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Welcome to 3FF3! Bio-organic Chemistry. Jan. 7, 2008. Instructor: Adrienne Pedrech ABB 417 Email: adriennepedrech@hotmail.com -Course website: http://www.chemistry.mcmaster.ca/courses/3f03/index.html Lectures: MW 8:30 F 10:30 (CNH/B107)

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Instructor: Adrienne Pedrech
    • ABB 417
    • Email: adriennepedrech@hotmail.com

-Course website: http://www.chemistry.mcmaster.ca/courses/3f03/index.html

Lectures: MW 8:30 F 10:30 (CNH/B107)

    • Office Hours: T 10:00-12:30 & F 1:00-2:30 or by appointment
    • Labs:

2:30-5:30 M (ABB 302,306) **Note: course timetable says ABB217 2:30-5:30 F (ABB 306)

    • Every week except reading week (Feb. 18-22) & Good Friday (Mar. 21)
    • Labs start Jan. 7, 2008 (TODAY!)
For Monday 7th & Friday 11th
  • Check-in, meet TA, safety and Lab 1 (Isolation of Caffeine from Tea)
  • Lab manuals: Buy today!
  • BEFORE the lab, read lab manual intro, safety and exp. 1
  • Also need:
    • Duplicate lab book (20B3 book is ok)
    • Goggles (mandatory)
    • Lab coats (recommended)
    • No shorts or sandals
  • Obey safety rules; marks will be deducted for poor safety
  • Work at own pace—some labs are 2 or 3 wk labs. In some cases more than 1 exp. can be worked in a lab period—your TA will provide instruction

Assignments 2 x 5% 10%

Labs: -write up 15%

- practical mark 5%

Midterm 20%

Final 50%

Midterm test:

Fri. Feb. 29, 2008 at 7:00 pm

Make-up test: TBD

Assignments: Feb.6 – Feb.13

Mar.7 – Mar.14

Note: academic dishonesty statement on outline-NO copying on assignments or labs (exception when sharing results)

  • Dobson “Foundations of Chemical Biology,” (Optional- bookstore)

Background & “Refreshers”

  • An organic chemistry textbook (e.g. Solomons)
  • A biochemistry textbook (e.g. Garrett)
  • 2OA3/2OB3 old exam on web

This course has selected examples from a variety of sources, including Dobson &:

  • Buckberry “Essentials of Biological Chemistry”
  • Dugas, H. "Bio-organic Chemistry"
  • Waldman, H. & Janning, P. “Chemical Biology”
  • Also see my notes on the website
What is bio-organic chemistry? Biological chem? Chemical bio?

Chemical Biology:

“Development & use of chemistry techniques for the study of biological phenomena” (Stuart Schreiber)

Biological Chemistry:

“Understanding how biological processes are controlled by underlying chemical principles” (Buckberry & Teasdale)

Bio-organic Chemistry:

“Application of the tools of chemistry to the understanding of biochemical processes” (Dugas)

What’s the difference between these???

Deal with interface of biology & chemistry


Simple organics

eg HCN, H2C=O


Cf 20A3/B3




large macromolecules; cells—contain ~ 100, 000 different compounds interacting

Biologically relevant organics: polyfunctional

1 ° Metabolism – present in all cell (focus of 3FF3)

2 ° Metabolism – specific species, eg. Caffeine (focus of 4DD3)

How different are they?


Round-bottom flask



Exchange of ideas:

Biology Chemistry

  • Chemistry explains events of biology: mechanisms, rationalization
  • Biology
    • Provides challenges to chemistry: synthesis, structure determination
    • Inspires chemists: biomimetics → improved chemistry by understanding of biology (e.g. enzymes)
key processes of 1 metabolism
Key Processes of 1° Metabolism

Bases + sugars → nucleosides nucleic acids

Sugars (monosaccharides) polysaccharides

Amino acids proteins

Polymerization reactions; cell also needs the reverse process

We will look at each of these 3 parts:

  • How do chemists synthesize these structures?
  • How are they made in vivo?
  • Improved chemistry through understanding the biology: biomimetic synthesis
properties of biological molecules that inspire chemists
Properties of Biological Molecules that Inspire Chemists
  • Large → challenges: for synthesis

for structural prediction (e.g. protein folding)

2) Size → multiple FG’s (active site) ALIGNED to achieve a goal

(e.g. enzyme active site, bases in NAs)

3) Multiple non-covalent weak interactions → sum to strong, stable binding non-covalent complexes

(e.g. substrate, inhibitor, DNA)

4) Specificity → specific interactions between 2 molecules in an ensemble within the cell

5) Regulated → switchable, allows control of cell → activation/inhibiton

6) Catalysis → groups work in concert

7) Replication → turnover

e.g. an enzyme has many turnovers, nucleic acids replicates

evolution of life
Evolution of Life
  • Life did not suddenly crop up in its element form of complex structures (DNA, proteins) in one sudden reaction from mono-functional simple molecules

In this course, we will follow some of the ideas of how life may have evolved:

rna world
RNA World
  • Catalysis by ribozymes occurred before protein catalysis
  • Explains current central dogma:

Which came first: nucleic acids or protein?

