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Biological Chemistry

A/Prof. Matthew Piggott Room 3.29, Bayliss www.lms.uwa.edu.au – unit information recording

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Assumed knowledge Amongst other things: Atomic structure: protons, neutrons and electrons 2.4 Electronic configurations, valence electrons 2.6, 2.7 Covalent bonds 3.1, 3.3, 3.6 Lewis structures 3.6 VSEPR theory (shapes of simple molecules) 3.9 All chapter references in red text are to “Introduction to General, Organic and Biochemistry” – e-book available through LMS.

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What is Biological Chemistry? The chemistry that occurs in living organisms

Why would we want to study that?

• It’s in our nature to find out how things work • Understand processes in health and diseased states • Facilitates treatment or prevention of disease • Optimisation of renewable resources (agriculture)

Most biological chemistry is organic chemistry

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What is Organic Chemistry? 10 Historically – the chemistry of compounds produced by living things

minerals inorganic materials ‘inanimate matter’

vis vitalis “vital force”

organic compounds

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Early Evidence Against Vitalism animal fat

glycerin (glycerol)

Na2CO3 H2O Michael Chevreul

+ fatty acids acid 1816 (30)

soap

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The Final Blows for Vitalism - 1828 Friedrich Wöhler

German chemist, 28 at the time of this discovery

O NH4+  OCN ammonium cyanate



C H2N

NH 2 urea

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The Final Blows for Vitalism – 1843–45 German chemist, Wöhler’s student 1838–42 Later studied under Bunsen 25 at the time of this discovery Hermann Kolbe

vinegar or pyrolysis of wood 3

carbon disulfide

acetic acid

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Many People Still Believe in Vitalism

Strychnos nux vomica (Hemlock) - produces strychnine “Marijuana can’t be bad for you; it’s a plant” Synthetic THC is indistinguishable from naturally derived THC.

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The Chemistry of Carbon Compounds • more organic compounds than all the inorganic compounds put together (>90% of the >180 million known compounds) • all known life in the universe is based on carbon

What is so special about carbon? • forms strong bonds with many other elements and with itself • has a variety of bonding modes - allows great structural variation • can combine to form chains and rings of carbon and other atoms The permutations are infinite!

linoleic acid (Drawing Chemical Structures 11)

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11

Line-Angle Formulas 11 What are the molecular formulas of the following molecules?

9-trans-tetrahydrocannabinol

strychnine

12 2

sucrose (table sugar)

adenosine 5'-triphosphate (ATP – body’s energy currency)

2

11-cis-retinal (visual pigment)

serotonin (a neurotransmitter)

13

Smells

menthol spearmint

-ionone boronia

prenyl acetate “juicy fruit”

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Smells

butyric acid rancid butter, parmesan, vomit Rafflesia arnoldii (Carrion Flower)

thiols skunk spray

putrescine rotting flesh

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Flavours

1 teaspoon in an Olympic swimming pool

aspartame 200 x sweeter than sugar

Bitrex (denatonium benzoate) - the bitterest substance known

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Colours

anthocyanins

2+

chlorophyll a

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Colours

Ventilago maderaspatana

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Herbicides and Pesticides

glyphosate

warfarin

pyrethrin-I, R = CH=CH2 allethrin, R = H

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Drugs

sildenaphil Viagra

methamphetamine (ice)

acetyl salicyclic acid Aspirin

heroin

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Carbon Bonding: Orbitals 2.6 In high school you learnt about electronic energy levels:

12, 28, 318 etc. Within energy levels electrons occupy regions of space: orbitals Each orbital can accommodate a max of 2 electrons. For C – 2 types of orbitals with different shapes:

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Carbon Bonding 3.6, 10.3 6C 12 1s2, 2s2, 2p2 4 valence electrons,  needs 4 more electrons to fill its valence energy level (achieve an octet). It can do this in four ways: x

x

x

x x

x x

x

x x

x x

x

x x x

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Carbon Bonding Modes 10.3 • 4 single bonds, e.g. carbon tetrachloride - CCl4 x x x x

x x x x

xx x

x x x

x xx

x x x x x

x x xx

x x

109.5

tetrahedral

Lewis structures

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Carbon Bonding Modes • 1 double bond and 2 single bonds e.g. phosgene

CCl2O Cl2CO

molecular formula structural formula

trigonal planar

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Carbon Bonding Modes • 2 double bonds e.g. carbon dioxide - CO2

linear

Note: CO, CO2, carbonates and bicarbonates and carbides are classed as inorganic compounds.

