Welcome to CHEM BIO 3OA3!

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1

Welcome to CHEM BIO 3OA3!

Bio
-
organic Chemistry

[OLD CHEM 3FF3]

Sept. 11, 2009

2


Instructor: Paul Harrison


ABB 418, ext. 27290


Email:
pharriso@mcmaster.ca


Course website:

http://www.elm.mcmaster.ca/

Lectures:
MW
08:30,

F

10:30 (ABB/106)


Office Hours: M 12:30
-
2:30 or by appointment


Labs:



2:30
-
5:30
R or F
(
ABB 217)


Every week


Labs start next Fri. Sept. 17, 2009

Web site update


ELM page:


Lectures 1: includes everything for today,
and approx. 1 week of material: intro and
bases


Course outline


Detailed course description: lecture
-
by
-
lecture


Calendar



4

For Thursday 11
th
& Friday 12
th


Check
-
in, meet TA, safety and Lab 1 (Isolation of
Caffeine from Tea)


Lab manuals: Available on web; MUST bring printed
copy


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

5

Evaluation


Assignments

2 x 5%


10%


Labs:


-
write up



15%




-

practical mark


5%



Midterm





20%


Final





50%

Midterm test:



Fri. Oct. 30, 2009 at 7:00 pm


Assignments: Oct. 9


Oct. 19


Nov. 13


Nov. 23

Note: academic dishonesty statement on outline
-
NO
copying on assignments or labs

(
exception when sharing
results
)


6

Texts:


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 slides on the website

7

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

8

BIOLOGY

CHEMISTRY

Simple organics


eg HCN, H
2
C=O

(mono
-
functional)

Cf 20A3/B3

Biologically relevant organics:
polyfunctional

Life

large macromolecules;
cells

contain
~ 100,
000 different
compounds interacting

1
°

Metabolism


present in all cells


(focus of 3OA3)


2
°

Metabolism


specific species, eg. Caffeine (focus of 4DD3)

CHEMISTRY:

Round
-
bottom flask

BIOLOGY:

cell

How different
are they?

9

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)

10

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 processes, forwards and
backwards, in 4 parts, comparing and contrasting the
reactions:

1)
How do chemists synthesize these structures?

2)
How might these structures have formed in the pre
-
biotic
world, and have led to life on earth?

3)
How are they made in vivo?

4)
Can we design improved chemistry by understanding the
biology: biomimetic synthesis?

11

Properties of Biological Molecules that Inspire
Chemists

1)
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





12

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


6) Catalysis
→ groups work in concert


7) Replication → turnover



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

13

Evolution of Life


Life did not suddenly crop up in its current 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:

HCN + NH
3
bases
H
2
C=O
sugars
nucleosides
phosphate
nucleotides
RNA
"RNA world"
catalysis
more RNA, other
molecules
CH
4
, NH
3
H
2
O
amino
acids
peptides
RNA
(ribozyme)
"pre-RNA world"
"pre-protein world"
14

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

DNA
transcription
RNA
protein
translation
requires
protein
requires RNA
+ protein
15

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


CATALYSIS & SPECIFICITY


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


BINDING)


a) in chemical synthesis


b) in the pre
-
biotic world


c) in vivo


how is the cell CONTROLLED?


d) in chemical models


can we design better chemistry
through understanding biochemical mechanisms?

16

Relevance of Labs to the Course

Labs illustrate:


1)
Biologically relevant small molecules (e.g. caffeine

Exp 1, related to bases)

2)
Cofactor chemistry


pyridinium ions (e.g. NADH,

Exp 2 & 4)

3)
Biomimetic chemistry (e.g. simplified model of NADH,
Exp 2)

4)
Chemical mechanisms relevant to catalysis (e.g.
NADH, Exp 2)

5)
Structural principles & characterization



(e.g. sugars: anomers of glucose, anomeric effect,

diastereomers, NMR, Exp 3)


17

6)
Application of biology

to stereoselective chemical
synthesis (e.g. yeast, Exp 4)

7)
Synthesis of small molecules


(e.g. peptides, drugs,
dilantin, esters, Exp 5,6,7)

8)
Chemical catalysis (e.g. protection & activation
strategies relevant to peptide synthesis in vivo and in
vitro, Exp 5)

9)
Comparison of organic and biological reactions (Exp.
6)

10)
Enzyme mechanisms and active sites (Exp. 7)



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


18

Two Views of DNA


1)
Biochemist’s view:





shows overall shape, ignores atoms & bonds


2)
Chemist’s view: atom
-
by
-
atom



structure, functional groups; illustrates concepts

from 2OA3/2OB3


GOAL: to think as both a chemist and a biochemist: i.e. a
chemical biologist!

19

Biochemist’s View of the DNA Double Helix

Major
groove

Minor
groove

20

N
N
H
O
O
O
H
O
H
H
O
H
H
H
O
P
O
O
O
H
H
O
P
O
O
O
2
o
alcohol
(FG's)
alkene

bonds
resonance
Ring
conformation
ax/eq
H-bonds
nucleophilic
electrophilic
substitution rxn
chirality

+


diastereotopic
Chemist’s View

21

BASES

N
N
H
pyridine
pyrrole

Aromatic structures:


all sp
2

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)


ArN:
H
+
ArNH
+
pKa?
22

N
H
N
H
H
+
+
6
π

electrons, stable cation


weaker
acid, higher pKa (~ 5) & strong conj.
base

sp
3

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

23


The lone pair also makes pyridine a H
-
bond acceptor
e.g. benzene is insoluble in H
2
O but pyridine is soluble:










This is a NON
-
specific interaction, i.e., any H
-
bond donor
will work








N
H
O
H
:
e
-
donor
e
-
acceptor
H-bond
acceptor
H-bond
donor
acid
base
What about pyrrole?


