Foundations

Herbal Chemistry

Phytochemical Elements

Structure of Phytochemicals

Carbon ‘backbone’

Structure of Phytochemicals

Oxygen atoms

Structure of Phytochemicals

Hydrogen atoms

Structure of Phytochemicals

Catechin

Elements in Phytochemicals Oxygen (red)

Carbon (magenta)

Hydrogen (cyan)

Catechin, an antioxidant molecule abundant in Green Tea

Elements in Phytochemicals

Catechin, an antioxidant molecule abundant in Green Tea

Elements in Phytochemicals

Catechin, an antioxidant molecule abundant in Green Tea

Elements in Phytochemicals Nitrogen (blue) Oxygen (red)

Carbon (magenta)

Hydrogen (cyan)

Berberine, an antimicrobial molecule in Oregon Grape

Elements in Phytochemicals

Berberine, an antimicrobial molecule in Oregon Grape

Elements in Phytochemicals

Berberine, an antimicrobial molecule in Oregon Grape

Elements in Phytochemicals Sulfur (yellow) Carbon (magenta)

Nitrogen (blue)

Hydrogen (cyan) Oxygen (red)

Alliin, a sulfur compound in Garlic

Elements in Phytochemicals

Alliin, a sulfur compound in Garlic

Elements in Phytochemicals

Alliin, a sulfur compound in Garlic

Elements in Phytochemicals Oxygen (red)

Hydrogen (cyan)

Phosphorus (yellow)

Carbon (magenta)

Geranyl pyrophosphate, precursor of the monoterpenes

Elements in Phytochemicals

Geranyl pyrophosphate, precursor of the monoterpenes

Phytochemical Bonding

Bonding in Phytochemicals

Carbon forms four bonds with a tetrahedral geometry

Bonding in Phytochemicals

Carbon forms four bonds with a tetrahedral geometry

Bonding in Phytochemicals

Carbon forms four bonds with a tetrahedral geometry

Bonding in Phytochemicals

Two carbon atoms can double bond with each other, introducing a ‘stiffness’ into the molecule

Bonding in Phytochemicals

Two carbon atoms can double bond with each other, introducing a ‘stiffness’ into the molecule

Bonding in Phytochemicals

Bonding in Phytochemicals

Two carbon atoms can double bond with each other, introducing a ‘stiffness’ into the molecule

Bonding in Phytochemicals

Two carbons can also triple-bond to each other, resulting in a linear architecture

Bonding in Phytochemicals

Two carbons can also triple-bond to each other, resulting in a linear architecture

Bonding in Phytochemicals

Two carbons can also triple-bond to each other, resulting in a linear architecture

Bonding in Phytochemicals

This immune-modulating isobutylamide from Echinacea has two carbon-carbon triple bonds

Bonding in Phytochemicals

This immune-modulating isobutylamide from Echinacea has two carbon-carbon triple bonds

Bonding in Phytochemicals

The benzene ring shares electrons all around

Bonding in Phytochemicals

Resonance delocalization results in stability

Bonding in Phytochemicals 3 single bonds to hydrogens and one to another carbon

Carbon forms four bonds with a tetrahedral geometry alpha-Linolenic acid

Bonding in Phytochemicals 3 single bonds to hydrogens and one to another carbon

Carbon-carbon double bond

Carbon atoms can also double bond with each other alpha-Linolenic acid

Bonding in Phytochemicals 3 single bonds to hydrogens and one to another carbon Carbon-oxygen double bond

Carbon-carbon double bond

Carbon-oxygen single bond

Carbon can also form one or two bonds to oxygen alpha-Linolenic acid

Bonding in Phytochemicals

Oxygen forms two bonds & has two non-bonding e- pairs

Bonding in Phytochemicals

Oxygen forms two bonds & has two non-bonding e- pairs

Bonding in Phytochemicals

Acetone

Oxygen can form a double bond with carbon

Bonding in Phytochemicals Acetone

Oxygen can form a double bond with carbon

Bonding in Phytochemicals

Rarely, you’ll see oxygen with both a double & a single bond, as in the anthocyanidins

Bonding in Phytochemicals

Ammonia

Nitrogen usually forms three single bonds and has one lone pair of electrons

Bonding in Phytochemicals

Ammonia

Nitrogen usually forms three single bonds and has one lone pair of electrons

Bonding in Phytochemicals

Ammonium ion

But sometimes it can form four bonds by carrying a positive charge (NH4+)

Bonding in Phytochemicals

Ammonium ion

But sometimes it can form four bonds by carrying a positive charge (NH4+)

