Chemistry of Drugs Flashcards
(272 cards)
1
Q
What is atomic number (Z) ?
A
Number of protons
2
Q
What is atomic mass number (A) ?
A
Number of protons + neutrons
3
Q
How many electrons can each sublevel hold?
A
s = 2
p = 6
d = 10
f = 14
4
Q
Electronic configuration order
A
1s → 2s → 2p → 3s → 3p → 4s → 3d → 4p → 5s → 4d
5
Q
What is the Aufbau principle?
A
States that electrons fill orbitals starting from the lowest energy level to the highest, following a specific order (e.g. 1s → 2s → 2p → 3s…)
6
Q
What are orbitals?
A
Regions in an atom where the electrons are most likely to be found (90% probability)
7
Q
What is the Pauli exclusion principle?
A
States that each orbital can hold a maximum of two electrons with opposite spins
8
Q
What is the shape of s orbitals?
A
Spherical
9
Q
What is the shape of p orbitals?
A
Dumbbell shaped
Are oriented along the x, y and z axes (px, py, pz)
10
Q
What is Hund’s rule?
A
Orbitals of the same energy are filled singly before pairing up
Analogy to help remember: bus seat theory
11
Q
What does electropositive mean?
A
The tendency to donate electrons and form positively charged cations
12
Q
What does electronegative mean?
A
The tendency to attract a bonding pair of electrons
13
Q
What is the trend in electronegativity in the periodic table?
A
Increases across a period
* the number of protons increases and therefore the charge of the nucleus, which attracts the bonding pair of electrons more strongly
Decreases down a group
* the distance between the nucleus and the outer electrons increases
* shielding of inner shell electrons increases
14
Q
What are the normal covalent bonding patterns of common elements?
A
Carbon = 4 bonds, no lone pairs
Oxygen = 2 bonds, 2 lone pairs
Nitrogen = 3 bonds, 1 lone pair
Halogens = 1 bond, 3 lone pairs
15
Q
What is polarity?
A
Uneven distribution of electrons within a covelant bond, due to difference in electronegativity
16
Q
How do differences in electronegativity determine the type of bonding?
A
Large difference → ionic bond
Small to moderate difference → polar covalent bond
No or very small difference → non-polar covalent bond
17
Q
What is a dipole moment?
A
A measure of polarity
Dipole Moment (µ) = Charge (e) x Distance (d)
18
Q
What is the octet rule?
A
The tendency of atoms to prefer to have eight electrons in the valence shell
19
Q
When is the octet rule violated?
A
When there are an odd number of valence electrons (so not all can pair up)
E.g. Nitrogen monoxide (NO)
When there are too few valence electrons
E.g. Borane (BH₃)
When there are too many valence electrons
E.g. Phosphorus pentachloride (PCl₅)
20
Q
What is molecular orbital theory (MO Theory)?
A
Atomic orbitals combine to form molecular orbitals that are spread over the entire molecule, where electrons are delocalised rather than belonging to individual atoms
21
Q
What are bonding and anti-bonding orbitals?
A
Bonding orbitals (σ, π)
* formed by constructive interference
* lower in energy
* stabilise the molecule
Anti-bonding orbitals (σ, π)
* formed by destructive interference
* higher in energy
* destabilise the molecule
22
Q
How many molecular orbitals can be formed?
A
The number of molecular orbitals formed must equal the number of atomic orbitals combined
23
Q
What happens if both bonding and anti-bonding molecular orbitals are fully occupied?
A
The molecule will be unstable, as the stabilising effect of bonding MOs is cancelled out by the destabilising anti-bonding MOs
24
Q
Why doesn’t He₂ exist as a stable molecule?
A
Each He atom has 2 electrons → total of 4 electrons.
2 electrons fill the bonding MO, and 2 fill the anti-bonding MO
The anti-bonding MO cancels the bonding effect, making He₂ unstable and unable to exist under normal conditions
25
Why are all four bonds in methane (CH₄) identical despite carbon having both 2s and 2p orbitals?
Because carbon undergoes sp³ hybridisation, where one 2s and three 2p orbitals mix to form four identical sp³ hybrid orbitals, each forming a C–H bond of equal energy and shape
26
What is sp³ hybridisation?
The mixing of one s orbital and three p orbitals to form four equivalent sp³ hybrid orbitals
Tetrahedral arrangement
Bond angle = 109.5°
27
What is a sigma (σ) bond?
A single covalent bond formed by the head-on (axial) overlap of two orbitals
Strongest type of covalent bond
Allows free rotation
28
What is a pi (π) bond?
A bond formed by the sideways (lateral) overlap of unhybridised p orbitals
Exists alongside a sigma bond in double or triple bonds
Restricts rotation/ No free rotation
Weaker than a σ bond
29
Why are π (pi) bonds shorter than σ (sigma) bonds?
Pi bonds involve sideways overlap of orbitals, leading to greater electron density above and below the bond axis, which pulls atoms closer together, making the bond shorter.
30
What is sp² hybridisation?
The mixing of one s and two p orbitals to form three equivalent sp² hybrid orbitals, leaving one unhybridised p orbital
Trigonal planar arrangement
Bond angle = 120°
31
What is sp hybridisation?
The mixing of one s and one p orbital to form two equivalent sp hybrid orbitals, leaving two unhybridised p orbitals
Linear arrangement
Bond angle = 180°
32
How do you determine the hybridisation of a central atom?
Determine the steric number
Steric number = no. atoms bonded to central atom + no. lone pairs on central atom
If the steric number is 4 → sp3
If the steric number is 3 → sp2
If the steric number is 2 → sp
33
How do you determine the formal charge of an atom?
Formal Charge = valence electrons/group number – number of covalent bonds – number of electrons in lone pairs
34
Why is sp2 generally more stable than sp3?
The closer the electrons are to the nucleus, the more stable they are
The s orbital is closer to the nucleus than the p orbital
sp = 50% s orbital
sp2 = 33.3% s orbital
sp3 = 25% s orbital
Therefore order of stability = sp > sp2 > sp3
35
What patterns suggest resonance is possible?
Lone pairs next to a double bond
Positive charge next to a double bond
Lone pairs next to a positive charge
Double bond between atoms of different electronegativities
Alternating pi bonds in a ring system
36
What factors decrease the stability of a resonance contributor?
Formal charges
Especially positive on electronegative atoms and negative on electropositive atoms
Incomplete octets
37
What do dashed and wedged lines represent in stereochemical drawings?
Dashed lines represent bonds going away from the viewer (into the paper)
Wedged lines represent bonds coming toward the viewer (out of the paper)
38
What do horizontal and vertical lines represent in fischer projections?
Horizontal lines represent bonds coming out of the plane of the paper
Vertical lines represent bonds going behind the plane of the paper
39
What is the difference between conformations and configurations?
Conformations are different spatial orientations of the same molecule due to rotation around single bonds
Configurations are fixed arrangements of atoms that cannot change without breaking and reforming bonds
40
What are constitutional isomers?
Compounds with the same molecular formula but different connectivity of atoms
41
What are stereoisomers?
Compounds with the same molecular formula and connectivity but different spatial arrangements of atoms
42
Why is stereochemistry crucial in drug-receptor interaction?
Correct stereochemistry ensures the drug fits properly into the receptor site, maximising interaction and therapeutic effect
43
What is the difference between cis and trans isomers?
Cis = identical groups are on the same side of a ring or C=C double bond
Trans = identical groups are on opposite sides of a ring or C=C double bond
44
What is the difference between E and Z isomers?
