened by carbon every cycle. Unlike Kiliani-Fischer, results in the formation of a single epimer The -stereocenter is lost in every cycle, so both C2 epimers of the original sugar produce the same product EXAMPLE: Circle the aldohexoses that would produce the same Wohl Degradation product. If none would share a degradation product, write N/A. Page 32

33 CONCEPT: MONOSACCHARIDES RUFF DEGRADATION Opposite to Kiliani-Fischer, aldose aldehydes can be oxidized to carboxylic acids and then decarboxylated to shorten chains Chain is shortened by carbon every cycle. Unlike Kiliani-Fischer, results in the formation of a single epimer The -stereocenter is lost in every cycle, so both C2 epimers of the original sugar produce the same product EXAMPLE: Circle the aldohexoses that would produce the same Ruff Degradation product. If none would share a degradation product, write N/A. Page 33

34 EXAMPLE: Predict the product for the following reaction. If multiple steps are indicated, include all intermediate structures. Page 34

35 CONCEPT: CONDENSATION INTO DISACCHARIDES Two monosaccharides bound by an O-glycosidic linkage (α or β) Two alcohols react in a condensation mechanism to release water and form an linkage Will not mutorotate, unless hydrolyzed Important Disaccharides: FUN FACT: Humans can t digest carbohydrates with O-(β-glycosidic) linkages, with one important exception PRACTICE: Identify the following disaccharides as reducing sugars (RS) or non-reducing sugars (NS) Page 35

36 PRACTICE: Draw a theoretical acid-catalyzed Fischer Glycosidation mechanism for the condensation of D-Glucose into cellubiose. (Note: This reaction would lead to very poor yields of cellubiose- can you hypothesize why?) Page 36

37 CONCEPT: POLYSACCHARIDES Trisaccharides = monosaccharides Oligosaccharides = monosaccharides Polysaccharides = More than monosaccharides Polysaccharides that are created by plants for use as an energy store are known as starches Polysaccharides can have straight vs. branched linkages - 1,4-linkages = Chains - 1,6 linkages = Chains EXAMPLE: Common Polysaccharides Amylopectin is the plant version of glycogen, but with branches every monosaccharides apart Page 37