Bonding in Phytochemicals

Betanidin, a purple antioxidant molecule in Beets & Pokeberries, has both types of nitrogen bonds

Bonding in Phytochemicals

Betanidin, a purple antioxidant molecule in Beets & Pokeberries, has both types of nitrogen bonds

Bonding in Phytochemicals

Sulfur can form various numbers of bonds, but most commonly two, four, or six

Bonding in Phytochemicals

Sulfur can form various numbers of bonds, but most commonly two, four, or six

Bonding in Phytochemicals

Phosphorus generally forms five bonds in phytomolecules

Bonding in Phytochemicals

Geranyl pyrophosphate, precursor of the monoterpenes

Bonding in Phytochemicals

Geranyl pyrophosphate

Stereochemistry

Stereochemistry of Phytochemicals Isomers Constitutional isomers Cis-trans (geometric) isomers

Stereoisomers

Isomers with chiral carbons

Stereochemistry of Phytochemicals

* A chiral carbon

Not a chiral carbon

A carbon atom bonded to four different kinds of atoms/groups has no plane of symmetry

Stereochemistry of Phytochemicals

Non-superimposable mirror images

Stereochemistry of Phytochemicals

Non-superimposable mirror images

Stereochemistry of Phytochemicals

These two molecules are stereoisomers or enantiomers

Stereochemistry of Phytochemicals

Chiral molecules have nonsuperimposable mirror images

Achiral molecules have superimposable mirror images

Enantiomers vs. identical molecules

Stereochemistry of Phytochemicals R enantiomer

S enantiomer

X Receptor binding site

X

Receptor binding site

Why isomerism matters: receptor specificity

Stereochemistry of Phytochemicals

Stereoisomerism is common in the monoterpenes

Stereochemistry of Phytochemicals

(+)-carvone: Caraway

(-)-carvone: Spearmint

Stereochemistry of Phytochemicals

• beta-D-glucose & alpha-D-glucose are stereoisomers • The polymers they form are very different from each other: cellulose vs. starch

Stereochemistry of Phytochemicals

beta-D-glucose units link up to form cellulose

Stereochemistry of Phytochemicals

Amylose: linked alpha-D-glucose units

Stereochemistry of Phytochemicals

Amylopectin: linked alpha-D-glucose units, branched

Stereochemistry of Phytochemicals

beta-D-glucose

alpha-D-glucose

Stereochemistry of Phytochemicals

Cis (Z) & trans (E) isomers

Stereochemistry of Phytochemicals

Trans-alpha linolenic acid

Cis-alpha linolenic acid

Cis (Z) & trans (E) isomers

Stereochemistry of Phytochemicals

All-trans beta-carotene

9-cis beta-carotene

Cis (Z) & trans (E) isomers

Stereochemistry of Phytochemicals

All-trans beta-carotene

9-cis beta-carotene

Cis (Z) & trans (E) isomers

Stereochemistry of Phytochemicals

Cis (Z) & trans (E) double bonds in an isobutylamide

Polarity

Polarity • Different elements have different electronegativities (tendencies to attract electrons) • Bonds between elements with similar electronegativities are non-polar • Bonds between elements with significantly differing electronegativities are polar • If the electronegativities of two elements are extremely different, the bond is ionic

Polarity H Li Be Na Mg

Increasing electronegativity

He B

C

N O

Al Si P

F Ne

S Cl Ar

K Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn Ga Ge As Se Br Kr • Carbon – carbon bond, non-polar: 2.55 to 2.55 • Carbon – hydrogen, non-polar: 2.55 to 2.20 (small e-neg difference, 0.35) • Carbon – sulfur, non-polar: 2.55 to 2.58 (tiny e-neg difference, 0.03) • Sulfur – sulfur, non-polar: 2.58 to 2.58 • Carbon – nitrogen, polar: 2.55 to 3.04 (diff = 0.49) • Carbon – oxygen, polar: 2.55 to 3.44 (diff = 0.89) • Sulfur – oxygen, polar: 2.58 to 3.44 (diff = 0.86) • Oxygen – hydrogen, polar: 3.44 to 2.20 (diff = 1.24)

Polarity + + +

+

+ +

• Water is very polar (O – H, 1.24) • Oxygens have partial negative charge • Hydrogens have partial positive charge • Oxygens of one molecule attract hydrogens of another • Result: hydrogen bonding in water

