organic chemistry iii...other synthesis reactions: いいね!1,513 follow synthesis of primary...
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Organic Chemistry III
後藤 佑樹 (Yuki Goto, Bioorganic Chemistry Lab.)
担当日:6/6 (Wed) 6/13 (Wed) 6/20 (Wed) 6/27 (Wed) 7/4 (Wed)
“Organic chemistry of biomolecules”
“Organic chemistry of radicals”
1
Review of the previous class
Classification of monosaccharidealdoses/ketoses, pentoses/hexoses
How to understand/draw Fischer projections4 tips to draw and modify Fischer projections
D/L nomenclatureconvenient way to categorize stereochemistry of biomolecules
Cyclic forms of sugarshemiacetal formation, furanoses/pyranosesanomers, definition of α- and β-anomers
Reactions of monosaccharidessimple transformation of aldehydes (reduction and oxidation)simple transformation of alcohols (alkylation and acylation)
2
Q and A
3
Q and A
Formation of cyclic sugars via hemiacetal formation
(R)(S)
“Squiggle” indicates both stereoisomers are present (mixed)
D-glucopyranose
α-D-glucopyranose
β-D-glucopyranose
=
=
*
*
new chiral center!
If the OH on the new chiral center is located on the same side with the OH on the D/L determining carbon in Fischer projection, it is “α-anomer”.
*
*
63
37
:
Review quiz: Identify the new stereogenic carbon in the α and β anomers as either (R) or (S).
“anomeric position”
“anomers”
56
Formation of cyclic sugars via hemiacetal formation
(R)(S)
“Squiggle” indicates both stereoisomers are present (mixed)
D-glucopyranose
α-D-glucopyranose
β-D-glucopyranose
=
=
*
*
new chiral center!
If the OH on the new chiral center is located on the same side with the OH on the D/L determining carbon in Fischer projection, it is “α-anomer”.
*
*
63
37
:
Review quiz: Identify the new stereogenic carbon in the α and β anomers as either (R) or (S).
“anomeric position”
“anomers”
56
Formation of cyclic sugars via hemiacetal formation
(R)(S)
“Squiggle” indicates both stereoisomers are present (mixed)
D-glucopyranose
α-D-glucopyranose
β-D-glucopyranose
=
=
*
*
new chiral center!
If the OH on the new chiral center is located on the same side with the OH on the D/L determining carbon in Fischer projection, it is “α-anomer”.
*
*
63
37
:
Review quiz: Identify the new stereogenic carbon in the α and β anomers as either (R) or (S).
“anomeric position”
“anomers”
56
OCHR2
OH
CH(OH)R
H
fix “OH” and rotate others
OCHR2
OHR(HO)HC
H
OCHR2
OHR(HO)HC
H 4
1
23
Formation of cyclic sugars via hemiacetal formation
(R)(S)
“Squiggle” indicates both stereoisomers are present (mixed)
D-glucopyranose
α-D-glucopyranose
β-D-glucopyranose
=
=
*
*
new chiral center!
If the OH on the new chiral center is located on the same side with the OH on the D/L determining carbon in Fischer projection, it is “α-anomer”.
*
*
63
37
:
Review quiz: Identify the new stereogenic carbon in the α and β anomers as either (R) or (S).
“anomeric position”
“anomers”
564
絶対立体配置(R/S表記)の仕方まずは、練習として
の立体を絶対立体配置で表記しよう
(1) 置換基にランキングをつける。 (a) 原子番号の大きな原子が順位が高い。ここでは1が高くて4が低いとする。
★★
5
(S)
1C
423
1
2 3
(R)
1C
4 23
鏡
鏡
1
3 2
S鏡像異性体1→2→3 は反時計回り
R鏡像異性体1→2→3 は時計回り
(2) 順位が一番低い(4番)置換基を遠くにもっていく。
絶対立体配置(R/S表記)の仕方
(3) 手前側の三つの官能基の順位が右回りならR体左回りならS体
★★
(4) RとSは()にいれてイタリックで。
6
絶対立体配置(R/S表記)の仕方まずは、練習として
の立体を絶対立体配置で表記しよう
★★
(S)
1C
423
1
2 3
(R)
1C
4 23
鏡
鏡
1
3 2
S鏡像異性体1→2→3 は反時計回り
R鏡像異性体1→2→3 は時計回り
RとSは()にいれてイタリックで。(1) (2) (3) (4)
(S)-bromochlorofluoromethane
7
Q and A
8
Q and A
Sucrose!Sucrose is detected by our tongues more happily in the presence of triacylglycerols.
