Chemistry of Carbohydrates PDF

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Lecture notes with additional research notes from textbooks and recommended module articles...

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Chemistry of Carbohydrates  Empirical formula of carbohydrate = Cm(H2O)n  Carbohydrates a synonym of saccharide.  Exist as: monosaccharides, disaccharides, oligosaccharides or polysaccharides  Mono- & disaccharides referred to as sugars. Name of sugars often end in the suffix ‘-ose’ e.g. Sucrose (table sugar)

 Carbohydrates are storage of energy (e.g. starch) and provide structure (e.g. cellulose)  Carbs are key components of other biomolecules e.g. ribose in RNA and deoxyribose in DNA. And components of cellular membranes (glycolipids e.g. cerebrosides)

Glycoproteins = proteins with oligosaccharides (sugars) attached to amino-acid side chains  Many integral membrane proteins are glycosylated- the carbohydrate protruding extracellularly. Play a role of cell-cell communications.  Enormous diversity due to vast array of oligosaccharides accessible from the

monosaccharide building blocks -> suggestion that nature utilises a glycocode for cellular communication  Industrial uses:  Food industry  Textiles  Plastic – packaging  Pharmaceuticals & cosmetics Carbohydrates  Carbs are polyhydroxylated aldehydes/ketones  Exist in either open chain (top structure) or ring form (bottom structure)  Ring form- one of the alcohols has cyclised on to the carbonyl to form a ’lactol’ Rings, Conformation  Fully saturated 6-membered rings are not planar.  6-membered rings can adopt ‘Chair’ or ‘Boat’ conformations  Chair conformation is generally considerably lower in energy as the substituents are staggered. Boat conformation, the substituents are eclipsed.  Unfavourable interaction in boat conformation is between the ‘flagstaff’ positions -> forming a steric clash

 Chair conformation substituents can adopt 2 possible positions: axial (ax) or equatorial (eq)  A substituted chair can adopt one of 2 conformations: interconvertible (flipping the ring -> i.e. by rotating bonds). Ring flip converts all substituents that were axial to equatorial and those equatorial to axial.  Bulky groups prefer to sit equatorial – less steric clash in these positions

Chair conformation tips -

Opposite ring bonds are parallel All axial bonds are vertically aligned and alternate up and down around the ring Equatorial bonds are parallel with bonds in the ring, with one bond separating them Carbon centres are tetrahedral

 Hexoses ring conformation similar to that for cyclohexane, with one of the ring atoms just replaced by an oxygen  Chair conformations preferred- with a ring flip interconverting two possible chairs  In glucose the eqm is one-sided as the favoured conformer has almost all of its substituents in the more stable equatorial positions

Monosaccharides  Monosac’s can be categorised to the number of carbon atoms they contain (from 3 upwards)  Each of carbon atoms of a monosac’s with a secondary alcohol group is a chiral centre

n  For a molecule with n chiral centres there are 2 possible stereoisomers

Stereochemistry of Carbs 

Stereoisomers: non-identical molecules which nonetheless have the same sequence of atoms and bond connectivity. Differ only in the position of the atoms in space



Enantiomers: stereoisomers related as object and non-superimposable mirror image. E.g. Derythrose and L-erythrose

Diastereoisomers (Diastereomers):  Stereoisomers not related as object and non-superimposable mirror image  E.g. cis- and trans- but-2-ene or D-threose and D-erythrose  Only one chiral centre is altered

Cahn-Ingold-Prelog system (absolute configuration at a chiral centre labelled either R or S): 1) Groups adjoining a tetrahedral chiral centre are labelled 1-4 according to ‘priority’: -

Highest atomic number has highest priority and labelled 1 and so on to 4

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Start with atoms directly attached to the chiral centre- if two or more are the same then move onto the next atom

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Greater number of highest priority atoms takes precedence e.g. – CHCl2> -CH2Cl

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Double bonds ‘count twice’; e.g. –CHO > -CH2OH.

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Lone-pairs are given the ‘atomic number’ zero.

2) Tetrahedron is then orientated to view 1,2,3 from the base i.e. with group 4 furthest away 3) If order 1-> 2-> 3 is

CLOCKWISE = R. ANTICLOCKWISE =S.

D or L  Absolute configuration of the sugar at highest numbered chiral carbon is designated D- or L 

D- sugar -> R configuration at highest numbered chiral centre L- sugar -> S configuration at highest numbered chiral centre (so in Dglucose we look at the chirality of carbon 5)

Epimers = stereoisomers that have more than one chiral centre, but only differ in configuration at one of them  Monosac’s with more than 3 carbon atoms = epimers

Diagrammatic representation of carbohydrates Fischer Projection -

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Backbone of molecule drawn vertically C1 carbon at the top (i.e. usually the aldehyde) Horizontal lines represent bond coming towards you out of the paper, vertical ones represent bonds going away from you

Diagrammatic representation of carbs -

Ring form of sugars can be represented in chair conformations, Mills or Haworth projections Mills / Haworth projections- stereochemistry is unambiguous represented, but conformation not favoured -> axial or equatorial nature of substituents not shown