Ethanol is Polar Ethane is a symmetrical, nonpolar molecule

–OH group

Ethanol (grain alcohol) is a polar molecule – not electrically symmetrical

Glycerol is Highly Polar

Glycerol (glycerin) is generally used for water-soluble constituents

Glycerol is Highly Polar –OH group

–OH group

–OH group

Glycerol (glycerin) is generally used for water-soluble constituents

Polarity • Salt (NaCl) is beyond polar: it’s ionic • Electronegativity difference between sodium & chlorine: 2.23 • In water, salt breaks up into Na+ ions & Cl– ions • The atoms are no longer bonded to each other

Polarity • The main constituents of Olive oil are triglycerides (neutral fats) • Their long hydrocarbon chains are electrically neutral: insignificant charge separation: non-polar

Hexane & CO2 are Nonpolar _ _

_

+

+

+ _ _

Hexane: no charge separation; electrically neutral molecule

_

Carbon dioxide: symmetrical shape cancels out effects of charge separation

Acetone is Amphiphilic: Both Oil & Water Soluble • Has been used as a solvent for certain constituents in standardized extracts • Alternative to hexane for many oil-soluble constituents: less toxic

Functional Groups

Functional Groups • Where the action is – areas on a molecule where chemical reactions occur • Phytomolecules consist of a ‘carbon backbone’ or ‘carbon skeleton’ &…

• One or more ‘functional groups’ • Many functional groups involve oxygen, as –OH or as =O • Some involve sulfur (S) or nitrogen (N) • Functional groups give a molecule some of its characteristics

Functional Groups: Amide

• Amide group: primary amide • Fairly common in phytomolecules • Extremely polar/hydrophilic

Functional Groups: Amide

• Amide group: secondary amide • Fairly common in phytomolecules • Extremely polar/hydrophilic

Functional Groups: Amide

• Amide group: tertiary amide • Fairly common in phytomolecules • Extremely polar/hydrophilic

Functional Groups: Amide

Amide group: isobutylamide

Functional Groups: Amide

Amide group: anandamide

Functional Groups: Amide

Amide group: piperine

Functional Groups: Amide

Piperine, another perspective

Functional Groups: Carboxyl

• Carboxylic acid group: ‘-oic acid’ • Common in phytomolecules • Very polar/hydrophilic

Functional Groups: Carboxyl

Carboxyl groups: citric acid

Functional Groups: Carboxyl

Carboxyl groups: citric acid

Functional Groups: Carboxyl

Carboxyl group: L-lysine

Functional Groups: Carboxyl

Carboxyl group: EPA

Functional Groups: Carboxyl

Carboxyl group: rhein

Functional Groups: Hydroxyl

• Hydroxyl or alcohol group: ‘-ol’ • Common in phytomolecules • Polar, hydrophilic

Functional Groups: Hydroxyl

Hydroxyl group: ethanol

Functional Groups: Hydroxyl

Hydroxyl groups: glycerol

Functional Groups: Hydroxyl

Hydroxyl groups: glycerol

Functional Groups: Hydroxyl

Hydroxyl groups: delphinidin

Functional Groups: Ketone

• Ketone group: ‘-one’ • Common in phytomolecules • Slightly less polar than hydroxyl group

Functional Groups: Ketone

Ketone groups: emodin

Functional Groups: Ketone

Ketone group: pulegone

Functional Groups: Ketone

Ketone group: pulegone

Functional Groups: Aldehyde

• Aldehyde group: ‘-al’ or ‘-aldehyde’ • Less common in phytomolecules • Similar polarity to ketone group

Functional Groups: Aldehyde

Aldehyde group: benzaldehyde

Functional Groups: Aldehyde

Aldehyde group: cinnamaldehyde

Functional Groups: Aldehyde

Aldehyde group: cinnamaldehyde

Functional Groups: Amine

• Amine groups: ‘-amine’ or ‘amino-’ • Common in phytomolecules • Less polar than ketones & aldehydes

Functional Groups: Amine

Amine groups: histamine

Functional Groups: Amine

Amine groups: caffeine

Functional Groups: Amine

Amine group: phenylalanine

Functional Groups: Amine

Amine group: californidine

Functional Groups: Amine

Amine group: californidine

Functional Groups: Ester

• Ester group: ‘-oate’ • Very common in phytomolecules • Less polar than amines

Functional Groups: Ester

Ester group: chlorogenic acid

Functional Groups: Ester

Ester group: chlorogenic acid

Functional Groups: Ester

Ester group: aconitine

Functional Groups: Ester

Ester groups: echimidine

Functional Groups: Acetate

• Acetate group: ‘-acetate’ or ‘acetyl-’ • Very common in phytomolecules • Polarity similar to esters