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Carbon Bonding Modes • 1 triple bond and 1 single bond e.g. hydrogen cyanide - HCN

o

linear

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Many Permutations Q. There are nine stable isomers with the molecular formula C4H6. Draw line-angle formulas of them all.

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Models of Covalent Bonding Two main models: 1. Valence bond theory (including hybridisation) sp3 = tetrahedral sp2 = trigonal planar sp = linear 2. Molecular orbital theory I encourage you to read about these topics, but they will neither be covered in class, nor examined. See for e.g. “Chemistry: human activity, chemical reactivity”

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Carbon’s Friends 10.3 Most organic compounds (certainly most biomolecules) comprise C and one or more of the following elements:

Valence: in neutral functional groups (no charge):

Lone pair (non-bonding) electrons are often omitted - but they're still there!

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Electronegativity and Polar Bonds 3.10 Bonding to C is mainly covalent = sharing of bonding e− pair(s). Sometimes the electrons are shared equally, sometimes not:

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Electronegativity and Polar Bonds 3.3, 3.10 partial positive charge

partial negative charge

(low electron density)

(high electron density)

Bond polarity is determined by the difference in electronegativity between the bonding atoms. I

VIII III IV V VI VII electronegativity

II

electronegativity

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Formal Charge

Charge is very common amongst biomolecules (why?). Arises when an atom has more or less valence electrons than required to neutralize the charge on the nucleus. Common formal charges: formal charges - not completely localised Periodic table group = # of valance e = # e to be neutral

IV

actual charge (localised)

V

VI

VII

# of bonds + non-bonding e

3

5

4

6

5

7

8

formal charge = blue take pink

C

C

N

N

O

O

X

S

S

P

www.masterorganicchemistry.com/2010/09/24/how-to-calculate-formal-charge/

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Formal Charge Determine the formal charge on the pink atoms:

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Reactive intermediates Cyanide is a type of stable carbanion Most carbanions are short-lived reactive intermediates Reactive

intermediates

biochemistry

are

often

involved,

transiently,

in

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Reactive intermediates Which species in each pair is more stable and why?

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Non-covalent interactions 5.7 As important to life as covalent bonds! Dispersion forces

Dipole-dipole interactions

attractive

repulsive

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Non-covalent interactions 5.7 Hydrogen bonding

Hydrophilic = water loving Hydrophobic = water hating Lipophilic Don’t forget ionic bonding!

= fat loving

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Classifying Organic Compounds 10.4 There are many ways to classify organic compounds One useful way is by their functional groups: - a group of atoms within a molecule that has characteristic properties Functional groups usually exhibit similar chemical behaviour no matter what molecule they are part of, e.g.

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Functional Groups You Should Know 10.4 Functional Group

Example

C C

H2C CH2

alkene

ethylene (ethene)

C C alkyne

H

H acetylene (ethyne)

arene sticks here represent 'free valency'

benzene

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Functional Groups You Should Know

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Functional Groups You Should Know

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Chemical Structure Every single property of a molecule is determined by its chemical structure – how the atoms are bonded and arranged in space. This determines the 3D shape of, and electrostatic distribution within, the molecule

Includes: Physical properties: e.g. melting point, solubility, colour Chemical properties: e.g. acidity, reactivity, catalytic ability, Biological properties: e.g., smell, taste, toxicity, therapeutic efficacy

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Cycloalkanes 11.6-11.8 Rings of carbon atoms (and heterocycles) are very common in nature Note that rotation about single bonds is restricted in rings Q. There are two compounds that can represented by the following structure. Draw unambiguous representations of them both.