Hemiacetal formation and open-chain to ring interconversion  If molecule has both aldehyde and alcohol groups present, they can react intramolecularly to form a cyclic hemiacetal -> LACTOL  Intramolecular reactions to form 5- and 6- membered rings are favoured entropically over intermolecular reactions  5- and 6- membered rings are thermodynamically more stable than 4- and 7membered rings as they are less strained  6-membered rings in chair conformations are essentially free from ring strain  Acyclic to cyclic conversion- you must rotate the molecule to place the OH and aldehyde adjacent to each other in the plan  The electrons from the oxygen can attack from either on top or behind face -> the alcohol produced can be in front or behind (equal chances) hence curvy bond Mechanism for glucopyranose formation  Acid or base catalysed (same as hemi-acetal formation)  Each step is reversible, under acid or base catalysis -> thermodynamic ratio of products is formed  At eqm there is no sig. contribution from 5-membered lactol (glucofuranose) or from the open chain sugar

 - and ß-D-glycopyranose forms 

At eqm the favoured form is ß-D-glucopyranose which has the newly formed OH equatorial

 - and ß-D-mannopyranose forms 

At eqm the favoured form is the  -D-mannopyranose which has the newly formed OH axial

Mutarotation = change in optical rotations observed when epimerisation takes place. This is the case when - and ß- forms of D-glucopyranose interconvert  If you dissolve pure  -D-glucopyranose (and pure ß-D-glucopyranose) in water and observe mutarotation taking over time [

]D

 We reach an intermediate time where 38% of +112 and 62% of +19 is

combined Anomeric effect (explain the ratios of both forms of -D-glucopyranose and -Dmannopyranose at eqm)  Usually bulky subs prefer equatorial position

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Electronegative substituents on the anomeric centre ‘1’ position, prefer to occupy an axial rather than an equatorial orientation due to the anomeric effect

 Rings oxygen atoms lone pair can stabilise the axial substituent due to a favourable interaction with the antibonding (σ* ) orbital of the C-X bond  Represented by an addition resonance form- which is only stable if X is an electronegative group able to stabilise the negative charge

 In D-mannopyranose, the anomeric effect is dominant ->  -anomer is preferred  Thus D-glucopyranose is an anomaly as it forms more ß- than anomer at eqm  Because the free hydroxyl group on the anomeric centre is heavily solvated. All the water molecules crowding around this position increase its relative steric bulk and thus sterics> electronics Reactivity of carbs – use of protecting groups in carb chemistry  Protecting groups are used to shield reactive functionality -> allow a specific reaction to take place  They can then be removed at a later point to reveal functionality again

 E.g. synthesis of di- and oligo- saccharides from monosaccharide building blocks. To achieve this careful use of protecting groups is required.

 We must protect the OH groups that we do not want to react by masking the OH  Leaving group present at the position we want to react Acetal formation  Hemi-acetal can be converted to acetals by treatment with an alcohol, catalysed by acid

 Acetal formation at the anomeric position is called Fischer Glycosidation

Hemi-acetal formation  Hemi-acetals can be converted to acetals by treatment with an alcohol, catalysed by an acid  Acetal formation at the anomeric position is called the Fischer Glycosidation

Fischer Glycosidation  To drive the reaction towards completion, we use a non-aq Bronsted acid e.g. SOCl2 with MeOH, or a Lewis Acid e.g. ZnCl2 as well as excess of the alcohol

 In this reaction it is primarily the alpha pyranoside formed, with smaller fractions of the ß pyranoside and the furanosides (5-membered ring forms)  Acetals can be hydrolysed via the reverse of this reaction upon treatment with aqueous acid (mechanism of acetal hydrolysis is the exact reverse of acetal formation). They are stable under almost all other reaction conditions  Thus, a sugars anomeric centre can be effectively protected as a glycoside at the beginning of any reaction sequence  By the Fischer Glycosidation we can protect the 1-OH group – selective protection

Protection of the -OH groups: Acetylation reactions  Alcohols can be converted to esters by addition of activated carboxylic acid derivatives, such as anhydrides. Acetylation using acetic anhydride protects OH groups in carbs  Acetyl protecting groups can be removed at a later point by treatment with suitable nucleophiles such as methoxide (e.g. NaOMe in MeOH -> giving us OMe-)  In the final product, all -OH groups are equally likely to react

 Acetate= Ac -> Ac2O is a small reagent -> no steric barrier

Protection of the -OH groups: Acetylation reactions  Free sugar (i.e. not the glycoside) acetylation of all the hydroxy groups including the anomeric one can be carried out using acetic anhydride.  Varying the conditions can lead to control of the stereochemistry at the anomeric centre

 Using pyridine (a base & also a nucleophilic catalyst) with acetic anhydride the acetylation reaction is accelerated to such an extent that it is much faster than mutarotation so the product mixture reflects the anomeric mixture of the starting material

 Using sodium acetate (a weaker base & doesn’t act as a nucleophilic catalyst in the reaction) leads to a slower reaction which needs heating to maintain a reasonable rate