Functional Groups: Acetate

Acetate group: linalyl acetate

Functional Groups: Acetate

Acetate group: linalyl acetate

Functional Groups: Acetate

Acetate group: acetylcholine

Functional Groups: Acetate

Acetate group: acetylcholine

Functional Groups: Carbonyl • Carbonyl: carbon double-bonded to oxygen • These groups contain carbonyls: – – – – – –

Ketones Aldehydes Carboxyls Esters Acetates Amides

Functional Groups: Ether

• Ether group • Somewhat common • Only slightly polar

Functional Groups: Ether

Ether groups: digitoxin

Functional Groups: Ether

Ether groups: a cyclic ether & a methyl ether (methoxy group)

Functional Groups: Alkane

• Alkane groups (i.e. methyl, ethyl, propyl) • Very common in phytomolecules • Nonpolar hydrocarbon moieties

Functional Groups: Alkane

Alkane group: stearic acid

Functional Groups: Alkane

Alkane groups: menthol

Functional Groups: Alkane

Alkane groups: beta-sitosterol

Functional Groups: Alkene

• Alkene groups • Very common in phytomolecules • Nonpolar, reactive

Functional Groups: Alkene

• Alkene groups: • Methylene groups in myrcene

Functional Groups: Alkene

Allyl methyl disulfide

• Alkene group: • Propene (allyl) group in allyl methyl disulfide

Functional Groups: Alkene

• Alkene groups: • Double bonds within a hydrocarbon ‘tail’

Functional Groups: Alkene

• Alkene groups: • Prenyl groups in hyperforin

Functional Groups: Alkene

Hyperforin

• Alkene groups: • Prenyl groups in hyperforin

Functional Groups: Chromophore

Functional Groups: Alkene

• Alkene section in center of molecule • Chromophore: yellow/orange compound • Nonpolar antioxidant

Functional Groups: Alkene

Lutein

• Alkene section in center of molecule • Chromophore: yellow/orange compound • Nonpolar antioxidant

Functional Groups: Alkene

Lutein

• Alkene section in center of molecule • Chromophore: yellow/orange compound • Nonpolar antioxidant

Functional Groups: Alkyne

• Alkyne groups • Uncommon in phytomolecules • Nonpolar, very reactive

Functional Groups: Alkyne

PHT

Alkyne groups: PHT

Functional Groups: Alkyne

Alkyne groups: PHT

Functional Groups: Alkyne

Alkyne groups: isobutylamide

Functional Groups: Alkyne

Alkyne group: lappaphene A

Functional Groups: Alkyne

Alkyne groups: cicutoxin

Functional Groups: Phenyl

Phenyl group

Phenolic group Polyphenolic

Functional Groups: Phenyl

Phenylalanine

A phenyl group on an amino acid

Functional Groups: Phenyl

A phenolic group on an isoflavone

Functional Groups: Phenyl

A polyphenolic compound

Functional Groups: Phenyl

Procyanidin C1

A polyphenolic compound

Functional Groups: Nitrile

• Nitrile groups • Uncommon in phytomolecules • Very polar, highly reactive

Functional Groups: Nitrile

Nitrile group: prunasin

Functional Groups: Nitrile

Nitrile group: linustatin

Functional Groups: Nitrile

Nitrile group: amygdalin

Functional Groups: Nitrile

Nitrile group: amygdalin

Functional Groups: Nitrile

• Hydrocyanic acid: HCN • Released from cyanogenic glycosides • Very toxic compound

Functional Groups: ‘Thio’

Isothiocyanate

Thiocyanate

Isothiocyanate & thiocyanate groups: active metabolites of glucosinolates

Functional Groups: ‘Thio’

Isothiocyanate group in allylisothiocyanate, the active metabolite of sinigrin

Functional Groups: ‘Thio’