E = higher priority groups are on opposite sides of the double bond
Z = higher priority groups are on the same side of the double bond
45
What is a chiral centre?
carbon with four different groups/atoms present
46
What are enantiomers?
Stereoisomers that are non-superimposable mirror images of each other
They have identical physical properties (except for the direction they rotate plane-polarised light) but can have different biological activities
47
How can you distinguish between enantiomers?
The direction in which they rotate plane-polarised light
48
What is a racemate?
A 1:1 mixture of two enantiomers
It has no net optical activity because the rotations cancel out
49
What is an eutomer and a distomer?
Eutomer = the enantiomer with the desired or more potent biological activity
Distomer = the less active or inactive enantiomer
50
What is the Eudismic Ratio (ER)?
The ratio of the activity of the eutomer to that of the distomer
51
How do you assign absolute configuration?
Step 1:
Assign priorities to the four groups attached to the chiral carbon (higher atomic number = higher priority)
Step 2:
Observe the sequence from priority 1 → 2 → 3 → 4
* Clockwise = R configuration
* Counterclockwise = S configuration
Step 3:
The lowest priority group should go into the paper/be facing away from me (dashed), if not change answer to the other configuration
52
What are diastereoisomers?
Stereoisomers that are not mirror images of each other
Occur when a molecule has two or more chiral centers and the configuration differs at some but not all of them
53
What are epimers?
Diastereomers which differ in configuration at one centre of chirality only
54
How many stereoisomers can a molecule with multiple chiral centres have?
A molecule with n chiral centres can have up to 2ⁿ stereoisomers
Symmetry (e.g. meso compounds) reduces the number
55
What are meso compounds?
Molecules with multiple chiral centres which are superimposable on their mirror image, because they have an internal plane of symmetry
Optically inactive
56
What are the methods of obtaining pure enantiomers?
Asymmetric synthesis
* Using chiral reagents or catalysts to favour one enantiomer
* Transition metal catalysis
* Organocatalysis
* Biocatalysis (enzymes)
Resolution of racemates
* Separating enantiomers from a racemic mixture
* Crystallisation
* Chiral chromatography
* (Dynamic) kinetic resolution
57
What are the different ways that drugs can interact with receptors?
Covalent bonds
* Strong, irreversible binding
* Requires an electrophile (electron deficient) and a nucleophile (electron rich)
Hydrogen bonds
* Between polar groups (e.g. –OH, –NH)
Ionic bonds
* E.g. salt bridges
Ion-Dipole interactions
* Between a charged ion and a polar molecule
π-stacking
* Parallel alignment of aromatic groups
Hydrophobic interactions
* Non-polar regions cluster to avoid water
Van-der Waals forces
* Weak interaction
58
Where are covalent bonds commonly seen in pharmacology?
drug–enzyme interactions
drug–DNA interactions
59
What are common nucleophilic functional groups involved in covalent bonding?
Thiol in the amino acid cysteine (-SH)
Hydroxyl in the amino acid serine (-OH)
Amine in the amino acid lysine (-NH2)
60
What are common electrophilic functional groups involved in covalent bonding?
Epoxide ring
Alkyl group attached to halogen (R-X)
Positively charged centre (R+)
61
What are common hydrogen bond acceptors in drug molecules?
Carbonyl oxygen (C=O)
Ether oxygen (R–O–R)
Nitrile nitrogen (C≡N)
Nitrogen in tertiary amines (R₃N)
Ring nitrogen in heterocycles (e.g. pyridine)
62
What are common hydrogen bond donors in drug molecules?
Hydroxyl groups (–OH)
Amine groups (–NH, –NH₂)
Amides (–CONH₂)
Phenol groups (Ar–OH)
Carboxylic acids (–COOH)
63
How can intramolecular hydrogen bonding affect a drug’s pharmacological action?
It can block key functional groups from interacting with the biological target, reducing activity
E.g. P-Hydroxybenzoate shows stronger antibacterial activity than methyl salicylate
Methyl Salicylate
The –OH group forms intramolecular H-bonds, making it unavailable for interaction with the target
Vs
P-Hydroxybenzoate
The –OH group is in the para position, preventing intramolecular bonding, so it remains available for H-bonding with the target
64
What is a pharmacophore?
Structural features that are essential for a drugs ability to interact with its target and produce the desired response
65
What is nucleophilic substitution?
A reaction in which a nucleophile replaces/displaces a leaving group in a molecule, typically at a saturated/tetravalent carbon (sp³)
66
What is a nucleophile?
A species that donates a pair of electrons to form a covalent bond
Electron-rich
Attracted to positive or electron-deficient centres
67
Common examples of nucleophiles
Hydroxide ion (OH⁻)
Alkoxide (C-O⁻)
Cyanide ion (CN⁻)
Ammonia (NH₃)
Halide ions (Cl⁻, Br⁻, I⁻)
Water (H₂O)
68
What are the two types of nucleophilic substitution reactions?
SN1
SN2
69
Describe the mechanism of SN1 reactions
1) Leaving group is removed (slow - rate determining step, reversible)
2) Formation of carbocation intermediate (trigonal planar, sp2 hybridisation)
3) Nucleophile attacks substrate (right or left, stereoisomer product)
70
Why does racemisation occur in SN1 reactions?
SN1 reactions proceed via a planar carbocation intermediate, which allows the nucleophile to attack from either side, leading to a racemic mixture of enantiomers
71
What does the energy profile of an SN1 reaction look like?
Two peaks:
First
* formation of carbocation (rate-determining step)
* large Ea
* endothermic, +ΔH
Second
* nucleophilic attack
* smaller Ea
* exothermic, -ΔH
Valley between peaks represents the carbocation intermediate
72
What are the kinetics of SN1 reactions?
First-order kinetics
The rate of reaction depends on the concentration of only the substrate and the formation of the carbocation intermediate
Rate = k[substrate]
73
What factors affect SN1 reactions?
Nature of the substrate
Nature of the leaving group
Solvent
74
How does the nature of the substrate affect SN1 reaction?
SN1 reactions are favoured when the carbocation intermediate is stable.
Stability increases with:
Inductive effects - electron-donating groups stabilise positive charge
Resonance effects - delocalisation of charge stabilises the carbocation
Hyperconjugation - delocalisation of electrons from adjacent C–H or C–C bonds stabilises the carbocation
Tertiary > Secondary > Primary > Methyl
alkyl groups can donate electronegativity to carbocation to offset the positive charge and therefore increase stability
Resonance effects > inductive effects
E.g. Primary with resonance > secondary with no resonance
75
How does the nature of the leaving group affect nucleophilic substitution reactions?
The more stable the anion, the better the leaving group
Good leaving groups include:
* Weak bases
* Halides (I⁻ > Br⁻ > Cl⁻ > F⁻)
* Tosylate (TsO⁻)
* Mesylate (MsO⁻)
* Water (H₂O)
76
How do you know which group is more inclined to stabilise the charge?
Electronegativity
* more electronegative atoms stabilise negative charge better
Size
* larger atoms spread out the negative charge better
Resonance stabilisation
* delocalise the negative charge
* e.g. Tosylate (TsO⁻)
The weaker the base, the more stable its conjugate anion, and the better it is at leaving
77
What is the effect of the solvent on SN1 reactions?
Polar protic solvents (e.g. water, alcohols, formic acid) stabilise the carbocation and leaving group through hydrogen bonding, increasing SN1 reaction rate
78
What is carbocation rearrangement in SN1 reactions?
