1. Organic Chemistry 2: Important Reactions
In the biological world, organisms are capable of synthesizing or degrading nearly any molecule
For the remainder of this class, we are going to look at the chemistry of basic biological molecules and the reaction mechanisms these molecules are involved in

2. Reaction Types We are going to focus on 3 basic reaction types:
Nucleophilic Substitution Reactions: An electron rich atom (nucleophile) attacks a electron deficient atom
Acid-Base Catalysis: Certain amino acid side chains of enzymes can accept or donate protons, making them act like acids (donate protons) or bases (accept protons)
Condensation Reactions: The involve the combining of two molecules to form a larger molecule and a smaller one
The reverse reaction is called a Hydrolytic Reaction. We’ll look at those as well.

3. Nucleophilic Substitution Reactions
Terminology:
Nucleophile: An electron rich atom. May be negatively charged or have an available lone pair
Electrophile: An electron poor atom. May or may not have a positive charge

4. Nucleophilic Substitution Reactions
Two types of Sn Reactions Exist
They are classified and named based upon the slowest (rate limiting) step: Sn1 and Sn2
The General form of these reactions is:
R:X + :Z --> R:Z + X
:Z is the nucleophile
X is the leaving group
In a condensation reaction for the formation of a lipid from a glycerol and a fatty acid, a glycerol hydroxyl is the nucleophile attacking the carbonyl carbon of the carboxylic acid
Remember: The nucleophile attacks atoms of partial positive charge

5. Types of Nucleophilic Substitution Reactions
Sn1: The rate is dependent on the leaving group leaving
Stands for: Substitution Nucleophilic Unimolecular
Note: The first step is the dissociation of the chlorine

6. Types of Nucleophilic Substitution Reactions
Sn2: The rate is dependent on the nucleophile and the substrate forming a bond at the SAME TIME the leaving group dissociates
Stands for: Substitution Nucleophilic Bimolecular
Steric hindrances may prevent Sn2 reactions
The concentration of both reactants affects the rate

7. Nucleophilic Substitution Reactions
Actually, many reactions are mixtures of Sn1 and Sn2 mechanisms
Many factors affect whether a reaction proceeds via the Sn1 or Sn2 route, including:
Nucleophilicity
Bond polarizability
Leaving group stability
Solvent composition
Think about these factors, you will see them again in Organic Chemistry

8. General Acid-Base Catalysis
In these reactions, groups accept or donate protons, thereby acting as acids or bases
In proteins, acid-base catalysis is mediated by side chains containing:
Imidazole, hydroxyl, carboxyl, sulfhydryl, amino and phenol groups
For an enzyme catalyzed reaction in which the enzyme abstracts a proton from a substrate, the protein is acting like a base
R-H+ + R-O- --> R + R-OH

9. General Acid-Base Catalysis
For an enzyme catalyzed reaction in which the enzyme donates a proton to a substrate, the protein is acting like an acid
R-H+ + R-O- --> R + R-OH
We would call this General Acid Catalysis
For an enzyme catalyzed reaction in which the enzyme abstracts a proton from a substrate, the protein is acting like a base
R-H+ + R-OH --> R + R-O-
We would call this General Base Catalysis

10. General Acid-Base Catalysis: An Example
Keto-Enol Tautomerization
Uncatalyzed
General acid catalysis: Partial proton transfer from an acid lowers the free energy of the high-free energy carbanionlike transition state of the keto-enol tautomerization
General base catalysis: The rate can be increased by partial proton abstraction by a base.
Concerted acid-base catalyzed reactions involve both processes occurring simultaneously.
Adapted from Voet, Voet and Pratt. Fundamentals of Biochemistry, 3rd Ed

11. General Acid-Base Catalysis: An Example
Enzymatic Degradation of 4-Nitrophenylacetate proceeds via a General Acid-Base mechanism
Imidazole nitrogen extracts proton from water initiating the reaction

12. Condensation Reactions
Two molecules combine with the generation of a smaller molecule

13. Condensation Reactions
Reaction of Acetic Acid and Ethanol

14. Looking at the Reaction Mechanism
The carbonyl carbon is:
Electron deficient
In a trigonal planar geometry
120º between substituents
The carbonyl oxygen is pulling electrons towards it
Resonance stabilization
The Lone Pair of the alcohol oxygen can react with the carbonyl carbon to set the whole thing in motion
Remember your VSEPR Geometry

15. Condensation Reactions: Making Lipids from Sugars and Fatty Acids
Your cells can synthesize lipids from glycerol and fatty acids in a condensation reaction 

16. Condensation Reactions: Polymerizing Carbohydrate Monomers

17. Condensation Reactions: Forming a Peptide Bond
What are the amino acids in the figure?
What function group is formed?
Its not really this simple, but it illustrates a point!