Isothiocyanate group in sulforaphane

Functional Groups: Sulfate

Sulfate group: polar

Functional Groups: Sulfate

Sulfate group: polar

Functional Groups: Sulfate

Sulfate group: sinigrin

Functional Groups: Sulfoxide

Sulfoxide group: polar

Functional Groups: Sulfoxide

Sulfoxide group: alliin

Functional Groups: Sulfoxide

Sulfoxide group: sulforaphane

Functional Groups: Sulfoxide

Sulfoxide group: ajoene

Functional Groups: Sulfoxide

Sulfoxide group: ajoene

Functional Groups: Thiosulfinate

Thiosulfinate group: polar

Functional Groups: Thiosulfinate

Allicin

Thiosulfinate group: allicin

Functional Groups: Thiosulfinate

Thiosulfinate group: allicin

Functional Groups: Sulfide

Sulfide group: nonpolar

Functional Groups: Sulfide

Sulfide group: diallyl disulfide

Functional Groups: Sulfide

Sulfide group: diallyl trisulfide

Functional Groups: Sulfide

Sulfide group: diallyl trisulfide

Functional Groups: Sulfide

Sulfide group: ajoene

Functional Groups: Phosphate

Phosphate group: polar

Functional Groups: Phosphate

Phosphate group: polar

Functional Groups: Phosphate

Phosphate group: phosphatidylcholine

Functional Groups: Pyrophosphate

Geranyl pyrophosphate

Pyrophosphate group composed of two phosphate groups

Functional Groups: Pyrophosphate

Geranyl pyrophosphate

Pyrophosphate group composed of two phosphate groups

Functional Groups: Epoxide

Epoxide group: polar

Functional Groups: Epoxide

Epoxide groups: violaxanthin

Functional Groups: Epoxide

Epoxide group: 23-epi-26-deoxyactein

Functional Groups: Epoxide

Epoxide group: catalpol

Functional Groups: Epoxide

Epoxide group: catalpol

Functional Groups: Epoxide

Epoxide group: didrovaltrate

Functional Groups: Methylenedioxy

Methylenedioxy group

Functional Groups: Methylenedioxy

Methylenedioxy group: apiole

Functional Groups: Methylenedioxy

Methylenedioxy group: berberine

Functional Groups: Methylenedioxy

Methylenedioxy group: methysticin

Ring Systems

Ring Systems: Cyclopropane

Cyclopropane ring

Ring Systems: Cyclopropane

Cyclopropane ring

Ring Systems: Cyclopropane

Cyclopropane ring: cycloartenol

Ring Systems: Cyclopropane

Cyclopropane ring: pyrethrins

Ring Systems: Cyclobutane

Cyclobutane ring

Ring Systems: Cyclobutane

Cyclobutane ring

Ring Systems: Cyclobutane

Cyclobutane ring: beta-caryophyllene

Ring Systems: Cyclobutane

Cyclobutane ring: alpha-pinene

Ring Systems: Cyclobutane

Cyclobutane ring: alpha-pinene

Ring Systems: Cyclobutane

Cyclobutane ring: alpha-pinene

Ring Systems: Cyclopentane

Cyclopentane ring

Ring Systems: Cyclopentane

Cyclopentane ring

Ring Systems: Cyclopentane

Cyclopentane ring: diosgenin

Ring Systems: Cyclopentane

Cyclopentane ring: nepetalactone

Ring Systems: Cyclopentane

Cyclopentane ring: nepetalactone

Ring Systems: Cyclopentane

Cyclopentane ring: capsorubin

Ring Systems: Cyclohexane

Cyclohexane ring

Ring Systems: Cyclohexane

Cyclohexane ring

Ring Systems: Cyclohexane

Cyclohexane ring

Ring Systems: Cyclohexane

Cyclohexane ring

Ring Systems: 6-Carbon Rings

Cyclohexane rings

Ring Systems: 6-Carbon Rings

Fused cyclohexane rings: ginsenoside

Ring Systems: 6-Carbon Rings

Fused cyclohexane rings: ginsenoside

Ring Systems: 6-Carbon Rings

Fused cyclohexane rings: ginsenoside

Ring Systems: 6-Carbon Rings

Fused cyclohexane rings: ginsenoside

Ring Systems: 6-Carbon Rings

Cyclohexane ring vs. benzene ring

Ring Systems: 6-Carbon Rings

Cyclohexane ring vs. benzene ring

Ring Systems: 6-Carbon Rings

Cyclohexane ring vs. Benzene ring

Ring Systems: Benzene

Resonance delocalization results in stability

Ring Systems: Phenolic

Adding an –OH group changes benzene into phenol

Ring Systems: Phenolic

This anthocyanidin contains phenolic rings

Ring Systems: 7-C & 8-C

Cycloheptane & cyclooctane rings

Ring Systems: 7-C & 8-C