These compounds have the same connectivity of atoms but a different arrangement in space = stereoisomers.

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cis/trans Isomerism in Cyclic Compounds 11.8 Cilomilast, used to treat asthma and chronic obstructive pulmonary disease (COPD):

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Alkenes 12 Alkanes are generally inert (chemically unreactive). Typically only react with very unstable species, esp. radicals. Alkenes are much more reactive. But a C=C is shorter than a C−C bond; shorter = stronger ??? ~133 pm H

H

Br2

H

H

H

H C H

C H H

Br

H C C H H H

C C H

Br

Br2 no reaction

~154 pm

The C=C double bond actually comprises two different types of bonds That’s why the single bond above does not break, even with excess Br2

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Alkenes - Structure Remember, electrons reside in orbitals – a maximum of 2 in each (as in all covalent bonds) Above and below plane of sigma bonds

 (sigma) bond axial (cylindrical) symmetry most electron density between nuclei

 (pi) bond planar symmetry lobes above and below plane of  bonds

lower in energy

higher in energy weaker more reactive

stronger

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cis/trans Isomerism in Alkenes 12.2 There is usually very rapid rotation about  bonds Several million rotations per second in H2C−CH2 at room temperature Rotation does not break the  bond or affect its strength There is no rotation about C=C; rotation would break the  bond Leads to cis and trans isomers, e.g. 2-butene:

bp = 4ºC

bp = 1ºC

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cis/trans Isomerism in Alkenes OH

OH

powerful, intensely green, grassy odor

CO2

fumarase (an enzyme) H2O

O2C

has a more fruity odor

fumarate

CO2 O2C

OH

malate

CO2

fumarase

CO2

H2O

no reaction

maleate

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Alkynes Also called acetylenes – contain a C≡C triple bond. increasing strength

H

H

H C H

C H H

~154 pm

H

H C C

H

H C C H H

~133 pm

~121 pm

2 -bonds, one -bond

Again, no rotation about the C≡C bond, but it has no consequence

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Benzene 12.7 The bonding in benzene cannot be adequately described by a single Lewis structure. This is because the -orbitals and the electrons that fill them are delocalised over the whole ring. Instead, we think of benzene as being the result of merging two Lewis structures = resonance.

Hercules the liger

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The Resonance Model for Benzene Evidence for -electron delocalisation:

120º

1.33 Å

120º

1.39 Å

1.50 Å

1.08 Å

All bond angles are equal All C−C bond lengths in benzene are equal (as are all C−H) C−C bond length is in between those of double and single bonds

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The Resonance Model for Benzene Resonance is not equilibrium It is an (imaginary) averaging effect not a rapid alternation The Kekulé structures do not actually exist - only the hybrid does

x

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Conjugation 3.8, 12.7 The double bonds in the Kekulé structures are conjugated or in conjugation. Other double bonds separated by one single bond are also conjugated, and resonance occurs in these systems too. Curly arrows are used to represent interconversion of resonance structures:

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Aromaticity The delocalisation of 6- electrons around a ring imparts a very special stability to benzene = aromaticity. Benzene is much less reactive than alkenes and alkynes Other rings with 6- electrons, fully conjugated are also aromatic, and share special stability with benzene. Due to their special stability, aromatic compounds are abundant. ~2/3 of the >180 million compounds known are aromatic!

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Aromatic Heterocycles Most aromatic compounds are heterocycles. Heteroaromatic compounds share properties with benzene such as stability and characteristic reactivity. 2

Cinchona pubescens cinchona (fever) tree

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Nomenclature 12.8 As substituents:

Substitution pattern:

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Alcohols 13 Contain an –OH (hydroxyl) group attached to tetrahedral C Bent (like water)

3

The hydroxyl group is polar and can hydrogen bond; significantly increases water solubility.