RNA world hypothesis suggests RNA was first molecule to act as both template & catalyst:

catalysis & replication

How did these reactions occur in the pre-RNA world? In the RNA world? & in modern organisms?


How are these achieved? (Role of NON-COVALENT forces– BINDING)

a) in chemical synthesis

b) in vivo – how is the cell CONTROLLED?

c) in chemical models – can we design better chemistry through understanding biochemical mechanisms?

relevance of labs to the course
Relevance of Labs to the Course

Labs illustrate:

  • Biologically relevant small molecules (e.g. caffeine –Exp 1)
  • Structural principles & characterization (e.g. anomers of glucose, anomeric effect, diastereomers, NMR, Exp 2)
  • Cofactor chemistry – pyridinium ions (e.g. NADH, Exp 3 & 4)
  • Biomimetic chemistry (e.g. simplified model of NADH, Exp 3)
  • Chemical mechanisms relevant to catalysis (e.g. NADH, Exp 3)
Application of biologyto stereoselective chemical synthesis (e.g. yeast, Exp 4)
  • Synthesis of small molecules (e.g. drugs, dilantin, tylenol, Exp 5,7)
  • Chemical catalysis (e.g. protection & activation strategies relevant to peptide synthesis in vivo and in vitro, Exp 6)

All of these demonstrate inter-disciplinary area between chemistry & biology

Two Views of DNA
  • Biochemist’s view: shows overall shape, ignores atoms & bonds
  • chemist’s view: atom-by-atom structure, functional groups; illustrates concepts from 2OA3/2OB3
  • Aromatic structures:
    • all sp2 hybridized atoms (6 p orbitals, 6 π e-)
    • planar (like benzene)
  • N has lone pair in both pyridine & pyrrole  basic (H+ acceptor or e- donor)

6 π electrons, stable cation  weaker acid, higher pKa (~ 5) & strong conj. base

sp3 hybridized N, NOT aromatic  strong acid, low pKa (~ -4) & weak conj. base

  • Pyrrole uses lone pair in aromatic sextet → protonation means loss of aromaticity (BAD!)
  • Pyridine’s N has free lone pair to accept H+
  •  pyridine is often used as a base in organic chemistry, since it is soluble in many common organic solvents
The lone pair also makes pyridine a H-bond acceptor e.g. benzene is insoluble in H2O but pyridine is soluble:
  • This is a NON-specific interaction, i.e., any H-bond donor will suffice
contrast with nucleic acid bases a t c g u specific
Contrast with Nucleic Acid Bases (A, T, C, G, U) – Specific!
  • Evidence for specificity?
  • Why are these interactions specific? e.g. G-C & A-T
    • If mix G & C together → exothermic reaction occurs; change in 1H chemical shift in NMR; other changes  reaction occurring
    • Also occurs with A & T
    • Other combinations → no change!

e.g. Guanine-Cytosine:

  • Why?
    • In G-C duplex, 3 complementary H-bonds can form: donors & acceptors = molecular recognition
Can use NMR to do a titration curve:
  • Favorable reaction because ΔH for complex formation = -3 x H-bond energy
  • ΔS is unfavorable → complex is organized  3 H-bonds overcome the entropy of complex formation
  • **Note: In synthetic DNAs other interactions can occur
Molecular recognition not limited to natural bases:

Forms supramolecular structure: 6 molecules in a ring

 Create new architecture by thinking about biology i.e., biologically inspired chemistry!

synthesis of bases nucleic
Synthesis of Bases (Nucleic)
  • Thousands of methods in heterocyclic chemistry– we’ll do 1 example:
    • May be the first step in the origin of life…
    • Interesting because H-CN/CN- is probably the simplest molecule that can be both a nucleophile & electrophile, and also form C-C bonds
other bases
Other Bases?

