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CH. 24 - CARBOHYDRATES

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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

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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.

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

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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:

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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

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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.

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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.

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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.

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

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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.

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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.

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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 = +112.2°; β-D-glucopyranose = +18.7°

□ 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:

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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:

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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:

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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:

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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:

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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:

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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)

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

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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.

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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.

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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.

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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)

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PRACTICE: Identify the following sugars as reducing sugars (RS) or non-reducing sugars (NS)

a.

b.

c.

d.

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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).

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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.

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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?

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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

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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.

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

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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”.

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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”.

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

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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)

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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?)

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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

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