18. Hydrolysis: The Opposite of Condensation
In a hydrolytic reaction, we add the elements of water (H+ and OH-) across a bond
Many enzymes use this kind of reaction to degrade polymers
Lipases: Hydrolyze lipid esters
Glycosidases: Hydrolyze carbohydrate polymers
Peptidases: Hydrolyze peptide bonds
Compound Name + ase : Usually indicates a hydrolase (but not always!)
If it isn’t a compound name and ase, then it usually does something else:
Lyase
Reductase
Kinase
Transferase

19. Hydrolysis of Sugar Polymers
We add water across the Glycosidic Bond of Maltose to break it and generate 2 monomers
Catalyzed by a glycosidase (Maltase perhaps?)

20. Hydrolysis of Peptides
Dipeptide (What are the amino acids) is hydrolyzed to ???
Catalyzed by a peptidase or a protease

21. Amino Acids Amino acids are the building blocks of proteins
They consist of an amino group bonded to an -carbon, a hydrogen bonded to the -carbon and a carboxylic acid

22. Amino Acids and Stereochemistry
The -carbon is all amino acids except for glycine is chiral
Stereoisomers exist that is non-superimposable
Any carbon with 4 different substituents can be chiral
We describe the chirality of the -carbon as being Levorotary or Dextrorotary
L- or D-
Refers to how the molecule rotates polarized light

23. Amino Acids and Stereochemistry

24. Amino Acid Side Chains: Where the Action is!
The amino acids are classified according to the chemical character of the R-grop attached to the -carbon
Important Criteria:
Polar or Nonpolar side chains
Acidic or Basic
Charged or uncharged Polar residues

31. Side Chain Classification
Nonpolar (hydrophobic) Amino Acids
G, A, V, L, I, P, F, W, M
These amino acids have aliphatic side chains
Phenylalanine and Tryptophan are aromatic
Proline is cyclic
Induces turns in proteins

32. Side Chain Classification
Polar, Uncharged Amino Acids
S, T, Y, C, N, Q
S, T, Y have hydroxyl groups (-OH)
C has a sulfhydryl (-SH)
N and Q have amide side chains
Uncharged at neutral pH

33. Side Chain Classification
Acidic Amino Acids
D and E have carboxylic acids on their side chains
The side chains are negatively charged at neutral pH
This means the pKa’s of the side chains are less than 7

34. Side Chain Classification
Basic Amino Acids
H, K and R have side chains that are positively charged at neutral pH
Because these side chains have basic groups, they accept protons at pH values lower than the pKa of the side chain

35. Titrating Amino Acids
Free amino acids can have up to 3 pKa values associated with them
Carboxylic acid
Amino group
R-group
The carboxylic acid group has the lowest pKa (~2.0)
The pKa of the -amino is around 9-10
D, E, H, C, Y, K and R have R-groups that can ionize and their pKa’s range from ~4 to 12

37. Titrating and Amino Acid: Alanine
We’ll start at a pH of 1
The carboxylic acid and the amino group are protonated
As we start adding base, more and more of the carboxylic acids start losing protons until we reach pH 2.34 (the pKa of COOH)
At this concentration, [NH3+CHCH3COOH]=[NH3+CHCH3COO-] (same as we learned with regular titrations)
As we add more base, we deprotonate all the carboxylic acids
Midway up the sharp slope increase
For alanine, this is the isoelectric point
As we add more base, we’ll start deprotonating the -amino group until we reach pH=9.69 (the pKa of the group)
[NH3+CHCH3COO-]=[NH2CHCH3COO-]
Finally we can keep adding base until the only species is: NH2CHCH3COO-

38. Titrating and Amino Acid: Histidine
We’ll start at a pH of 1, the only species is the fully protonated form.
pK1 (COOH) = 1.82
pK2 (Imidazole nitrogen) = 6.0
pK3 (Amino) = 9.17
As we start adding base, the pH increases as the carboxylic acid converts to carboxylate
At pK1, the concentration of the carboxylate specie equals the concentration of the carboxylic acid species
As we add more base, we start deprotonating the imidazole nitrogen
At pK2, the conc. of the deprotonated imidazole group equals that of the protonated state
The pI is reached then the imidazole group is completely deprotonated
As we add more base, we’ll start deprotonating the -amino group until we reach pH=9.17 (the pKa of the group)

39. Amino Acid Titrations
At the isoelectric point, the molecule has zero net charge
The pH where this occurs is called the pI
We can calculate the pI of an amino acid using the following equation:
We average the pK values from the higher pKa that lost a hydrogen and the lowest pKa that is still protonated
For example: Histidine
pK1 = 1.82
pK2 = 6.0
pK3 = 9.17
We’d use the last two values
Usually it will be the alpha amino and the R group pK’s that are used
But we must take care to use the correct pK values!

40. The Peptide Bond
Amino acids are joined together in a condensation reaction that forms an amide known as a peptide bond

41. The Peptide Bond
A peptide bond has planar character due to resonance hybridization of the amide
This planarity is key to the three dimensional structure of proteins