Carbocations may rearrange to form a more stable intermediate for nucleophilic attack, via:
Hydride shift - H⁻ from adjacent carbon shifts to C+
Methyl shift - a methyl group CH3⁻ from adjacent carbon moves if no H is available
79
What are the possible fates of carbocations?
Capture a nucleophile (SN1 reaction)
Lose a proton to forms a π /double bond (β-elimination)
Rearrangement to form more stable carbocation
80
Describe the mechanism of SN2 reactions
1) Nucleophile attacks substrate
2) Transition state
3) Leaving group is removed
81
Why does inversion of configuration occur in SN2 reactions?
SN2 reactions involve a backside attack of the nucleophile. This forces the leaving group to leave from the opposite side, leading to inversion of configuration.
82
What does the energy profile of an SN2 reaction look like?
One peak representing the transition state where the nucleophile and leaving group are both partially bonded to the carbon
83
What are the kinetics of SN2 reactions?
Second-order kinetics
The rate of reaction depends on the concentrations of both the nucleophile and substrate
Rate = k[substrate][nucleophile]
84
What factors affect SN2 reactions?
Nature of the nucleophile
Nature of the substrate
Nature of the leaving group
Solvent
85
How does the nature of the nucleophile affect SN2 reactions?
Stronger nucleophiles increase the SN2 reaction rate
Nucleophilicity increases:
* Down the periodic table (e.g. I⁻ > Br⁻ > Cl⁻ > F⁻)
* Anionic species (negatively charged) > neutral species
86
How does the nature of the substrate affect SN2 reactions?
Rate of reaction increases if a nucleophile can approach the electrophilic carbon easily
Reactivity order:
Methyl > Primary (1°) > Secondary (2°) > Tertiary (3°)
Hindered by bulky substrates due to steric hindrance
87
How does the solvent affect SN2 reactions?
Favoured by polar aprotic solvents (e.g. DMSO, acetone, acetonitrile)
Aprotic = cannot act as a hydrogen bond donor + solvate cations but not anions
Protic solvents are unfavourable as they hydrogen-bond with nucleophiles, causing steric hinderance and reduced activity
88
What is the dielectric constant threshold for a solvent to be considered polar?
Polar solvents have a dielectric constant > 15
89
What are the key differences between SN1 and SN2 reactions?
SN1
* Unimolecular
* Two-step mechanism
* Formation of a trigonal planar carbocation intermediate (rate limiting step)
* First-order kinetics → Rate = k[substrate]
* Rate does not depend on nucleophile concentration
* Racemisation occurs
* Faster in polar protic solvents
* Favoured by tertiary substrates (more stable carbocations) + weak nucleophiles
Weak nucleophiles
SN2
* Bimolecular
* One-step process
* Transition state with simultaneous bond breaking and bond forming
* Second-order kinetics → Rate = k[substrate][nucleophile]
* Rate depends on nucleophile concentration
* Inversion of configurations
* Faster in polar aprotic solvents
* Favoured by primary substrates (less steric hindrance) + strong nucleophiles
90
What are biological examples of SN reactions?
Methyltransferases
* SN2 mechanism
* Methylation of neurotransmitters (e.g. catecholamines)
* A methyl group is transferred from SAM to the acceptor molecule (e.g. amine group, OH group)
Nucleotide biosynthesis
* SN1 mechanism
Nitrosamines
* Found in cured meats, smoked fish, alcoholic beverages and tobacco smoke
* Can undergo SN1 reactions to form carcinogens (cancer causing)
Activation of prodrugs
Neutralising toxic drug metabolites (e.g. MESNA)
91
What are nitrogen mustards?
Alkylating agents derived from sulphur mustard, used as chemotherapeutic agents
Form covalent bonds with DNA, via SN mecahnism, disrupting replication and transcription in rapidly dividing cancer cells
E.g. Mechlorethamine
92
How does the electronic environment affect the reactivity of nitrogen mustards?
Aromatic groups decrease the reactivity of nitrogen mustards due to the delocalisation of the lone pair on nitrogen (via resonance)
93
What is an acid?
Arrhenius = H⁺ or H₃O⁺ producer
Brønsted-Lowry = proton (H⁺) donor
Lewis = electron pair acceptor
94
What is a base?
Arrhenius = OH⁻ producer
Brønsted-Lowry = proton (H⁺) acceptor
Lewis = electron pair donor
95
What are conjugate pairs?
When an acid donates a proton, it forms its conjugate base
When a base accepts a proton, it forms its conjugate acid
A strong acid has a weak conjugate base
* because it dissociates completely in water, forming a conjugate base that is unlikely to accept protons
A weak acid has a strong conjugate base
* because it partially dissociates in water, forming a conjugate base that is more likely to accept protons
96
What makes an acid strong or weak?
A strong acid completely dissociates in water
A weak acid partially dissociates in water
97
What is the acid dissociation constant (Ka) ?
Measures the degree of dissociation of an acid in water
Higher Ka = stronger acid
98
What is pKa?
pKa = -logKa
Low pKa = strong acid
High pKa = strong base
99
How can you determine degree of ionisation?
Henderson-Hasselbalch equation
For acids:
pH = pKa + log [A⁻]/[HA]
For bases:
pH = pKa + log [B]/[BH⁺]
If pH = pKa, 50% will be ionised, 50% unionised
If pH > pKa, acid will be ionised, base will be unionised
If pH < pKa, base will be ionised, acid will be unionised
100
What factors affect the strength of an acid?
Stability of the conjugate base
Resonance
Electronegativity
Atom size
Hybridisation
Solvation
Bond strength (A – H)
101
How does resonance affect the strength of an acid?
Delocalisation of the negative charge via resonance → stabilises the conjugate base → increases acid strength
Note: meta position does not participate in resonance because it's not conjugated
102
How does electronegativity affect the strength of an acid?
More electronegative atoms can better stabilise negative charge of conjugate base (via inductive effect) → stronger acid
Electronegative groups = Cl, F, Br, N, O, NO₂ , CN
Electropositive groups (e.g. CH₃, B, Si) decrease strength as they “push” electron density towards the negative charge
Inductive effect gets smaller with distance:
ortho > meta > para
Stronger when the EWG is closer to the acidic site
103
How does atom size affect the strength of an acid?
As the size of the atom bearing the negative charge increases, the negative charge is spread over a larger volume → more stable conjugate base → stronger acid
104
How does hybridisation affect the strength of an acid?
The more s-character in the hybrid orbital, the stronger the acid
sp > sp² > sp³
105
How does solvation affect the strength of an acid?
A well-solvated conjugate base is more stable → stronger acid
106
How does bond strength affect the strength of an acid?
Weaker A–H bonds → easier to break → stronger acid
107
pKa of common groups
Carboxylic acids ~4
Phenol ~10
Alcohols ~16-18
Aromatic amines ~4
108
What is a base?
A substance that can accept a proton by donating a pair of electrons
109
Common basic functional groups
Amines
–NH₂, –NHR, –NR₂
110
Why are amides not basic?
The lone pair on nitrogen is delocalised into the carbonyl group (C=O) via resonance therefore less likely to accept protons
111
How can charged molecules be separated by acid-base extraction?
Ionised/charged molecules will be soluble in aqueous layer
Neutral/uncharged molecules will be soluble in organic layer
To extract a basic compound:
* Add acid → becomes protonated → moves to aqueous layer
* Add base → becomes neutral/uncharged → moves to organic layer
To extract an acidic compound:
* Add base → becomes deprotonated → moves to aqueous layer
* Add acid → becomes neutral/uncharged → moves to organic layer
112
What is a buffer?