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Alcohols 13.1 - classified as primary (1°), secondary (2°) or tertiary (3°) depending on how many C’s are attached to the carbon bearing the OH group (CH3OH is a special case). 3 3

3 3

i

3 3

t

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Oxidation of Alcohols 13.2 - one of the most important reactions of alcohols

With many reagents, [O] of 1 alcohols cannot be stopped at RCHO.

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Ethers 13.3

Generally inert, and less water soluble than alcohols:

Ethers may be acyclic or cyclic

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Carboxylic Acids 17 Carboxylic acids contain a carboxyl group – can be represented in different ways:

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Acidity – pKa 8

Recall: acids are proton (H+) donors

An acid’s strength relates to how much it dissociates in water, i.e. by the position of equilibrium of the following reaction:

For any reaction at equilibrium, the position of equilibrium can be expressed as the equilibrium constant K. For the ionisation of acids this is called the acid ionisation (or dissociation) constant Ka Ka

=

[H3O+] [A] [HA]

Thus, Ka for very strong acids is very large (larger numerator). Ka for weak acids is small (larger denominator)

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Acidity – pKa 8.5 Ka values are often unwieldy (to large or too small). Thus, as for pH, a logarithmic scale is used: pKa = –log 10 Ka Acid

Ka

pKa

HCl CH3CO2H PhOH EtOH

1 x 107 1 x 10–5 1 x 10–10 1 x 10–16

–7 5 10 16

When pH = pKa there is 50% ionisation, i.e. [HA] = [A–].

increasing acid strength

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Acidity 17.5 Carboxylic acids are only weakly acidic compared to mineral acids like HCl and H2SO4.

2

3

A 0.1 M solution of acetic acid in water is only about 1% ionised. However, because pKa < pH 7, carboxylic acids are primarily ionised at physiological pH (actually ~99% ionised). Carboxylates are far more prevalent in biological system than carboxylic acids (but they are in equilibrium)

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Acidity Acid strength is primarily determined by the stability of the (solvated) conjugate base.

Why are carboxylates more stable than alkoxides in water?

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Resonance in Carboxylates Concentrated charge is generally unstable; ions are usually stabilised when the charge is delocalised O

O

O

BO = ~1.5

BO = 1

H O

O

O

O resonance forms

BO = 2

resonance hybrid

hydroxide

acetate

very limited capacity to share charge

charge delocalised over 2 O's

very strong base (unstable)

weak base (stable)

127 pm

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Solubility Carboxylates are much more water soluble than carboxylic acids Many drugs are marketed as carboxylates, e.g. NSAIDs

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Phenols 12.10 Contain a hydroxyl group directly attached to a benzene ring.

Phenols are not alcohols – some properties are quite different (e.g. acidity, reactivity) – some properties are shared (e.g. the hydroxyl group enhances water solubility.

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Phenols are Weak Acids

Recall, aliphatic alcohols, pKa ≈ 16 (phenols are 106 x stronger acids) But, because pKa > 7, primarily protonated at physiological pH. Form resonance-stabilised anions – phenoxides (phenolates)

Q. Draw curly arrows to show how the resonance forms “interconvert”

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Thiols and Thioethers 13.4

Q. Which form, thiol or thiolate, predominates at pH 7?

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Organic bases 8, 15 Recall, bases are proton acceptors:

Bases have a high energy electron pair (most commonly non-bonding) that can form a bond with a proton With bases, pKa refers to the reverse reaction (i.e. dissociation of the conjugate acid) - sometimes written pKaH Thus, the higher the pKaH, the stronger the base

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Organic bases Most organic bases have a basic nitrogen atom Amines:

pKaH ~8–10 Amines are primarily protonated at pH 7

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Ammonium ions Amines are very common functional groups in drugs. Usually marketed as salts: more stable, more water soluble

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Other Basic Functional Groups O H2 N

O

O OH

H2 N

NH2

H3 N

OH

OH

N HN

NH

NH O

H2 N N-het...