CH1601 Organic and Biological Chemistry I Lectures 10-16 Notes

Lecture 10: Introduction to the Carbonyl Group

• Introduction to the carbonyl group: chemistry, structure and bonding; molecular orbitals for the carbonyl group; $π$ and $π*$ orbitals.
• Typical properties and reactivities of carbonyl groups; $pK_a$ (protons adjacent to a carbonyl are acidic); nucleophilic addition to the carbonyl group.
• C-H acidities are affected by hybridization and markedly by carbonyl groups.
• Deprotonation adjacent to a carbonyl generates a delocalized anion. Substituent effects - $pK_a$ values of aldehydes, ketones, esters, malonates.

Lectures 11-12: Chemistry of the Carbonyl Group I

• Nucleophilic addition to carbonyls (aldehydes and ketones)
• Nucleophiles add to the $sp^2$ carbon of carbonyl compounds, generating a tetrahedral ($sp^3$) species.
• Examples of nucleophilic addition; addition of cyanide to generate cyanohydrins, equilibrium (steric effects) and mechanism; addition of water to aldehydes and ketones (hydration), equilibrium (substituent effects) and mechanism; acid and base catalysis of hydration of aldehydes and ketones.
• Other reactions and mechanisms; bisulfite addition; hydride ($NaBH<em>4$ and $LiAlH</em>4$) addition; organometallic addition ($R-MgBr$ (Grignard) and $R-Li$ (alkyllithium).

Lectures 13-14: Chemistry of the Carbonyl Group II

• Nucleophilic addition to carbonyls (aldehydes and ketones) II;
• Substitution reactions in which the carbonyl oxygen is replaced by other groups.
• Hemi-acetal formation (addition of alcohols); acid and base catalysis of hemi-acetal formation. Acetal formation (hemi-acetals undergo further reaction with alcohols under acid catalysis) and hydrolysis. Mechanism and oxonium ions.
• Reactions of primary amines with aldehydes and ketones (imine formation), pH effects and imine hydrolysis. Mechanism and iminium ions. Secondary amines react to form enamines.
• Reaction asymmetry in nucleophilic addition reactions to carbonyl groups - formation of racemic mixtures.

Lectures 15-16: Chemistry of the Carbonyl Group III

• Nucleophilic addition to carbonyls III (Substitution at C=O);
• Reactions, preparation and interconversion of carboxylic acid derivatives; acid chlorides, esters, anhydrides and amides. Preparation of esters through the reaction of an acid chloride or anhydride with alcohols - mechanisms, tetrahedral intermediates and leaving group ability (using $pK_aH$ as a guide to leaving group ability). Amines react with acid chlorides to form amides, and with carboxylates to form anhydrides - mechanisms, tetrahedral intermediates and leaving group ability.
• Order of reactivity of carboxylic acid derivatives to substitution (with $H_2O$ as an example) and reasons for this reactivity.
• Acid and base catalysis of the reactions of carboxylic acid derivatives. Ester formation and hydrolysis under acidic conditions and equilibrium; ester hydrolysis under basic conditions is irreversible. Acid and base promoted hydrolysis of amides. Preparation of acid chlorides from acids.
• Preparation of ketones, aldehydes and alcohols from acid derivatives; the problem of over-reduction and how to combat this.
• Summary of mechanistic concepts and mechanistic short-cuts.

Recommended Textbooks

• “Organic Chemistry”; Klein (Wiley VCH; ISBN 978-0-471-75614-9); Chapters 20 and 21 (1st or 2nd Edition)
• “Organic Chemistry”; (second edition); Clayden, Greaves, Warren (Oxford University Press; Oxford, 2012; ISBN 978-0-19-927029-3); Chapters 6, 10 and 11.
• “Chemistry3”; Burrows, Holman, Parsons, Pilling, Price, (Oxford University Press, Oxford, 2009; ISBN 978-0-19-927789-6). Chapters 23 and 24.
• “Organic Chemistry”; Vollhardt and Schore, (Freeman Palgrave Macmillan, 2011; ISBN 978-1-4292-3924-0). Chapters 17 and 19.
• “Chemistry of the Carbonyl Group - A Programmed Approach”’ Stuart Warren - this is an excellent text that teaches a step-by-step approach to arrow-pushing.

Other Recommended Purchases

• Molecular Models: Useful for viewing and visualizing molecules in 3D, can be used in examinations.

Other Sources of Information

• All course information including handouts, tutorials (and answers), class tests and recordings of the lectures, as well as supporting recordings for the workshops will be available through the CH1601 page on moodle.
• Lecture Recordings will contain the audio for the lectures and will sync with the lecture handouts and contain a screen capture of material drawn on the board.
• QR codes: Some lecture handouts contain embedded QR codes that allow you to see and manipulate molecules in 3-dimensions.
• Self-guided learning: Weekly quizzes are available from the CH1601 moodle page; pre-recorded live answers to the questions, as well as full written answers will allow you to monitor your learning and will help with the tutorial material for this course.
• Workshop Recordings: contain worked answers and explanations of the workshop material.