A solution that resists pH changes when small amounts of acid or base are added
Work by neutralising the added acid or base to maintain a stable pH
Common components
* Weak acid + its conjugate base
* Weak base + its conjugate acid
Most effective when pH ≈ pKa of the buffering species (within ±1 pH unit of target)
113
What are carbonyls?
Contain a carbonyl group (C=O)
Includes:
Aldehydes (R–(C=O)–H)
carbonyl group is bonded to at least one hydrogen atom
Ketones (R–(C=O)–R)
carbonyl group is bonded to two carbon atoms
114
Why is the carbonyl group reactive?
The C=O bond is polarised:
* the carbon is electrophilic (δ⁺) so it is susceptible to nucleophilic attack
* oxygen is nucleophilic (δ⁻)
115
What is nucleophilic addition?
A reaction in which a nucleophile donates a pair of electrons to the electrophilic carbon in a carbonyl group
The carbonyl group is planar (sp2 hybridised) so nucleophiles can attack from either top or bottom
116
How does nucleophilic addition differ under basic/neutral vs. acid-catalysed conditions?
Basic/Neutral Conditions:
* The nucleophile directly attacks the electrophilic carbonyl carbon first
* Common with strong nucleophiles/bases (e.g. CN⁻, OH⁻, R⁻)
Acid-Catalysed Conditions:
* The carbonyl oxygen is protonated first, increasing the electrophilicity of the carbonyl carbon
* The nucleophile attacks second, after activation
* Favours weaker nucleophiles (e.g. water, alcohols)
117
What does addition of cyanide to carbonyl compounds form?
Cyanohydrins (R₂C(OH)CN)
118
Why does addition of cyanide need to be conducted in buffered conditions?
Buffered to pH 6-8
In acidic solution, most of CN⁻ is protonated to form HCN, which is:
* toxic/poisonous
* a weaker nucleophile, reducing reaction efficiency
119
How are α-hydroxyacids synthesised?
Cyanohydrin is first formed via nucleophilic addition of CN⁻ to a carbonyl compound
The nitrile group (-CN) is then hydrolysed to a carboxylic acid (-COOH)
R-CH(OH)-CN → R-CH(OH)-COOH
120
How are nitriles synthesised?
Nucleophilic substitution of a halogenoalkane with CN⁻
R-X + NaCN → R-CN + NaX
Best with primary halogenoalkanes to favour SN2 reaction
121
What is a Grignard reagent?
Organomagnesium halide: R–MgX
Formed by reacting an alkyl or aryl halide (R–X) with magnesium (Mg) in ether solvent
122
Why must Grignard reagents be prepared in ether solvent?
Grignard reagents are extremely reactive with water/moisture to form alkanes
R–MgX + H₂O → R–H + Mg(OH)X
Ether stabilises the Grignard reagent by coordinating to the magnesium atom, helping keep it in solution
123
What type of reaction do Grignard reagents undergo with carbonyl compounds?
Nucleophilic addition
* The carbon in R–MgX is δ⁻ and nucleophilic
* Attacks the electrophilic carbon in C=O groups
Grignard + formaldehyde → primary (1°) alcohol
Grignard + aldehydes → secondary (2°) alcohol
Grignard + ketones → tertiary (3°) alcohol
124
Why are Grignard reactions useful?
Chain extension (formation of new C-C bonds)
Can build more complex alcohols and acids from simpler molecules
125
What does addition of water to carbonyl compounds form?
Hydrates
126
Why are carbonyl hydrates generally unstable?
The equilibrium lies to the left so most hydrates will revert back to an aldehyde or ketone
Two C–OH bonds are less favourable that a C=O bond
Steric hindrance or electron-donating groups on the carbonyl carbon can reduce hydrate stability
127
Why are chloral hydrates stable?
Electron-withdrawing Cl groups stabilise the hydrate by dispersing electron density
128
What does addition of alcohol to carbonyl compounds form?
Acid-catalysed
Addition of one alcohol molecule → hemiacetal R₂C(OH)(OR′)
Addition of excess alcohol → acetal R₂C(OR′)₂ + H₂O
Stable in neutral/basic conditions, hydrolysed in acid
129
What is cyclisation of monosaccharides?
Aldoses and ketoses (simple sugars/monosaccharides) form cyclic hemiacetals/hemiketals via an intra-molecular nucleophilic addition reaction between the carbonyl group (C=O) and a hydroxyl group on the same molecule
Form furanose (5 membered) or pyranose (six-membered) rings
130
How are esters synthesised?
Carboxylic acid + alcohol → ester + water
Acid-catalysed
Nucleophilic addition-elimination reaction:
* Alcohol (the nucleophile) attacks the carbonyl carbon of the carboxylic acid
* Elimination of the leaving group water
131
What type of reaction mechanism is ester hydrolysis?
Nucleophilic acyl substitution
Nucleophile (water in acid hydrolysis or hydroxide in base hydrolysis) attacks the carbonyl carbon of the ester, forming a tetrahedral intermediate
Alcohol leaving group is expelled
132
What conditions are needed for ester hydrolysis?
Strong base + heating under reflux
OR
Strong acid catalyst (e.g. H₂SO₄) + water (excess)
Protonation increases electrophilicity
133
Why must an excess of water/solvent be added in acid-catalysed ester hydrolysis?
The protonated carboxylic acid is sufficiently electrophilic to be attacked by an alcohol
Excess water/solvent drives completion of reaction
134
How are triglycerides metabolised?
Ester hydrolysis
Lipase enzyme
Mild conditions: ~37°C, neutral pH
Produces glycerol and fatty acids
135
How is enalapril converted to enalaprilat?
Ester hydrolysis
Enalapril (a prodrug) is hydrolysed by esterases in the liver to produce enalaprilat (active form)
136
Which common drug class contains ester groups?
Local anaesthetics (e.g. procaine, benzocaine)
Esters are hydrolysed by esterases → short duration of action
137
What reactions do acid derivatives undergo?
Nucleophilic substitution as they have leaving groups
Acid derivatives = acyl chlorides, esters, amides, anhydrides, carboxylic acids
Aldehydes and ketones don’t → they undergo nucleophilic addition or nucleophilic addition elimination (where the leaving group is water)
138
What affects the reactivity of carboxylic acid derivatives?
Inductive effect
* Electron-withdrawing groups increase electrophilicity of the carbonyl → more reactive
Resonance
* Strong resonance donation decreases reactivity
* E.g. amides - lone pair on N delocalises into C=O → less electrophilic
Steric hindrance
* Bulky groups hinder attack by nucleophiles → lower reactivity
Nature of leaving group
* Good leaving groups (e.g. Cl⁻ in acyl chlorides) → more reactive
* Poor leaving groups (e.g. NH₂⁻ in amides) → less reactive
139
What is the general mechanism of nucleophilic acyl substitution?
Nucleophile attacks carbonyl → tetrahedral intermediate
Elimination of leaving group → regenerates carbonyl
140
What factors determine whether nucleophilic acyl substitution will occur?
Nucleophile strength
* Stronger nucleophiles are more likely to attack the carbonyl carbon efficiently (e.g. OH⁻, NH₂⁻, alkoxides)
* Weak nucleophiles (e.g. water, alcohols) may require acid catalysis to protonate the carbonyl and make it more electrophilic
* Nucleophilicity depends on factors like charge (anions are better), size (less steric hindrance is better) and basicity
Reactivity of the carbonyl compound
* Electrophilicity of the carbonyl carbon
* Nature of the substituent attached to carbonyl
* Acid chlorides are highly reactive, while esters and amides are less so due to resonance stabilisation
* Electron-withdrawing groups increase carbonyl reactivity by making the carbon more δ⁺ and open to nucleophilic attack
Leaving group ability
* The group originally attached must be a better leaving group than the incoming nucleophile
* Good leaving groups =
* Poor leaving groups =
Thermodynamics
* Is the product more stable (less reactive) than the starting material?