まじか。I am going to change the topic in the last class (or skip it).
9
Q and A
7/10(Wed)7/17(Wed)7/19(Fri)7/24(Wed)7/31(Wed)
candidate dates for final exam.
10
Amino acids
11
Topics
• structure of amino acids- classification and examples - acidity and basicity of amino acids
• synthesis of amino acids- amine synthesis
- side chain addition - COOH synthesis - enantioselective synthesis
• synthesis of amines- by SN2 reactions - Gabriel synthesis - reductive amination
12
What are amino acids
amine + acid
H2NOH
O
H2NOH
O
α-amino acids
γ-amino acids
(glycine)
(γ-amino butyric acid, GABA)
Proteinogenic amino acids are
α-amino acids (Fischer projection)
side chain (側鎖)
Review
H2NOH
O
R
13
What are amino acids
amine + acid
H2NOH
O
H2NOH
O
α-amino acids
γ-amino acids
(glycine)
(γ-amino butyric acid, GABA)
Proteinogenic amino acids are
L-α-amino acids
H2NOH
O
R
(Fischer projection)
side chain (側鎖)
Review
14
Examples/names of amino acids
Gly (G)
Ala (A)
Val (V)
Phe (F)
e.g.)
A total of 20 different amino acids is found in proteins. See others in the appendix.
15
acidity/basicity of amino acids
(双性イオン)
When the pH = pI (等電点: isoelectronic point), the net charge of amino acid becomes zero.
In this pH, the amino acid is mainly present as zwitterion.
Quiz pKa values of general carboxylic acids are 4~5. Why the pKa values of COOH in amino acids are unusually small?
Review Quiz Explain the aqueous structures of alanine in buffers of pH = 2.34, 6.00, and 9.69.
Quiz Estimate the pI values of Glu, His, and Tyr.
16
Topics
• structure of amino acids- classification and examples - acidity and basicity of amino acids
• synthesis of amino acids- amine synthesis
- side chain addition - COOH synthesis - enantioselective synthesis
• synthesis of amines- by SN2 reactions - Gabriel synthesis - reductive amination
17
Synthesis of amino acids-1 amine synthesisSN2 of α-halo acids with NH3
18
Synthesis of primary amines (general organic chemistry)
・SN2 of alkyl halides with NH3
RX
RNH2
R
HN
R+ NH3
RX
RN
R
R
R N R
R
R
RX
RX
pKaH: (R = Et)
9.21 10.63 10.98
10.75
19
2017/06/02 21(35Gabriel synthesis ~ Name-Reaction.com
1 / 2 ページhttp://www.name-reaction.com/gabriel-synthesis
Copyright © 2017 Name-Reaction.com All rights reserved. Terms of Use Privacy Policy About Us
Gabriel synthesis
The Gabriel synthesis is an organic reaction used to convert an alkyl halide to a primary amine using
phthalimide with base and followed by hydrazine. The reaction begins with the deprotonation of the
phthalimide which then aHacks the alkyl halide in an SN2 fashion to give an N-alkylphthalimide
intermediate. The intermediate is then cleaved by hydrazine in a series of steps that end with the liberation
of the final primary amine product and phthalhydrazide by-product.[1]
References:Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224–2236.
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Mechanism
Mechanism
Mechanism
Mechanism
1.
Other Synthesis Reactions:
いいね! 1,513 Follow
Synthesis of primary amines (general organic chemistry)
・SN2 of alkyl halides with N3-
RX + NaN3 R
NH2R
N3R3P other reductants:
Pd/C & H2, LAH, etc.