Cycloheptane & cyclooctane rings

Ring Systems: 7-C & 8-C

Cycloheptane & cyclooctane rings

Ring Systems: 7-C & 8-C

7-C: chamazulene

8-C: eschscholtzidine

Ring Systems: 10-Carbon

A ten-membered ring in parthenolide

Ring Systems

Not really a carbon ring: macrocyclic PAs

Ring Systems

Not really a carbon ring: macrocyclic PAs

Ring Systems: Oxygen Heterocycles

Furan rings

Ring Systems: Oxygen Heterocycles

Furan ring: carlina oxide

Ring Systems: Oxygen Heterocycles

Furan ring: carlina oxide

Ring Systems: Oxygen Heterocycles

Furan ring: benzofuran: psoralen

Ring Systems: Oxygen Heterocycles

Furan ring: benzofuran: psoralen

Ring Systems: Oxygen Heterocycles

Furan ring: coumestrol

Ring Systems: Oxygen Heterocycles

Furan ring: coumestrol

Ring Systems: Oxygen Heterocycles

Furan ring: fructose

Ring Systems: Oxygen Heterocycles

Furan ring: fructose

Ring Systems: Oxygen Heterocycles

Oxygen heterocycles: pyran rings

Ring Systems: Oxygen Heterocycles

Pyran ring: glucose

Ring Systems: Oxygen Heterocycles

Pyran ring: sugar in a glycoside (salicin)

Ring Systems: Oxygen Heterocycles

Pyran ring: sugar in a glycoside (salicin)

Ring Systems: Oxygen Heterocycles

Pyran rings: procyanidin A7

Ring Systems: Oxygen Heterocycles

Pyran rings: procyanidin A7

Ring Systems: Oxygen Heterocycles

Pyran ring: pelargonidin

Ring Systems: Oxygen Heterocycles

Pyran ring: pelargonidin

Ring Systems: Oxygen Heterocycles

Pyran ring: pyranone: naringenin

Ring Systems: Oxygen Heterocycles

Pyran ring: pyranone: naringenin

Ring Systems: Oxygen Heterocycles

delta-lactone

ester

gamma-lactone

Oxygen heterocycles: cyclic esters: lactones

Ring Systems: Oxygen Heterocycles

delta-lactone

gamma-lactone

Oxygen heterocycles: cyclic esters: lactones

Ring Systems

Oxygen heterocycles: cyclic esters = lactones: originate from bonding of hydroxyl groups to carboxylic acid groups within the same molecule

Ring Systems: Oxygen Heterocycles

Delta-lactone: kavain

Ring Systems: Oxygen Heterocycles

Delta-lactone: kavain

Ring Systems: Oxygen Heterocycles

Delta-lactone: gentiopicrin

Ring Systems: Oxygen Heterocycles

Delta-lactone: gentiopicrin

Ring Systems: Oxygen Heterocycles

Gamma-lactone: lactucin

Ring Systems: Oxygen Heterocycles

Gamma-lactone: lactucin

Ring Systems: Oxygen Heterocycles

Gamma-lactone: convallatoxin

Ring Systems: Oxygen Heterocycles

Gamma-lactone: convallatoxin

Ring Systems: Oxygen Heterocycles

Oxygen heterocycles: dioxans

Ring Systems: Oxygen Heterocycles

Oxygen heterocycles: dioxan ring

Ring Systems: Oxygen Heterocycles

Dioxan ring: silybin

Ring Systems: Oxygen Heterocycles

Dioxan ring: silybin

Ring Systems: Oxygen Heterocycles

• Dioxin has a dioxan ring • Carcinogenic xenoestrogen • Not a phytomolecule

Ring Systems: Oxygen Heterocycles

• Dioxin has a dioxan ring • Carcinogenic xenoestrogen • Not a phytomolecule

Ring Systems: Oxygen Heterocycles

Macrocyclic ester: macrocyclic PA: senkirkine

Ring Systems: Oxygen Heterocycles

Macrocyclic ester: macrocyclic PA: senkirkine

Ring Systems: Nitrogen Heterocycles

Nitrogen heterocycles: 5-membered rings

Ring Systems: Nitrogen Heterocycles

Nitrogen heterocycles: 6-membered rings

Ring Systems: Nitrogen Heterocycles

Nitrogen heterocycles: fused 5- & 6-membered rings

Ring Systems: Nitrogen Heterocycles

Nitrogen heterocycles: fused 6membered rings & a pyrrolizidine

Ring Systems: Nitrogen Heterocycles

Nitrogen heterocycles in alkaloids

Ring Systems: Sulfur Heterocycle

Thiophene ring

Ring Systems: Sulfur Heterocycle

Thiophene ring

Ring Systems: Sulfur Heterocycle

Thiophene rings: arctinal

Ring Systems: Sulfur Heterocycle

Thiophene rings: arctinal

Solubility

Solubility • Solubility: which solvents (menstrua) will extract the desired constituents or leave undesirable ones?