* Order of stability = Carboxylate > Amide > Ester > Ketone > Aldehyde > Anhydride > Acid Chloride
141
What is the order of reactivity for carbonyl compounds?
Acid chlorides > Aldehydes > Ketones > Esters > Amides
142
Why is amide hydrolysis harder than ester hydrolysis?
NH₂⁻ is a poor leaving group (compared to OH⁻)
Reversible - equilibrium favours amide reformation
Deprotonation of the acid drives the reaction
143
What is the catalytic triad of serine proteases?
Ser-195
acts as nucleophile (OH⁻) to attack peptide bond
His-57
abstracts proton from Ser-195
Asp-102
helps deprotonate His-57
144
What are the main steps of the serine protease mechanism?
Nucleophilic attack by catalytic triad → tetrahedral intermediate
* Ser-195 acts as nucleophile (OH⁻)
* His-57 abstracts proton from Ser-195
* Asp-102 helps deprotonate His-57
Tetrahedral intermediate collapses → amine leaving group released
Water attacks ester intermediate
Second collapse → carboxylic acid released
145
How do protease inhibitors work in HIV treatment?
Bind to the active site of HIV protease, preventing cleavage of viral polyproteins and therefore virus maturation
146
What are transition state inhibitors?
Compounds which mimic the transition state of an enzymatic reaction
They bind tightly to the enzyme active site, blocking access of the natural substrate
147
Examples of transition state inhibitors
Saquinavir
Ritonavir
Indinavir
148
What are elimination reactions?
Reactions where two atoms or groups are removed from a molecule to form a π bond (unsaturation)
149
What are the two types of elimination reactions?
E1
* Unimolecular
* Two-step mechanism
* Favoured by weak bases (e.g. H₂O, ROH)
* Favoured by polar protic solvents (e.g. H₂O, ROH) which stabilise the carbocation intermediate
* Does not occur for 1° alkyl (form highly unstable carbocation)
* Less useful as mixture of SN1 and E1 products form
E2
* Bimolecular
* Concerted one-step mechanism
* Favoured by strong bases (e.g. HO⁻, RO⁻)
* Favoured by polar aprotic solvents (base is stronger as its not solvated)
* Stereoselective - favour trans isomers over cis isomers
* Rate increases with more alkyl substitution on the carbon bearing the leaving group (3° > 2° >> 1°)
* More useful
150
Describe the mechanism of E1 reactions
1) Leaving group is removed (slow - rate determining step, reversible)
2) Formation of carbocation intermediate
3) Nucleophile attacks hydrogen on adjacent carbon (base removes proton/deprotonation)
4) Formation of π bond
151
What does the energy profile of an E1 reaction look like?
Two peaks:
1st
* formation of carbocation (rate-determining step)
* large Ea
2nd
* formation of alkene via deprotonation
* smaller Ea
Valley between peaks represents the carbocation intermediate
152
What is the difference between E1 and SN1 reactions?
Both share the same first step - formation of a carbocation
SN1 - nucleophile attacks carbocation → substitution product
E1 - base attacks/removes a β-H → alkene
Occur under similar conditions (e.g. polar protic solvents, weak nucleophiles/bases, 3° > 2° )
153
Describe the mechanism of E2 reactions
1) Electron rich base attacks hydrogen
2) Hydrogen donates electrons to carbon
3) Carbon shares electrons with neighbouring carbon forming a π bond
4) Leaving group is removed
154
What does the energy profile of an E2 reaction look like?
One peak representing the transition state where proton abstraction and leaving group departure occur simultaneously
155
What is the difference between E2 and SN2 reactions?
Both share concerted one-step mechanisms, but differ in how R groups affect the reaction rate:
* For E2: as the number of R groups on the carbon bearing the leaving group increases → rate increases
* For SN2: as the number of R groups increases → rate decreases (due to steric hindrance blocking nucleophile attack)
156
What is Zaitsev’s Rule?
States that in elimination reactions, the most substituted alkene is favoured because it is more stable (via hyperconjugation and electron-donating inductive effects)
The hydrogen which is lost will come from the more highly-branched carbon
157
Under which conditions is the the least substituted alkene favoured (Hofmann Eliminations)?
The base is bulky
The leaving group is bulky
158
What is regioselectivity?
The preference for forming one constitutional isomer over another
Both E1 and E2 reactions are regioselective - generally favour the more substituted and stable alkene
159
Why are E2 reactions stereoselective?
E2 reactions favour trans isomers over cis isomers as they require antiperiplanar geometry, a staggered confirmation where the β-hydrogen and leaving group are in the same plane but point in opposite directions
Allows optimal orbital overlap for the new π bond to form
Trans isomer is more stable due to reduced steric repulsion (bulky groups are further apart)
160
What factors determine whether a reaction undergoes substitution or elimination?
Substitution is favoured when:
* Nucleophilic weak bases (e.g. I-, Br-, CN-, CH3COO-)
* Polar aprotic solvents (e.g. DMSO, acetone) → SN2
* Polar protic solvents (e.g. H₂O, ROH) → SN1
* 1° carbons with strong nucleophiles → SN2
* 3° carbons with weak nucleophiles → SN1
* Steric hindrance is low → easier nucleophilic attack
Elimination is favoured when:
* Strong bulky bases (e.g. DBU, DBN and KOC(CH3)3) → E2
* Poor nucleophiles/weak bases (e.g. H₂O, ROH) → E1 (with 3° carbons)
161
What types of reactions can primary alkyl halides undergo?
Do not undergo SN1 (primary carbocations are unstable)
SN2 reaction occurs with strong nucleophiles (e.g. OH⁻, CN⁻)
E2 reaction occurs with strong, bulky bases (e.g. KOtBu)
162
What types of reactions can secondary alkyl halides undergo?
Mixture of E2 and SN2 products observed with strong bases and nucleophiles
E2 mechanism observed with strong, sterically hindered bases
Mixture of SN1 and E1 observed formed with weak nucleophiles and bases
163
What types of reactions can tertiary alkyl halides undergo?
Do not undergo SN2 (steric hindrance blocks backside attack)
E2 reaction observed with strong bases
Mixture of SN1 and E1 products observed with weak nucleophiles or bases
164
What products are formed when an amine reacts with a carbonyl compound?
Primary amine + carbonyl → imine R₂C=NR
Secondary amine + carbonyl → enamine R₂C=CR(NR₂)
Tertiary amine → no reaction (no proton for elimination)
165
What is the mechanism of imine formation?
Nucleophilic addition
Lone pair on the nitrogen of the primary amine attacks the electrophilic carbonyl carbon
Proton exchange → formation of hemiaminal intermediate
Elimination of water → formation of iminium ion
Deprotonation to form imine
Acid-catalysed
166
How can imine/enamine formation be driven forward if all steps are reversible?
Remove water using:
4 Å molecular sieves
Drying agents (e.g. magnesium sulphate, MgSO₄)
Reflux conditions (Dean-Stark apparatus)
167
What happens to imines in excess aqueous acid?
They hydrolyse back to the aldehyde/ketone and amine
Less common for insoluble imines
168
What is the mechanism of enamine formation?
