Why study Organic Synthesis?
Heart of Chemistry
Broad applications
• Petrochemicals
• Pharmaceuticals
• Agrochemicals
• (Bio)Polymers
• Dyes & Pigments
• Cosmetics
• Food (Additives)
• Household products
• Electrochemicals
• Display materials
• Semiconductors
• Organic electronics
• and so on…..
“Chemists make new things and we st udy reactions. That’s the core of this profession” - D.G. Nocera (MIT) in C
&EN (Jan. 1998)
Petrochemicals
+ H+
cumene O2
OOH
cumene hydroperoxide cat.
H3O+ OH
+
O
phenol acetone
Pharmaceuticals & Medicinal Chemistry
OH
1. HNO3 2. Pd, H2
OH
NH2
Ac2O
OH
NHAc
Tylenol
N RCONH S
O CO2H
R = PhCH2; Pen G
R = PhCH(NH2); ampicillin R = (4-OH)-PhCH(CH2);
amoxycillin
Agrochemicals
O O
H H
multistriatin: a pheromone of the elm bark beetle
1. Lindlar, H2
3-pentanone O
H
O O H
H+ Aldrich, $20.0/500g
O H
OH
2. acetone, H+
O O
1. mCPBA 2. Me2CuLi
O O
Me OH 1. HCl
2. TsCl, py 3. NaI
O O
Me I H
LDA
Polymers & Biopolymers
O O
O O NH H
Ac(H) O
H
O O O
O NH HO NH
O H
Ac(H) Ac(H) O
H HO
CO2Me
MeO2C
CO2CH2CH2
O2C
n
+ - MeOH
polyester (Dacron)
chitin (chitosan)
HOCH2CH2OH
Biology & Biochemistry
CHO
opsin N
H2
N+ opsin H
-H2O
vitamin A CHO
(retinol)
11
retinol
dehydrogenase
h
H2O
all-trans-retinal 11-cis-retinal
retinal isomerase
nerve pulse
Electrochemicals
O O
O
O
(better electrolyte) (poor electrolyte)
ethylene carbonate THF
Display Materials
*
* n
PPP
* n *
polyacetylene
NH
* n *
polypyrrole
*
n *
PPV
* S n *
polythiophene
Components of Organic Synthesis
Synthetic work
Synthetic design
Retrosynthetic analysis
‘disconnection approach’
1. C-C bond formation 2. functional group
interconversion (FGI) experimental
procedures TARGET
O H O O H
- +
Disconnection Approach: An Example
O O
multistriatin: a pheromone of the elm bark beetle
O H O OH
acetal H+ (-H2O)
alkylation
LiN(iPr)2
O
O H O H X
synthonssynthetic equivalents
X
OsO4 oxidation
A Stereorandom Synthesis of Multistriatin
O H
TsCl, py
TsO
O LiN(iPr)2
O mCPBA
O O
O O
SnCl4 Aldrich, $31.50/g
1
2
4 3
A Stereoselective Synthesis of Multistriatin
1. Lindlar, H2
3-pentanone O
H
O O H
O O
H H
H+ Aldrich, $20.0/500g
1 8
O H
OH
2. acetone, H+
O O
1. mCPBA 2. Me2CuLi
O O
Me OH
1. HCl 2. TsCl, py 3. NaI
O Me I H
LDA
5 6
AcO
AcO
$42.9/25mL
Design and Synthesis
Retrosynthetic Analysis
1. recognise the functional groups in the target molecule 2. disconnect by known methods and reliable reactions
3. repeat 1 and 2 until the readily available starting materials are obtained
4. design as many alternative retrosynthetic routes as possible
Synthesis
1. write down the synthetic schemes containing the detailed reaction conditions according to the analyses
2. compare the pros and cons between the syntheses designed;
the number of steps, availability of reagents/starting materials, selectivity (chemo-/regio-/stereo-), economy, process, etc
3. modify the selected synthetic plan whenever unexpected problems are encountered
What to Know for Organic Synthesis
molecular structure
reaction mechanisms
stereochemistry
dependable reactions
availability of compounds
selectivity
analytical methods
lab technique
process
“ 그저 익숙하도록 읽는 것뿐이다
.