• Which solvent & concentration gives maximum medicinal power?

• Solubility of one component changes according to what else is dissolved • Sometimes difficult to predict; must be determined by experience or laboratory analysis

Solubility • Based mainly on ‘positive’ & ‘negative’ electrical charges • Polar molecules have partially positive regions & partially negative regions • Nonpolar molecules have no ‘charge separation’ … they are electrically neutral

Extraction Media/Solvents • • • • •

Olive oil (& other ‘fixed’ plant oils) Ethanol (Everclear®, vodka, grain alcohol) Water Glycerol (glycerin) Vinegar (acetic acid)

Solubility: Water

+ +

+

+ _ _

Water is highly polar: + region of one molecule attracts – region of another molecule

+

_

+

Solubility: Ethanol (EtOH) Ethane is a symmetrical, nonpolar molecule

–OH group

Ethanol (grain alcohol) is a polar molecule – not electrically symmetrical

Solubility: Glycerol –OH group

–OH group

–OH group

Glycerol (glycerin) is highly polar; generally used for water-soluble constituents

Solubility: Olive Oil • The main constituents of Olive oil are triglycerides (neutral fats) • Also known as triacylglycerols, their long hydrocarbon chains are electrically neutral

Solubility: Supercritical CO2 • High-pressure, low-temperature process • No chemical solvents; very clean CO2 is ideal for extracting gingerols & essential oil components

Photo courtesy of FLAVEX GmbH Germany

Solubility: Supercritical CO2 _ _

_

+

+

+ _ _

_

• CO2 has oxygen atoms but…

• Molecule is symmetrical • Opposite vectors cancel each other out • Overall result: a non-polar molecule

Acetone is Amphiphilic: Both Oil & Water Soluble • Has been used as a solvent for certain constituents in standardized extracts • Alternative to hexane for many oil-soluble constituents: less toxic

Solubility: Ethyl Acetate

• Used to extract terpenes in Ginkgo & other lowpolarity constituents • Less toxic than most other organic solvents • Water-immiscible but not totally non-polar: it’s an ester

Solubility: Ether

• Diethyl ether extracts constituents of very low polarity • Ethers are water immiscible

Solubility: Hexane

• Hydrocarbon: no oxygen atoms • No charge separation • Non-polar: water-insoluble

Solubility: Polarity of Solvents • Acetone: 2.88 • Glycerol: 2.68 • Water: 1.85 • Ethyl acetate: 1.78 • Acetic acid: 1.7 • Ethanol: 1.69 • Diethyl ether: 1.15 • Hexane: ~ 0 • Olive oil: ~ 0 • Supercritical CO2: ~ 0, adjusted with ethanol

The unit of polarity is D for ‘debye’; it measures the ‘dipole moment’ or the overall charge distribution in the molecule but can be

Solubility: Octanol/water Coefficient • Glycerol: - 1.76 • Ethanol: - 0.31 • Acetone: - 0.24 • Acetic acid: - 0.17 • Ethyl acetate: 0.73 • Diethyl ether: 0.89 • Hexane: 3.9 • Oleic acid (main constituent of Olive oil): 7.73

The octanol-water coefficient (Kow) indicates the relative watersolubility of a molecule: lower Kow = higher solubility in water

Solubility: D vs. Kow Polarity

(D)

Solubility

(Kow)

Acetone

2.88

Glycerol

- 1.76

Glycerol

2.68

Ethanol

- 0.31

Water

1.85

Ethyl acetate

1.78

Acetone

- 0.24

Acetic acid

1.7

Acetic acid

- 0.17

Ethanol

1.69

Ethyl acetate

0.73

Diethyl ether

1.15

Diethyl ether

0.89

Hexane

~0

Hexane

3.9

Olive oil (oleic acid)

~0

Oleic acid

7.73

[H+] > [OH-]

Acidic

[OH-] > [H+]

Neutral

Basic

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

pH Affects Solubility Gastric HCl Lemon juice Vinegar Tomato juice Coffee Urine Pure water Human blood Sea water Milk of magnesia Ammonia Bleach Oven cleaner