N-Heterocyclic carbenes (NHCs)

• The carbonyl group (C=O) is the most important functional group in organic chemistry

• The carbonyl group is the key part of a range of functional groups:

• Initially we will focus upon the chemistry and structure of aldehydes and ketones

  *Aldehyde: $RCHO$
  *Ketone: $R<em>2CO$ *Carboxylic acid: $RCOOH$ *Ester: $RCOOR$ *Acid chloride: $RCOCl$ *Anhydride: $(RCO)</em>2O$

Revision: Structure

• The carbonyl double bond (C=O) is made up of two parts, a $σ$ bond and a $π$ bond
• Consider formaldehyde as a simple model:
  • 3 x $sp^2$ hybridized orbitals on C unused p orbitals can overlap to form a $π$ bond
  • $sp^2$ orbitals can overlap to form a $σ$ bond

Structure, Chemistry, and Bonding of the Carbonyl Group

• The C=O bond is shorter than a C=C bond but is constructed in a similar manner.
• $sp^2$ hybridized O and C form the $σ$ bonding framework
• 2p orbitals on adjacent C and O atoms interact to form a $π$ molecular orbital
• In alkenes these p orbitals are approximately equal energy, but they are not in the carbonyl group.
• The 2p orbital on electronegative O is lower in energy than 2p on carbon giving rise to polarized molecular orbitals
• The bonding $π$ molecular orbital has a larger proportion of electron density on O (closer in energy to the atomic orbital on O).
• The anti-bonding $π*$ molecular orbital has a larger proportion of electron density on C (closer in energy to the atomic orbital on C).
• This is important in understanding the reactivity of carbonyl compounds in terms of addition reactions.
• The C=O bond is polarized, meaning that nucleophiles add to the carbon atom; a nucleophile adds electron density into the $π<em>$ molecular orbital (compare to an SN2 reaction where a nucleophile adds into a $σ</em>$ orbital), forming a new $σ$ bond.

Typical properties of carbonyl containing functionalities:

1. $pK_a$ - protons adjacent to a carbonyl group are relatively acidic
2. the C=O group readily undergoes nucleophilic attack

• Reminder: Hybridization can affect the $pK_a$ of C-H containing compounds
• s orbitals are held closer to the nucleus than p orbitals
• the more s character an orbital has, the more tightly held the electrons in it
• Use this to rationalize the $pK<em>a$ values of ethane, ethene and ethyne $\newline$ *Ethane ($sp^3$): $pK</em>a ≈ 50$
  $<br />\newline$ *Ethene ($sp^2$): $pK<em>a ≈ 40$$\newline$ *Carbonyl ($sp^2$): $pK</em>a ≈ 15-20$

Markedly Affected $pK_a$

• protons (C-H bonds) adjacent to a carbonyl group are much more acidic than alkanes

• For example: Consider the $pK<em>a$ trends in the following C-H acids (remember to always consider equilibrium between the C-H acids and their conjugate base) *Why does the C=O group make such a difference to $pK</em>a$?

• Deprotonation at a C-H adjacent to a C=O group generates an anion that can be stabilized by delocalization

• The negative charge formed by deprotonation is delocalized over the $π$ system and can be placed on an electronegative oxygen - remember the orbitals have to be co-planar in order to overlap

• You must be able to draw this delocalization - you have seen resonance forms already!

Variation of the Carbonyl Group Affects $pK_a$

• The functional group that the C=O is part of plays a role in determining its $pK_a$.

• Substituent effects of carbonyl functionalities plays a major role in determining $pK_a$.

• Consider the following example acidity aldehyde > ketone > ester. Why?

  1. Classify the electronic properties of the substituents attached to the C=O group as either inductively donating / withdrawing or mesomerically donating / withdrawing.
     *Aldehyde: one alkyl group inductively donating.
     *Ketone: two alkyl groups inductively donating.
     *Ester: inductively electron withdrawing BUT mesomerically electron donating.

• Predict that electron donating substituents would destabilize the conjugate base and therefore lead to a higher $pK_a$ value (decreasing acidity)

• These substituent effects upon $pK_a$ are additive.

• The more carbonyl groups adjacent to a C-H bond the more acidic it is

• Compare $pK_a$ of ethyl acetate and diethyl malonate

• By incorporating multiple conjugating groups we can affect the $pK_a$ of C-H compounds

Chemistry of the Carbonyl Group I: Nucleophilic Addition

• Lewis structures tell us:
  • The carbonyl group is polarized (O is more electronegative than C)
  • The carbon atom is relatively electron deficient so the carbonyl group is electrophilic at carbon.
• Consideration of the molecular orbitals of a carbonyl tell us:
  • The $π*$ orbital (LUMO) of C=O has its largest coefficient on C and the C=O bond is polarized.
  • Nucleophiles add to the carbon atom of a carbonyl group; a nucleophile adds electron density into the $π<em>$ molecular orbital (compare to an SN2 reaction where a $σ</em>$ orbital), forming a new $σ$ bond.
• Nucleophiles attack at the carbon of C=O (bond formed from nucleophile to carbon)
• The $π$ bond is broken, leaving a $σ$ bond intact (electrons move onto electronegative oxygen atom)
• The hybridization of the C atom undergoing nucleophilic attack changes from $sp^2$ (planar) to $sp^3$ (tetrahedral) after the addition

Nucleophilic Addition to Carbonyls (Aldehydes and Ketones)

• Addition of cyanide to aldehydes and ketones gives cyanohydrins
• The nucleophile (-CN) attacks the electrophile (C=O) at C
• This generates a tetrahedral ($sp^3$) species
• The reaction is usually carried out in acid which protonates the intermediate to form the product.
• This reaction is reversible; aqueous base catalyzes the decomposition of cyanohydrins to give the carbonyl component and cyanide
• This means that cyanohydrin formation is an equilibrium between starting material and product
• The equilibrium is more favorable for aldehyde derived cyanohydrins than ketone derivatives cyanide
• Why?