Acidity - Summary PDF

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Acidity & basicity of organic molecules • Organic chemistry of functional groups • This resonance effect can also delocalise a charge by moving it to a different position • A charge that is delocalised is more stable • Conjugation and resonance can affect acidity by the ability to delocalise (and so stabilise) the negative charge formed when an acid dissociates •

Carboxylic acids are stronger than phenols. Alcohols are very weak acids. Hydrocarbons are essentially non-acidic

Carboxylic acids

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conjugate acid conjugate base COOH can act as an acid because the negative charge on the conjugate base generated by donating H+ can be delocalised

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Halogen-substituted aliphatic carboxylic acids

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The inductive properties of X will affect the stability of the negatively charged conjugate base This affects position of the equilibrium, i.e. acid strength

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The more electronegative the group X, the stronger the corresponding acid should be e.g. Halogen series

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In general, all groups with a negative inductive effect increase the strength of an acid They do so most effectively when closest to the carboxylic acid group Question What about aromatic carboxylic acids? Which do you think would be the strongest acid?

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IMPORTANT – INDUCTIVE EFFECTS ONLY Question What about aromatic carboxylic acids? Which do you think would be the strongest acid?

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IMPORTANT – INDUCTIVE EFFECTS ONLY

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Phenols and substituted phenols

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Phenols have the potential for resonance forms involving lone pairs on oxygen Resonance stabilisation is present in both the phenol and the phenoxide ion The resonance forms are favourable for the phenoxide ion

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One aromatic resonance form with OThree non-aromatic resonance forms (-ve C) Three other resonance forms delocalise negative charge around the ring – but at the expense of losing the aromaticity Some stabilisation of the –ve charge Phenols are weaker acids than RCOOH Effects of electron-withdrawing groups on phenols Inductive effect - same as carboxylic acids  Additional RESONANCE effects Some positions are conjugated with the negative charge on oxygen so extra resonance forms are possible Nitro groups on a benzene ring: conjugated when in the 2- and 4- positions out of conjugation at the 3-position Resonance effect at positions 2 and 4 – conjugation leads to extra resonance form

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Inductive effect at all positions Relative acidity RCOOH – delocalisation of –ve charge over the two oxygen atoms, both resonance forms equally favourable

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Phenol – delocalisation of –ve charge but not as energetically favourable as COOH

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Aliphatic alcohols – no way to delocalise –ve charge, essentially non-acidic In solution in water a base B: will establish the following equilibrium

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Basicity constant:

pKb = -log Kb

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We get two scales describing acids and bases: pKa and pKb However, it is possible to define the strengths of bases in terms of ‘K a’ and ‘pKa’ of their conjugate acid, BH+

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This has the advantage of producing a single continuous scale

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Importance of pKa in medicine The majority of drugs are either weak acids or weak bases Why is this important? pKa affects the proportion of the drug molecule in the ionised and un-ionised form ratio of ionised/un-ionised determines: drug solubility in water lipid solubility permeability binding etc. Summary Acidity determined by stability of negatively charged conjugate base Resonance (mesomeric) effect: conjugation can help to delocalise negative charge Inductive effect: electron withdrawing (-I) groups help to stabilise negative charge Effect of substituents: inductive effects for aliphatic and aromatic carboxylic acids, phenols resonance effects for phenol substituents only Acidity/basicity important when considering drug solubility and absorption through cell membranes Revision questions Which of the following compounds is the strongest acid?

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a. b. c. d. e.

p-nitrobenzoic acid p-bromobenzoic acid m-methylbenzoic acid m-methoxybenzoic acid benzoic acid

Revision questions Which of the following statements is not true? Phenol is more acidic than an aliphatic alcohol because the negative charge on the conjugate base can be delocalised A 4-nitro group increases the acidity of phenol by inductive and resonance effects A 4-nitro group increases the acidity of benzoic acid by inductive and resonance effects 2-Chloropropanoic acid is a stronger acid than 3-chloropropanoic acid because the inductive effect decreases with distance Chloroacetic acid is more acidic than iodoacetic acid because chlorine is more electronegative than iodine...