Investigation of Anomalous Effects in the Deprotonation and Alkylation of Ketones Patrick Kelly-Goss 2004.
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Investigation of Anomalous Effects in the Deprotonation and
Alkylation of KetonesPatrick Kelly-Goss
2004
Background
• Development of new methods for synthesizing amino acids is highly desired– Often biologically active– Useful for biochemistry experiments– Medicine
Background
•Alkylation of aminoketones
- Adds alkyl group
- Deprotonated (H+ removed) by base
- 2 or 3 eq. usually used.
• 1980 Hoye et al. study
- Used 1 eq.
O
N
H
O
N
H
O
O
R
Problem
• Mid-1990s Tetrahedron Letters study
• Should bond at No. 1 carbon– Most acidic
• Bonds at No. 3 carbon– 2nd most acidic
N
H
O
O
R
N
H
O
O
R
Hypothesis
• During Cr-mediated oxidation, Cr+6 ion bonds to No. 1 carbon.
• Blocks most receptive bond site, forcing alkyl group to bond to No. 3 carbon.
O
N
H
O
Cr
R
Methods
Synthesis–Two ketones
• Oxidation–Two methods
• Alkylation• Testing
Synthesis of Ketones• Under Schotten Baumen conditions
– Derived from aminopropanol
– Using benzyl chloride (top) and benzoyl chloride (bottom)
• Produces two alcohols
N
H
2
O
H
Cl
N
H
O
H
C
h
2
C
l
2
+
N
H
2
O
H
Cl
O
N
H
O
H
O
C
h
2
C
l
2
+
Oxidation of Ketones
• Two different methods used– RuCl3
– Chromic acid (H2CrO4)
• Total of four test groups
• Purified using MPLC
Oxidation of Ketones
N
H
O
H
Cr
O
O
O
H
O
H
N
H
O
H
O
Cr
O
O
O
H
O
H
N
H
O
O
N
H
O
H
N
H
O
N
H
O
H
O
N
H
O
O
R
u
C
l
3
R
u
C
l
3
N
H
O
Alkylation of Ketones
• Add alkyl (R–) group to ketone using standard procedures
• Check structure via NMR• Not completed
N
H
O
O
N
H
O
O
R
Strong Base
R'X
Results
• No alkylations completed– Testing impossible
• Difficulty encountered in oxidation– Very low yields (< 2%)– Confusing NMR spectra– TLC revealed wrong product taken– Most lost in MPLC
Results
NMR spectrum of middle (incorrect) layer
NMR spectrum of top(correct) layer
Results
• MPLC allowed to run for significantly longer than expected requirement– Ketones successfully synthesized, oxidized
• Work halted due to time constraints– No alkylation completed– No meaningful data
Discussion• Original Tet. Letters study
– Wrong eq. base used
– Would change which protons stripped
– May explain bonding “error”
• Little to explain• Should future work be desired:
– Determine if different bases would have effect
N
H
O
O
R
Acknowledgements
• Ms. Fruen
• Team Research
• Dr. Rita Majerle
Investigation of Anomalous Effects in the Deprotonation and
Alkylation of KetonesPatrick Kelly-Goss
2004
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