Nucleophilic addition
Lone pair on the nitrogen of the secondary amine attacks the electrophilic carbonyl carbon
Proton exchange → formation of hemiaminal intermediate
Elimination of water → formation of iminium ion
Deprotonation at the α-carbon forming a C=C double bond → enamine product
Acid-catalysed
169
What is reductive amination?
Formation of imine or iminium ion from an amine and a carbonyl compound
The iminium ion is reduced to an amine using a mild reducing agent
Primary amines are transformed into secondary amines
Secondary amines are transformed into tertiary amines
Tertiary amines do not react since no iminium cation can form
170
What influences the choice of reducing agent for reductive amination?
Weak reducing agents are favoured as they selectively reduce the iminium ion, not the carbonyl compound (aldehyde/ketone)
E.g.
* Sodium cyanoborohydride, NaBH₃CN
* Sodium triacetoxyborohydride, NaBH(OAc)₃
171
Why is reductive amination preferred over SN2 for amine synthesis?
SN2 overreacts, forming secondary, tertiary and quaternary products
Reductive amination allows for selective formation without overalkylation:
* Ammonia → primary amine selectively
* Primary amines → secondary amines selectively
* Secondary amines → tertiary amines selectively
172
What is conjugate (1,4-) addition of amines?
Reaction of amines with α,β-unsaturated aldehydes/ketone to form β-amino ketones
No acid catalyst needed as amines act as good nucleophiles
Can be base catalysed to regenerate the amine and stabilise intermediates
Cannot occur with tertiary amines (cannot deprotonate)
173
What do neuromuscular blocking agents (NMBAs) do?
Block acetylcholine signaling at the NMJ causing skeletal muscle paralysis
Used in surgery alongside anaesthetics
174
How are NMBAs metabolised?
Hofmann elimination
175
How do aromatic substituents affect NMBA metabolism?
Electron-donating groups slow elimination but increase potency
Halogens increase elimination rate but reduce potency
Methoxy groups (e.g. 3,4-dimethoxy) balance potency with acceptable elimination rate
176
What role does HMG-CoA reductase play in cholesterol biosynthesis?
Catalyses conversion of HMG-CoA to mevalonate
The rate-limiting step in cholesterol synthesis
177
Describe the catalytic mechanism of HMG-CoA reductase
Two-step NADPH-dependent reduction
178
What are the key catalytic residues of HMG-CoA reductase?
Lys691 – stabilises the negatively charged oxygen of mevaldyl-CoA intermediate
His866 – helps activate the carbonyl group (acts as an acid catalyst)
Glu559 – acts as an acid/base
Asp767 – involved in proton transfer
179
What are the structural features of statins?
Resemble the tetrahedral intermediate/transition state from the first stage of the reaction
Key features:
* Polar head group
* Hydrophobic moiety
* Decalin ring (type I) or fluorophenyl group (type II)
180
What are the structural similarities between statins and the HMG-CoA reductase substrate?
Statins contain a polar head group that resembles the HMG portion of the natural substrate
The polar head of statins forms similar hydrogen bonds in the active site as the intermediate of HMG-CoA
181
What is the mechanism of action of statins?
Competitive inhibitors of HMG-CoA reductase
Bind to the active site, mimicking the reaction intermediate
Block conversion of HMG-CoA → mevalonate
Reduces cholesterol biosynthesis in the liver → lowering blood LDL levels
182
What are the two types of statins?
Type I:
* Natural or semi-synthetic
* Derived from fungal metabolites
* E.g. Lovastatin, Simvastatin, Pravastatin
* Contain a decalin ring
* Cleared quicker (shorter half-life)
* Greater risk of side effects
Type II:
* Synthetic
* E.g. Fluvostatin, Atorvastatin, Cerivastatin, Rosuvastatin
* Contain a fluorophenyl group
* Contain larger hydrophobic moiety
* No asymmetric centres
* Easier to synthesise
* Longer half-life
* Lower risk of side effects
* Stronger binding and potency
183
What are the limitations of type I statins?
Increased risk of side effects (due to higher hydrophobicity → non-specific tissue distribution)
Difficult to synthesise (due to natural origin)
Large number of asymmetric centres (complicates synthesis and limits modification)
Limited structural flexibility due to rigid decalin ring
Lower binding affinity than type II statins (fewer interactions with active site)
184
Why do type I statins have a higher risk of side effects?
More hydrophobic → cross cell membranes more easily/readily
Can enter non-hepatic tissues, increasing off-target effects
Higher chance of causing muscle-related side effects like rhabdomyolysis
Less selective for liver tissue compared to more hydrophilic statins
185
What modifications were made to form type II statins?
Larger hydrophobic moiety (e.g. fluorophenyl) → enhances van der Waals interactions
Replaced decalin ring with synthetic aromatic groups → allows greater binding affinity
Addition of polar groups (e.g. sulfonamide in rosuvastatin) → enhanced binding and selectivity
Results = stronger binding, greater potency, reduced off-target effects
186
What is the prodrug mechanism of lovastatin and simvastatin?
Contain a lactone ring in the inactive form which is hydrolysed in vivo to produce the active polar head form
187
What is rhabdomyolysis?
Involves breakdown of skeletal muscle tissue
Can lead to kidney damage due to release of myoglobin
A rare but serious side effect of statins
188
What are the binding interactions of statins?
Hydrophobic moiety interacts via van der Waals forces with Leu, Val, Ala residues in the hydrophobic pocket
Arg-590 forms polar interaction with fluorophenyl substituent
Ser-565 forms hydrogen bond with amide (and sulfone group in rosuvastatin)
Planar guanidinium group of Arg-590 may stack over aromatic rings (e.g. phenyl) to stabilise the complex
189
Summarise the drug development process of statins
First lead compound = Mevastatin (natural fungal product)
Modified by adding methyl group → Lovastatin
Extra methyl group added for better lipophilicity → Simvastatin
Further modifications (e.g. fluorophenyl, sulfonamide) introduced for stronger binding and potency → type II statins
190
How does potency and hydrophobicity vary among different statins?
Rosuvastatin = most potent → due to sulfonamide group enhancing binding
Cerivastatin = most hydrophobic → may increase membrane penetration but also side effects
Pravastatin + Rosuvastatin = least hydrophobic → better solubility, fewer adverse effects
191
Compare statins and HIV protease inhibitors
Both are reversible competitive inhibitors
Both mimic the transition state to block enzymatic activity
Differ in target and therapeutic use
192
What are tautomers?
Species in equilibrium that differ in the position of a proton or other group
Structural isomers that are in equilibrium with each other and interconvert through the migration of a proton (hydrogen atom) and a shift in double bonds
193
Keto-Enol tautomerism
keto ⇌ enol
Keto form predominates because enols are unstable due to the presence of an -OH group directly attached to a double bond
194
What catalyses tautomerism?
Traces of acid or base
195
What happens during base-catalysed keto tautomerism?
Base removes an α-hydrogen to form an enolate ion (conjugate base), which is resonance-stabilised
196
What happens during acid-catalysed keto tautomerism?
A proton is added to the carbonyl oxygen, followed by proton transfer to form the enol
197
What is aldol condensation?
A reaction where an enolate ion reacts with a carbonyl compound to form a β-hydroxy aldehyde or ketone (aldol), which can lose water to form an α,β-unsaturated aldehyde or ketone under acid or base catalysed conditions
198
α,β-unsaturated carbonyls have three resonance contributors
199
What is a Michael addition?
A type of conjugate addition where a nucleophile (Michael donor) adds to the β-carbon of an α,β-unsaturated carbonyl compound (Michael acceptor)
200
What are Michael donors?