・Gabriel synthesis
2017/06/02 21(35Gabriel synthesis ~ Name-Reaction.com
1 / 2 ページhttp://www.name-reaction.com/gabriel-synthesis
Copyright © 2017 Name-Reaction.com All rights reserved. Terms of Use Privacy Policy About Us
Gabriel synthesis
The Gabriel synthesis is an organic reaction used to convert an alkyl halide to a primary amine using
phthalimide with base and followed by hydrazine. The reaction begins with the deprotonation of the
phthalimide which then aHacks the alkyl halide in an SN2 fashion to give an N-alkylphthalimide
intermediate. The intermediate is then cleaved by hydrazine in a series of steps that end with the liberation
of the final primary amine product and phthalhydrazide by-product.[1]
References:Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224–2236.
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Mechanism
Mechanism
Mechanism
Mechanism
1.
Other Synthesis Reactions:
いいね! 1,513 Follow
2017/06/02 21(35Gabriel synthesis ~ Name-Reaction.com
1 / 2 ページhttp://www.name-reaction.com/gabriel-synthesis
Copyright © 2017 Name-Reaction.com All rights reserved. Terms of Use Privacy Policy About Us
Gabriel synthesis
The Gabriel synthesis is an organic reaction used to convert an alkyl halide to a primary amine using
phthalimide with base and followed by hydrazine. The reaction begins with the deprotonation of the
phthalimide which then aHacks the alkyl halide in an SN2 fashion to give an N-alkylphthalimide
intermediate. The intermediate is then cleaved by hydrazine in a series of steps that end with the liberation
of the final primary amine product and phthalhydrazide by-product.[1]
References:Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224–2236.
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Mechanism
Mechanism
Mechanism
Mechanism
1.
Other Synthesis Reactions:
いいね! 1,513 Follow
2017/06/02 21(35Gabriel synthesis ~ Name-Reaction.com
1 / 2 ページhttp://www.name-reaction.com/gabriel-synthesis
Copyright © 2017 Name-Reaction.com All rights reserved. Terms of Use Privacy Policy About Us
Gabriel synthesis
The Gabriel synthesis is an organic reaction used to convert an alkyl halide to a primary amine using
phthalimide with base and followed by hydrazine. The reaction begins with the deprotonation of the
phthalimide which then aHacks the alkyl halide in an SN2 fashion to give an N-alkylphthalimide
intermediate. The intermediate is then cleaved by hydrazine in a series of steps that end with the liberation
of the final primary amine product and phthalhydrazide by-product.[1]
References:Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224–2236.
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Mechanism
Mechanism
Mechanism
Mechanism
1.
Other Synthesis Reactions:
いいね! 1,513 Follow
2017/06/02 21(35Gabriel synthesis ~ Name-Reaction.com
1 / 2 ページhttp://www.name-reaction.com/gabriel-synthesis
Copyright © 2017 Name-Reaction.com All rights reserved. Terms of Use Privacy Policy About Us
Gabriel synthesis
The Gabriel synthesis is an organic reaction used to convert an alkyl halide to a primary amine using
phthalimide with base and followed by hydrazine. The reaction begins with the deprotonation of the
phthalimide which then aHacks the alkyl halide in an SN2 fashion to give an N-alkylphthalimide
intermediate. The intermediate is then cleaved by hydrazine in a series of steps that end with the liberation
of the final primary amine product and phthalhydrazide by-product.[1]
References:Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224–2236.
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Mechanism
Mechanism
Mechanism
Mechanism
1.
Other Synthesis Reactions:
いいね! 1,513 Follow
2017/06/02 21(35Gabriel synthesis ~ Name-Reaction.com
1 / 2 ページhttp://www.name-reaction.com/gabriel-synthesis
Copyright © 2017 Name-Reaction.com All rights reserved. Terms of Use Privacy Policy About Us
Gabriel synthesis
The Gabriel synthesis is an organic reaction used to convert an alkyl halide to a primary amine using
phthalimide with base and followed by hydrazine. The reaction begins with the deprotonation of the
phthalimide which then aHacks the alkyl halide in an SN2 fashion to give an N-alkylphthalimide
intermediate. The intermediate is then cleaved by hydrazine in a series of steps that end with the liberation
of the final primary amine product and phthalhydrazide by-product.[1]
References:Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224–2236.