 The mutarotation is faster than acetylation in this case  Result = more reactive anomer to acetylation (ß-anomer in this case) is acylated preferentially resulting in the major product as the ß-anomer  ß-anomer is more reactive -> lone pair does not overlap with other orbitals

 Lewis acids such as ZnCl2 (likes to pull electrons towards it), can catalyse the acetylation of alcohols  These lewis acids also catalyse the equilibration of the resulting anomeric acetates  Results in the major product being the more stable alpha-anomer  ß-anomer is much slower equilibration process as the orbitals and lone pairs are not as easily lined

Other protecting groups for -OH: Ethers  Benzyl ethers are formed by reaction of a benzyl halide with an alcohol in the presence of a strong base such as sodium hydride  Benzyl protecting group can be removed by catalytic hydrogenation e.g. H2/Pd/C

 Trityl ethers are particularly useful for the selective protection of the primary alcohol which is less hindered  It can be cleaved under mild acidic conditions (e.g. AcOH)

 The 6th position is very remote in comparison Example application  Careful use of protecting groups can provide us with a single OH group available for subsequent reaction

Protection of the -OH groups: Acetal formation  Acetals are formed upon reaction of carbonyls with alcohols under acidic conditions  Reaction can be used either to protect the alcohols or the carbonyl  Cyclic acetals: 5-ring and 6-ring acetal can be readily formed from diols

 6-membered rings are generally more stable; however, we find that the outcome depends on the nature of the carbonyl compound used:

 Cyclic acetals derived from acetone = acetonides

 We must consider the 6-membered ring chair conformations that can be adopted in each case

 In acetone one of the methyl groups must be axial resulting in an unfavourable 1,2diaxial interaction -> the 5-membered ring is favoured  In contrast, when benzaldehyde is used the substituent sits equatorial, avoiding the 1,2 diaxial interaction- thus the 6membered ring is favoured 

Ketones react with compound possessing several hydroxyl groups to preferentially form 5ring cyclic acetal products. Whereas, aldehydes react to preferentially form 6-ring cyclic acetal products

Acetonide protection of carbs hydroxyl groups  We expect a 5-membered ring acetal to be favoured (as a ketone’s being used)  When a 5-membered ring is fused to a 6membered ring the cis-fused product is nearly always going to be favoured thermodynamically as the trans-fused product will be too strained  Thus, the reaction will take place via neighbouring hydroxyls in the way which best avoids ring strain  The outcome of acetal formation of glycosides (like methyl glycoside above) are relatively easy to predict according to these general rules  Free sugars on the other hand can undergo mutarotation and pyranose to furanose inter conversion are much more difficult  The pyranose structure is in eqm with the open chain & also with the 5membered furanose form

Reaction of glucose with acetone and acid  Pyranose form of glucose has no cis-oriented hydroxyl groups -> only 5-ring actetonide that could be formed is the C1-C2 ring incorporating the anomeric centre  But in acidic conditions the pyranose is in eqm with the glucofuranose

 The glucofuranose can react with two equivalents of acetone to form two cyclic 5-ring acetonides, C1-C2 and C5-C6  Since all of these reactions are reversible, the most stable thermodynamic product is formed preferentially- this is the diacetone glucofuranose (i.e. it is favourable to form as many 5-membered rings, cis-fused acetonides as possible and the furanose can form two, whereas the pyranose can form only one)

Reaction of galactose with acetone and acid  Galactose is epimeric with glucose at C4  The C3 and C4 positions have cis hydroxyl groups  The pyranose form can access a diacetonide which the preferred product  In the acidic conditions the pyranose ring is in eqm with open chain and furanose forms, but in this case the thermodynamic product is the diacetone galactopyranose  No rearrangement to form 5 membered ring

Reaction of Mannose with acetone and acid  Mannose is epimeric with glucose at C2  As for glucose, mannose in its pyranose form can only form one acetonide (either between C2 and C3 or between C1 and C2 as the ß-anomer)  Mannofuranose has cis C2-C3, as well as the possibility of acetonide formation at C5-C6. The resultant diacetonide product is the favoured product, diacetone mannose  In this case, unlike in the examples of glucose or galactose, it is the anomeric centre which remains as a free hydroxyl

Selective OH functionalisation and acetal hydrolysis  Protection strategy provides single free OH groups for functionalisation:

Selective OH functionalisation:  Individual reactive OH groups can undergo a range of reactions leading to modifications of the sugar. e.g.:

Nucleophilic substitution at the anomeric centre  Goal: selective disaccharide formation. Need to activate one of the anomeric centres- a leaving group must be installed

 Mechanism of glycosidic bond formation can then occur via a Sn1 mechanism and thus the approaching sugar nucleophile can attack from either face affording the alpha or ß anomeric products  In many cases it is unclear if the reaction proceeds entirely by a Sn1 mechanism or by a mixture of Sn1 and Sn2 pathways

Neighbouring group participation  Controlling the stereochemical outcome (alpha or ß) is crucial to a successful disaccharide synthesis  Neighbouring groups can provide control:...