Nucleophiles (e.g. enolate ions) that donate electrons in a Michael addition
201
What are Michael acceptors?
Electrophiles which accept electron pairs during a Michael addition
202
What is glutathione (GSH)?
A tripeptide composed of glutamate, cysteine and glycine that acts as a nucleophile in detoxification reactions
203
What role does glutathione play in drug metabolism?
Adds to electrophilic centres via conjugate addition to detoxify reactive species
204
What enzyme catalyses glutathione conjugation?
Glutathione S-transferase (GST)
205
What are the main metabolic pathways for paracetamol?
Largely undergoes glucuronidation and sulfation (phase II conjugation)
A small portion undergoes phase I metabolism where it is oxidised by CYP450 enzymes to form N-acetyl-p-benzoquinone imine (NAPQI)
NAPQI binds covalently to cellular proteins, leading to liver cell damage and hepatotoxicity
It is detoxified conjugation with glutathione
206
What is a treatment for paracetamol toxicity?
Administration of N-acetylcysteine (NAC) to replenish glutathione levels
207
What is the mobile phase?
A solvent that flows through the supporting medium
208
What is the stationary phase?
A layer or coating on the supporting medium that interacts with the analytes
209
What are the different types of chromatography?
Thin Layer Chromatography (TLC)
Column Chromatography
High Performance Liquid Chromatography (HPLC)
Size Exclusion Chromatography (SEC)
Ion exchange chromatography
Gas Chromatography (GC)
Chiral chromatography
Affinity chromatography
210
What is the distribution coefficient (Kx)?
A measure of how much a component (analyte) prefers the stationary phase over the mobile phase
Kx = conc in stationary phase / conc in mobile phase
211
What are the different modes of separation in chromatography?
Adsorption
Partition
Ion exchange
Size exclusion
212
What is the principle of adsorption chromatography?
Separation based on analytes’ adsorption affinity to solid stationary phase
Stronger interactions (e.g. H-bonding, van der Waals) = retained longer
Weaker interactions = elute faster
213
What are the phases used in adsorption chromatography?
Stationary phase = solid (e.g. silica gel, alumina)
Mobile phase = liquid or gas
214
What techniques use adsorption chromatography?
Thin Layer Chromatography (TLC)
Column Chromatography
215
What is the principle of partition chromatography?
Separation is based on differences between the solubility of the sample analytes in the mobile and stationary phases
216
What are the phases used in partition chromatography?
Stationary phase = immobilised liquid
Mobile phase = liquid or gas
217
What techniques use partition chromatography?
Gas Chromatography (GC)
High Performance Liquid Chromatography (HPLC)
218
What is the principle of ion exchange chromatography?
Separation is based on charge interactions between analytes and charged groups on stationary phase
Elution occurs by changing pH or ionic strength of the mobile phase
219
What are the phases used in ion exchange chromatography?
Stationary phase = resin with functional groups that can exchange ions (e.g. sulphonic acid for cations, quaternary amine for anions)
Mobile phase = aqueous buffer or salt solutions
220
What are the two types of ion exchangers?
Cation exchanger = stationary phase is negatively charged
Anion exchanger = stationary phase is positively charged
221
What is the principle of size exclusion chromatography?
Separation based on molecular size and shape
Large molecules are not retained (bypass pores) and elute faster
Small molecules are retained in the pores of the gel and elute slower
222
What are the phases used in size exclusion chromatography?
Stationary phase = porous beads (e.g. agarose, dextran, silica)
Mobile phase = aqueous or organic solvent
223
What are the two types of size exclusion techniques?
Gel permeation chromatography:
* uses polymers that swell in organic liquids
* organic mobile phase + hydrophobic stationary phase (e.g. polyacrylamide gel)
Gel filtration chromatography:
* uses polymers that swell in water
* aqueous mobile phase + hydrophilic stationary phase (e.g. sephadex - polysucrose polymer)
224
What is affinity chromatography?
Separates based on specific binding interactions between the target molecule and a ligand on the stationary phase
Only the target molecule binds, others are washed away
225
What is the difference between normal phase and reverse phase chromatography?
Normal phase:
* Polar stationary phase (e.g. silica, alumina)
* Non-polar mobile phase (e.g. hexane)
Compounds elute in order of increasing polarity, i.e. least polar first
* Commonly used in TLC, Flash Column Chromatography
Reverse phase:
* Non-polar stationary phase (e.g. C4, C18)
* Polar mobile phase (e.g. water, ethanol)
* Compounds elute in order of decreasing polarity, i.e. most polar first
* Commonly used in HPLC
226
Predicting elution in TLC and HPLC
Separated according to polarity
Normal phase
* polar retained more (lower Rf)
* non-polar elute first (higher Rf)
Reverse phase
* non-polar retained more (lower Rf)
* polar elutes first (higher Rf)
227
What is retention factor (Rf)?
Rf = distance moved by compound / distance moved by solvent
Lower Rf = retained longer
228
How does mobile phase polarity affect Rf in normal phase chromatography?
Increasing mobile phase polarity → reduces interactions with stationary phase → analytes move faster → higher Rf
Decreasing mobile phase polarity → increases retention → decreases Rf
229
Commonly used stationary phases
Silica gel (polar)
Alumina (polar)
C18, Octadecylsilane (non-polar)
C8, Octylsilane (non-polar)
Polyacrylamide/agarose/dextran gels (polar)
230
Commonly used solvents as mobile phase
Polar
* Water
* Methanol
* Ethanol
* Propanol
* Acetonitrile
* Acetone
Non-polar
* Hexane
* Chloroform
* Diethyl ether
* Toluene
231
What is response ratio (RR)?
232
What are the uses of spectroscopy in pharmacy?
Identify unknown
Quantify samples
* the degree of interaction is proportional to the concentration of matter
Understand properties
Determine functional groups and molecular structures
Investigate conjugation and molecular transitions
Analyse purity and identity of compounds
233
What is UV-Vis spectroscopy?
Measures absorption of UV light by a molecule
Absorption occurs when electrons are promoted from lower to higher energy molecular orbitals
Involves π → π* and n → π* transitions in chromophores
234
What is a chromophore?
A part of a molecule responsible for absorbing UV/Vis light
E.g. C=C, C=O, NO₂, aromatic rings
235
Key UV-Vis chromophores and their transitions:
C=C π → π* (190–210 nm)
C=O n → π* (270–290 nm)
Aromatic rings π → π* (200–280 nm)
236
How does conjugation affect UV-Vis absorption?
Increases wavelength of maximum absorption (λmax)
Decreases energy required for electronic transitions
237
What is the Beer-Lambert law?
Used to determine concentration using UV-Vis
A = εcl
Where:
* A = absorbance
* ε = molar absorptivity
* c = concentration
* l = path length
238
Why should absorbance ideally be within the 0.2–1.2 range?
Ensures linearity with Beer-Lambert law
Below 0.2 = signal too weak, low accuracy
Above 1.2 = light absorption too strong, less light reaches detector
239
What is specific absorbance (A₁%₁cm)?
Absorbance of a 1% w/v solution in 1 cm path length
240
What is λmax?
The wavelength at which a compound shows maximum absorbance
241
How can you determine concentration using UV-Vis?
1) Prepare standard solutions of known concentration
2) Measure absorbance at λmax
3) Plot absorbance vs concentration to create a calibration curve
4) Use the curve to find unknown concentration
242
Why is it important to select the correct solvent in UV-Vis spectroscopy?