• pH = – log [H+] • Log scale means a diff. of 1 pH represents a 10-fold change in hydrogen ion concentration • Acidic: pH < 7.0 • Neutral: pH = 7.0 • Basic: pH > 7.0

pH Affects Solubility: Acids

Protonated

Ionized

pKa: pH at which molecule loses its hydrogens

pH Affects Solubility: Acids

Protonated

Ionized

pKa differs for diff. hydrogens & diff. molecules

pH Affects Solubility: Acids

Protonated

Ionized

When pH = pKa, half of the molecules are protonated

pH Affects Solubility: Acids

Protonated And half are ionized

Ionized

pH Affects Solubility: Acids

Protonated

Ionized

Ionized acids are more water-soluble

pH Affects Solubility: Acids

Protonated

Ionized

Protonated acids are more oil-soluble

pH Affects Solubility: Acids

Protonated: neutral

Ionized: negative charge

Depending on pH, acid can be protonated or charged

pH Affects Solubility: Acids

Protonated: neutral

Ionized: negative charge

Low pH: fully protonated (lots of H+ ions around)

pH Affects Solubility: Acids

Protonated: neutral

Ionized: negative charge

High pH: fully charged (not many H+ ions around)

pH Affects Solubility: Acids

To isolate acidic compounds in the lab, first the whole plant is extracted with ethyl acetate or a similar solvent

pH Affects Solubility: Acids

Next the extract is mixed with a water solution that has been basified with an inorganic base like NaHCO3

pH Affects Solubility: Acids

And the ionized acid, being water-soluble, partitions down into the aqueous layer

pH Affects Solubility: Phenolics

Phenolic compounds are weakly acidic & will be more soluble in a high-pH aqueous solution

pH Affects Solubility: Bases

For a base, protonated = ionized Depending on pH, base can be neutral or protonated

pH Affects Solubility: Bases

For a base, protonated = ionized Low pH: fully protonated (lots of H+ ions around)

pH Affects Solubility: Bases

For a base, protonated = ionized High pH: neutral (not many H+ ions around)

pH Affects Solubility: Bases

To isolate basic compounds in the lab, first the whole plant is extracted with ethyl acetate or a similar solvent

pH Affects Solubility: Bases

Next the extract is mixed with a water solution that has been acidified with an inorganic acid like dilute HCl

pH Affects Solubility: Bases

And the ionized base, being water-soluble, partitions down into the aqueous layer

pH Affects Solubility: Bases

Aromatic amines are generally water-soluble at pH below 4 because they are positively charged (protonated)

pH Affects Solubility: Bases

H+

H+

OH-

H

+

H+

OH H+

H

+

H

H

+

H+

+

OH

-

OH OH-

OH

-

OH-

-

-

OH-

OH-

H+

Many alkaloids are soluble in acidic solutions, but will precipitate from basic solutions

pH: Summary

Example: Berberine vs. Hydrastine

Berberine: more water soluble Hydrastine: less water soluble

Other Factors Affecting Solubility • Temperature (generally, heat enhances extraction) – But watch out for thermal degradation – Exception: polysaccharides (mucilages) extract very well in cold water

• Solubility of one constituent may be altered by other constituents present – Interactions between constituents – Tannins can complex with other constituents – Common ion effect

Solubility: Precipitates • Dissolved constituents can precipitate out of solution if the polarity of the solvent system changes significantly • Example: In a water extract (infusion, decoction) of Echinacea, gradual addition of ethanol will cause the polysaccharides to precipitate out of solution • Example: In an ethanolic extract of Kava, gradual addition of water will cause the kavalactones to precipitate

Polar & Nonpolar Solvents Polar Water Ethanol (grain alcohol, Everclear速, vodka, wine) Acetic acid (vinegar) Glycerol (glycerin) Methanol (wood alcohol poisonous) Acetone (polar, amphiphilic) Ethyl acetate

Nonpolar Olive oil & other fixed oils Supercritical CO2 Hexane (some toxicity) Benzene (carcinogenic) Acetone is amphiphilic; will dissolve nonpolar substances as well

Like Dissolves Likeâ&#x20AC;ŚMostly Polar Water-soluble constituents Alcohol-soluble constituents Mono- & Disaccharides Oligo- & Polysaccharides Many polyphenols (esp. glycosides) Vitamins B, C Alkaloids (usually, alcohol) Essential oils (alcohol) Resins (high % of alcohol)

Nonpolar Oil-soluble constituents Lipids Essential oils Terpenoids Carotenoids Some polyphenols (esp. aglycones) Vitamins D, E, A, K Sterols Fixed oils

End

Lisa Ganora www.herbalchem.net info@herbalchem.net 720-890-4935 Louisville, CO Š Lisa Ganora 2005