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Mechanism
Mechanism
Mechanism
Mechanism
1.
Other Synthesis Reactions:
いいね! 1,513 Follow
2017/06/02 21(35Gabriel synthesis ~ Name-Reaction.com
1 / 2 ページhttp://www.name-reaction.com/gabriel-synthesis
Copyright © 2017 Name-Reaction.com All rights reserved. Terms of Use Privacy Policy About Us
Gabriel synthesis
The Gabriel synthesis is an organic reaction used to convert an alkyl halide to a primary amine using
phthalimide with base and followed by hydrazine. The reaction begins with the deprotonation of the
phthalimide which then aHacks the alkyl halide in an SN2 fashion to give an N-alkylphthalimide
intermediate. The intermediate is then cleaved by hydrazine in a series of steps that end with the liberation
of the final primary amine product and phthalhydrazide by-product.[1]
References:Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224–2236.
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
Mechanism
Mechanism
Mechanism
Mechanism
1.
Other Synthesis Reactions:
いいね! 1,513 Follow
+
isolatable, storable
(phosphine)
20
Synthesis of amines (general organic chemistry)
・Reductive amination(還元的アミノ化)
can be performed in one-pot often done in weak acidic cond.
Review Quiz Show the mechanism of imine formation and explain why reductive amination reactions are often performed in weak acidic conditions.
aldehydes can be also the SM.
21
Synthesis of amines (general organic chemistry)
22
Topics
• structure of amino acids- classification and examples - acidity and basicity of amino acids
• synthesis of amino acids- amine synthesis
- side chain addition - COOH synthesis - enantioselective synthesis
• synthesis of amines- by SN2 reactions - Gabriel synthesis - reductive amination
23
Synthesis of amino acids-2 side chain addition・Alkylation of acetamidomalonate
1. Base 2. R-X 3. H+, Δ
hydrolysis &
decarboxylation
1. Base 2. R-X 3. H+, Δ
Note; homologous to malonic ester synthesis see P.957 of Jones OC 5th Ed.
24
Synthesis of amino acids-3 COOH synthesis・Strecker synthesis
25
Reaction of monosaccharides - 3Elongation of chains in monosaccharides (Kiliani-Fischer synthesis)
“cyanohydrin”
partial hydrogenation
“imine”
Review quiz: Draw the mechanism of the hydrolysis of the imine under acidic conditions.
hydrolysis
cf.
26
Enantioseparation of amino acids・Formation of diastereomeric salts
D/L mixture
27
Enantioseparation of amino acids・Kinetic resolution
D/L mixture
28
(Advanced) Enantioselective synthesis of amino acids・Maruoka catalyst
Maruoka catalyst
29
What are amino acids
amine + acid
H2NOH
O
H2NOH
O
α-amino acids
γ-amino acids
(glycine)
(γ-amino butyric acid, GABA)
Proteinogenic amino acids are
L-α-amino acids
H2NOH
O
R
COOH
HH2N
Rside chain (側鎖)
(Fischer projection)Review
30
acidity/basicity of amino acids
(双性イオン)
Quiz pKa values of general carboxylic acids are 4~5. Why the pKa values of COOH in amino acids are unusually small?
Review Quiz Explain the aqueous structures of alanine in buffers of pH = 2.34, 6.00, and 9.69.
Quiz Estimate the pI values of Glu, His, and Tyr.
When the pH = pI (等電点: isoelectronic point), the net charge of amino acid becomes zero.
In this pH, the amino acid is mainly present as zwitterion.
31
Synthesis of amines (general organic chemistry)
・Reductive amination(還元的アミノ化)
can be performed in one-pot often done in weak acidic cond.
Review Quiz Show the mechanism of imine formation and explain why reductive amination reactions are often performed in weak acidic conditions.
aldehydes can be also the SM.
32
Synthesis of amines (general organic chemistry)
https://www.masterorganicchemistry.com
33