Solvent must not absorb in the same region as the analyte
Avoid deionised water as it doesn’t remove uncharged organics
Avoid dehydrated alcohol as it may contain benzene which absorbs strongly
243
What are the solvent effects in UV-Vis spectroscopy?
Aromatic chromophores show sharper features in non-polar solvents
π → π*:
* Excited state is more polar
* Polar solvent stabilises it → red-shift (longer λ)
n → π*:
* Ground state is more polar
* Polar solvent destabilises excited state → blue-shift (shorter λ)
244
What are the advantages of UV-Vis spectroscopy?
Works well with solutions in low concentrations
Simple and fast to perform
Non-destructive
Good for quantitative analysis
Useful for identifying chromophores and conjugation
245
What are the disadvantages of UV-Vis spectroscopy?
Limited structural information
Broad absorbance bands (less specificity)
Requires suitable solvent
Sensitive to solvent and pH effects
Only detects compounds with chromophores
246
What is IR spectroscopy?
Measures absorption of IR light
Absorption corresponds to vibrational transitions (bond stretching or bending)
247
What is the importance of dipole moment changes in IR spectroscopy?
Only vibrations causing a dipole change absorb IR radiation
Larger dipole change = greater molar absorptivity (ε)
No dipole change = IR inactive
248
What are the two main types of vibrations?
Stretching (symmetric and asymmetric)
Bending (scissoring, rocking, wagging, twisting)
249
What determines the frequency of molecular vibration in IR spectroscopy?
Bond strength (k) - stronger bonds vibrate faster (higher frequency)
Atomic mass (m) - lighter atoms vibrate at higher frequencies
250
How do you calculate the number of vibrational modes in a molecule?
For non-linear molecules → 3N – 6
For linear molecules → 3N – 5
Where, N = number of atoms
251
Key IR absorption bands
O-H: ~3600 – 2600 cm⁻¹
N-H: ~3300 cm⁻¹
C=O (carbonyl): ~ 1800-1600 cm⁻¹
C≡N or C≡C: ~2100–2260 cm⁻¹
C-H (alkane): ~2800–3000 cm⁻¹
C=C (alkene): ~1600–1680 cm⁻¹
Aromatic C=C: ~1450–1600 cm⁻¹
252
What is the fingerprint region in IR spectroscopy?
1500–500 cm⁻¹
Contains complex, unique vibration patterns
253
What causes differences in IR spectra for the same molecule?
H-bonding changes, due to:
* solvent effects
* different crystalline form (polymorphism)
Dissociation
* e.g. COOH to COO⁻ causes shift from ~1700 cm⁻¹ to ~1550 & ~1400 cm⁻¹ (two peaks)
254
What are the advantages of IR spectroscopy?
Provides detailed structural information
Identifies functional groups (e.g., OH, C=O, NH)
Can work on diff phases (solid, liquid, gas)
Peaks are sharp and characteristic
Allows identification of polymorphs and hydrogen bonding
255
What are the disadvantages of IR spectroscopy?
Not ideal for quantitative analysis
Water and CO₂ interfere
Sample preparation can be complex for solids
Requires dipole change so homonuclear diatomics (e.g. O₂, N₂) are IR-inactive
fingerprint region can be quite complicated to interpret
256
What is signal-to-noise ratio?
Ratio of the desired analytical signal to the background noise
High SNR = clearer, more reliable spectrum
* at least 3 for detection
* at least 10 for quantitative purpose
Low SNR can obscure peaks and lead to incorrect identification or quantification
257
What are the two types of NMR spectroscopy?
1H NMR - used to determine the type and number of H atoms in a molecule
13C NMR - used to determine the type of carbon atoms in a molecule
258
What determines if a nucleus has spin?
Number of protons and neutrons are both even = no spin
Total number of protons and neutrons is odd = half-integer Spin
Number of protons and neutrons are both odd = integer Spin
259
How can you determine the number of possible orientations using spin quantum number (I)?
A nucleus of overall spin I will have 2I + 1 possible orientations
260
What happens to nuclear spin states in the absence of a magnetic field?
All orientations are random and degenerate (of equal energy)
No energy difference between spin states
261
What happens to nuclear spin states in the presence of a magnetic field (B₀)?
Energy levels split into two states:
α (lower energy) – aligned with B₀
β (higher energy) – opposed to B₀
More nuclei are orientated with the applied field (α) because this arrangement is lower in energy
262
How does NMR work?
When nuclei absorb radiofrequency (RF) radiation equal to the energy difference (ΔE) between their two spin states, resonance occurs and a spin flip happens from α (lower energy) to β (higher energy)
This energy absorption depends on the nucleus's environment, leading to different chemical shifts that provide structural information
263
What effect does shielding have on the NMR signal?
Increased electron density → creates an induced magnetic field that opposes the external field (B₀) → lower RF frequency required for resonance → signals appear at lower chemical shifts (upfield)
264
What effect does deshielding have on the NMR signal?
Decreased electron density → nuclei feel a larger B₀ → higher RF frequency required for resonance → signals appear at higher chemical shifts (downfield)
265
What types of groups cause deshielding?
Electronegative atoms (e.g. Cl, Br, O, N) – pull electron density away
Electron-withdrawing groups (e.g. carbonyls, nitriles, nitro groups)
Aromatic rings – due to ring current effects
Double and triple bonds
Positive charges – reduce electron density near the proton (e.g. quaternary ammonium ions)
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What is the role of tetramethylsilane (TMS) in NMR spectroscopy?
Used as an internal standard in ¹H and ¹³C NMR
All other signals are measured relative to TMS
Assigned a chemical shift of 0 ppm
Highly shielded volatile inert compound that gives a single peak upfield/away from typical NMR absorptions
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How do you interpret an NMR spectra?
Number of protons signals = no. non-equivalent proton environments
Integral = area under the peak, proportional to the number of protons in each environment
Splitting patterns = neighbouring protons
* n + 1 rule – a proton with n equivalent neighbours splits into n + 1 peaks
* Singlet = no neighbours
* Doublet = 1 neighbour
* Triple = 2 neighbours
* Quartet = 3 neighbours
* Multiplet
* must have the same coupling constant if they are splitting each other
Chemical shift = indicates the electronic environment of the proton
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What are common chemical shift values for ¹H NMR?
Alkyl (–CH₃, –CH₂–) ~0.9–2.0 ppm
Allylic (C=C–CH) ~1.6–2.5 ppm
Aromatic (Ar–H) ~6.0–8.5 ppm
Aldehyde (–CHO) ~9.0–10.0 ppm
Carboxylic acid (–COOH) ~10.5–12.0 ppm
Alcohols/phenols (–OH) ~1.0–5.0 ppm
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Approx chemical shifts
Methyl (R-CH₃) = 0.9
Methylene (R-CH₂-R)= 1.3
Methine (R₃-CH) = 1.5
π (e.g. C=C, C=O, aromatic) = 1.3
OH = 2.5
N = 1.5
F = 3.2
Cl = 2.1
Br = 1.8
I = 1.2
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What happens to an NMR spectra when deuterated water (D₂O) is added?
Exchangeable protons (e.g. –OH, –NH) undergo proton exchange with D₂O
Their signals disappear completely from the ¹H NMR spectrum
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What is the NMR behaviour of enantiotopic vs. diastereotopic protons?
Enantiotopic protons are chemically equivalent → 1 signal
Diastereotopic protons are chemically non-equivalent → 2 distinct signals
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How can you identify diastereotopic protons in a molecule?
Found adjacent to chiral centres
If one proton is replaced with a different group (D), does a diastereomer form?
If yes → the protons are diastereotopic
