Welcome to 3ff3 bio organic chemistry
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Welcome to 3FF3! Bio-organic Chemistry. Jan. 7, 2008. Instructor: Adrienne Pedrech ABB 417 Email: [email protected] -Course website: http://www.chemistry.mcmaster.ca/courses/3f03/index.html Lectures: MW 8:30 F 10:30 (CNH/B107)

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Welcome to 3FF3!Bio-organic Chemistry

Jan. 7, 2008

  • Instructor: Adrienne Pedrech

    • ABB 417

    • Email: [email protected]

      -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 ABB2172:30-5:30 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


Assignments2 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

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

  • 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

  • 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

  • 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

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-atomstructure, functional groups; illustrates concepts from 2OA3/2OB3

Biochemist’s View of the DNA Double Helix

Minor groove

Major groove

Chemist’s View


  • 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!

  • Evidence for specificity?

  • Why are these interactions specific? e.g. G-C & A-T

  • Evidence?

    • 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)

  • 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?

** Try these mechanisms!

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

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

  • 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

  • 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

    • 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

    oxonium ion

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

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