글을 읽는 사람이,
비 록 글의 뜻은 알았으나,
만약 익숙하지 못하면 읽자마자 곧 잊 어버리게 되어,
마음에 간직할 수 없을 것은 틀림없다.
이미 읽고 난 뒤에
,
또 거기에 자세하고 익숙해질 공부를 더한 뒤라야 비로소 마음에 간직할 수 있으며,
또 흐뭇한 맛도 있을 것이다.” -
퇴계 이황(
금장태 著)
Chapter 2 Functional Group Transformations
selectivity/specificity: chemo-, regio- & stereo-
functionalization of alkanes: unreactive
radical reaction: selectivity; 5 bottom
functionalization of alkenes: addition & substitution
addition to double bonds: 6 Scheme 2.1
‘(anti)Markovnikov’/oxymercuration/hydroboration/HBr: 7 top
stereoselectivity: 7 bottom
Chemoselectivity
regioselectivity & stereoselectivity
O OH
O H2, Pt NaBH4
Br Br
OAc
Nu Nu:, DMF OAc
Nu
Nu:, Pd(PPh3)4
Regioselectivity
OH OH
H3O+ 1. BH3•THF
2. H2O2, NaOH
more electropositive metals: Mo, W
Hg2+, H2O/NaBH4
OAc Mo(CO)6 malonate
CH(CO2Me)2 Pd(PPh3)4
malonate CH(CO2Me)2
Diastereoselectivity (I)
O H
MeMgI
OH +
OH
major minor
R1 O
O
R2 H2, 1 atm Pd/C or Rh
R1 O
O
R2 5.5:1 (Pd/C) 1:0 (Rh, MeOH) R1=R2=OH or -OC(CH3)2O-
Diastereoselectivity (II)
R CO2Me Si(OEt)3
(Ph3P)3RuH2(CO) R CO2Me
(CH2)2Si(OEt)3 H2O2 KHCO3
O
R O
OAc Pd(0) Nu- 1. Pd(0) Nu
2. RM R
Enantioselectivity
X*
O +
R H
O
N O
O
i-Pr R'2BOTf
R''3N R X* = O
OH
+
R H
R'CH2NO2 O cat.
R R'
NO2 OH
cat. = La
O O
O O
O
O OH
Li OH Li
Li R
R
R R
R R
R
R
Functionalization of Alkynes
addition / substitution reactions:
9 Scheme 2.2 reduction to alkenes: 165 bottom – 166
C-C bond formation: 51 – 52 top
electrophilic addition: largely anti addition
a mixture of products: syn addition & participation of the reaction solvent, 8 bottom – 9 top
ketones with oxymercuration: 9 middle
Functionalization of Aromatic Hydrocarbons
electrophilic substitution: the ring;
10 Scheme 2.3 substituted benzenes: depending on the substituents
the rate & the orientation: 11 Table 2.1 & 12
lower selectivity with a radical substitution: 13 top
nucleophilic substitution: p-chloronitrobenzene
Chichibabin reaction ( 14 & 44) & benzyne intermediate
benzylic oxidation: the side chain;
189~192
autoxidation of cumene: acetone & phenol; 11 top
chlorination/bromination: radical mechanism; 11 top
Functionalization of Aromatic Heterocycles
pyridine: weak base & e
--poor ring,
14 Scheme 2.4 electrophilic substitution: difficult but higher e--density at C-3
nucleophilic substitution at C-2: ‘Chichibabin’; 14 Scheme 2.5
substitution of pyridine-N-oxide at C-4: 15 Scheme 2.6
pyrrole, furan, thiophene: e
--rich;
16 Scheme 2.7 substitution at C-2 / C-5: resonance-stabilized
Interconversion of Functional Groups
alcohols & phenols: less basic;
17 Scheme 2.8
amines: basic & nucleophilic;
20 Scheme 2.9 amines as electrophiles: pyridinium ions; 18 bot & 19 top
halides: good leaving groups;
21 Scheme 2.10
aryl nitro compounds:
22 Scheme 2.11
aldehydes & ketones: addition, substitution, enolates
carboxylic acids:
23 Scheme 2.12