** Try these mechanisms!

properties of pyridine
Properties of Pyridine
  • We’ve seen it as an acid & an H-bond acceptor
  • Lone pair can act as a nucleophile:
Balance between aromaticity & charged vs non-aromatic & neutral!
  •  can undergo REDOX reaction reversibly:

electical discharge

CH4 + N2 + H2

  • Interestingly, nicotinamide may have been present in the pre-biotic world:
  • NAD or related structure may have controlled redox chemistry long before enzymes involved!
another example of n alkylation of pyridines
Another example of N-Alkylation of Pyridines

This is an SN2 reaction with stereospecificity



  • Amines: basicity ch.20
    • Pyridine & pyrrole pp 644-5
    • NAD+/NADH pp 645-6, 537-8, 544-6
  • Bases in nucleic acids ch. 25

Also see Dobson, ch.9

Topics in Current Chemistry, v 259, p 29-68

sugar chemistry glycobiology
Sugar Chemistry & Glycobiology
  • In Solomons, ch.22 (pp 1073-1084, 1095-1100)
  • Sugars are poly-hydroxy aldehydes or ketones
  • Examples of simple sugars that may have existed in the pre-biotic world:
Most sugars, i.e., glyceraldehyde are chiral: sp3 hybridized C with 4 different substituents

The last structure is the Fischer projection:

  • CHO at the top
  • Carbon chain runs downward
  • Bonds that are vertical point down from chiral centre
  • Bonds that are horizontal point up
  • H is not shown: line to LHS is not a methyl group
In (R) glyceraldehyde, H is to the left, OH to the right  D configuration; if OH is on the left, then it is L
  • D/L does NOT correlate with R/S
  • Most naturally occurring sugars are D, e.g. D-glucose
  • (R)-glyceraldehyde is optically active: rotates plane polarized light (def. of chirality)
  • (R)-D-glyceraldehyde rotates clockwise,  it is the (+) enantiomer, and also d-, dextro-rotatory (rotates to the right-dexter)

 (R)-D-(+)-d-glyceraldehyde

& its enantiomer is: (S)-L-(-)-l-glyderaldehyde

(+)/d & (-)/l do NOT correlate

Glyceraldehyde is an aldo-triose (3 carbons)
  • Tetroses → 4 C’s – have 2 chiral centres
    • 4 stereoisomers:

D/L erythrose – pair of enantiomers

D/L threose - pair of enantiomers

  • Erythrose & threose are diastereomers: stereoisomers that are NOT enantiomers
  • D-threose & D-erythrose:
    • D refers to the chiral centre furthest down the chain (penultimate carbon)
    • Both are (-) even though glyceraldehyde is (+) → they differ in stereochemistry at top chiral centre
  • Pentoses – D-ribose in DNA
  • Hexoses – D-glucose (most common sugar)
reactions of sugars
Reactions of Sugars
  • The aldehyde group:
    • Aldehydes can be oxidized

“reducing sugars” – those that have a free aldehyde (most aldehydes) give a positive Tollen’s test (silver mirror)

    • Aldehydes can be reduced
Reaction with a Nucleophile
  • Combination of these ideas  Killiani-Fischer synthesis: used by Fischer to correate D/L-glyceraldehyde with threose/erythrose configurations:
reactions of aldehydes with internal nucleophiles
Reactions (of aldehydes) with Internal Nucleophiles
  • Glucose forms 6-membered ring b/c all substituents are equatorial, thus avoiding 1,3-diaxial interactions
Can also get furanoses, e.g., ribose:
  • Ribose prefers 5-membered ring (as opposed to 6) otherwise there would be an axial OH in the 6-membered ring
Why do we get cyclic acetals of sugars? (Glucose in open form is << 1%)
  • Rearrangement reaction: we exchange a C=O bond for a stronger C-O σ bond  ΔH is favored
  • There is little ring strain in 5- or 6- membered rings
  • ΔS: there is some loss of rotational entropy in making a ring, but less than in an intermolecular reaction:1 in, 1 out.

** significant –ve ΔS! ΔG = ΔH - TΔS

Favored for hemiacetal

Not too bad for cyclic acetal

  • Generate a new chiral centre during hemiacetal formation (see overhead)
  • These are called ANOMERS
    • β-OH up
    • α-OH down
    • Stereoisomers at C1 diastereomers
  • α- and β- anomers of glucose can be crystallized in both pure forms
  • In solution, MUTAROTATION occurs

In solution, with acid present (catalytic), get MUTAROTATION: not via the aldehyde, but oxonium ion

  • At equilibrium, ~ 38:62 α:β despite α having an AXIAL OH…WHY? ANOMERIC EFFECT
anomeric effect
Anomeric Effect

oxonium ion

O lone pair is antiperiplanar to C-O σ bond  GOOD orbital overlap (not the case with the β-anomer)