Is it soluble in water?

Other groups form H
-
bonds


Electronegative atoms, e.g. carbonyl group:


Acetone is soluble in water, but propane is not:







Again, non
-
specific interactions

O
O
H
O
H
.
.
.
.
Bifunctional compounds

N
O
H
N
H
O
N
O
mp 105-107
o
C
bp 280-281
o
C
mp -42
o
C
bp 115
o
C
mp -47
o
C
bp 155
o
C
Bifunctional compounds

N
H
O
N
O
H
28

Contrast with Nucleic Acid Bases

(A, T, C, G, U)


Specific!

N
N
N
N
N
H
2
H
N
N
N
N
H
O
N
H
2
H
N
N
H
O
O
H
N
N
H
O
O
H
N
N
O
N
H
2
H
Thymine (T)
Guanine (G)
Adenine (A)
Uracil (U)
Cytosine (C)
*
*
*
*
*
Pyrimidines (like pyridine):
Purines
(DNA only)
(RNA only)
* link to sugar

Evidence for specificity?


Why are these interactions specific?

e.g. G
-
C & A
-
T


29


Evidence?


If mix G & C together

exothermic reaction occurs; change in
1
H
chemical shift in NMR; other changes


reaction

occurring


Also occurs with A & T


Other combinations
→ no change!


N
H
N
N
N
O
N
H
H
H
N
H
N
O
N
H
H
G
C
2 lone pairs
in
plane
at 120
o
to
C=O bond
e.g. Guanine
-
Cytosine:


Why?


In G
-
C duplex, 3 complementary H
-
bonds can form: donors &
acceptors =
molecular recognition


30


Can use NMR to do a titration curve:









Favorable reaction because
Δ
H for complex formation =
-
3 x H
-
bond energy


Δ
S is unfavorable → complex is organized







3 H
-
bonds overcome the entropy



of complex formation



**Note: In synthetic DNAs other interactions can occur

G + C
K
a
G C
get equilibrium constant,

G = -RT ln K =

H-T

S
31


Molecular recognition not limited to natural bases:





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

Forms supramolecular
structure: 6 molecules in a
ring

32

Synthesis of the Bases in Nucleic Acids


Thousands of methods in heterocyclic chemistry


we’ll
do 1 example:





Juan Or (1961)


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

N
H
N
N
N
N
H
2
NH
3
+
HCN
Adenine
Polymerization of HCN
33

Mechanism?

C
N
N
H
H
+
N
H
N
H
N
H
N
N
H
H
N
H
C
N
N
H
H
N
H
N
H
N
H
+
N
H
N
N
N
H
N
H
N
H
H
+
N
N
N
N
H
N
H
2
N
H
3
H
+
N
N
N
N
N
H
2
H
H
H
H
+
N
N
N
H
N
N
H
2
H
H
+
tautomerization
34

N
N
H
3
N
N
N
H
HC
G, U, T and C
(cyanogen)
(cyanoacetylene)
Other Bases?

** All these species are found in interstellar space: observed
by e.g. absorption of IR radiation: a natural example of IR
spectroscopy!

Try these mechanisms!

35

Properties of Pyridine



We’ve seen it as an acid & an H
-
bond acceptor


Lone pair can act as a nucleophile:








N
R
X
N
+
R
N
X
O
N
O
+
S
N
2
+
+
N
O
N
H
2
P
h
N
O
N
H
2
P
h
N
O
N
H
2
P
h
H
H
+
+
aromatic, but
+ve charge
electron acceptor:
electrophile
"H
-"
reduction
(like NaBH
4
)
non-aromatic,
but neutral
[O]
oxidation
e.g. exp 2: benzyl dihydronicotinamide: R = PhCH
2
36


Balance between aromaticity & charged vs non
-
aromatic
& neutral!




can undergo REDOX reaction reversibly:



NAD-H
NAD
+
+ "H
-
"
reductant
oxidant
37


Interestingly, nicotinamide may have been present in the
pre
-
biotic world:












NAD or related structure may have controlled redox
chemistry long before enzymes involved!


N
H
C
N
N
H
C
N
N
N
H
2
O
Diels-
Alder
[O],
hydrolysis of CN
1% yield
electrical
discharge

CH
4

+ N
2

+ H
2

38

Another example of
N
-
Alkylation of Pyridines

N
H
N
N
N
H
O
O
N
N
N
N
O
O
C
H
3
C
H
3
C
H
3
Caffeine
This is an S
N
2 reaction: stereospecific with INVERSION

R
N
H
R
C
H
3
S
+
Met
A
d
R
N
R
C
H
3
S
Met
A
d
+
+
S-adenosyl-methionine
(SAM, important co-factor)
39

References

Solomons


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