Conversion of Secondary Aliphatic Amine Moiety to Ketone by
Andrew Worth1, Dwight J. Tshudy1, Terrence J. Collins2 , Longzhu Q. Shen2
III
Fe —TAML
System
1Department
of Chemistry, Gordon College, Wenham MA
2Institute for Green Science, Carnegie Mellon University, Pittsburgh PA
Introduction
GC-MS
TAMLs (Tetra-Amido Macrocyclic Ligands) are a family of green oxidation catalysts
that activate hydrogen peroxide and have been reported to have the ability to
degrade numerous persistent pollutants in aqueous conditions. The degradation
reactions take place under ambient conditions over a wide pH range from neutral
to highly basic. Previous work involving FeIII –TAML and components of
antidepressant medications such as Zoloft® (sertraline) suggest that the TAML
system is able to convert methyl amines into ketones.1,2 A secondary aliphatic
amine moiety based on sertraline’s structure is used as a reference model
compound to study the reaction. The ketone formation was confirmed using gas
chromatography mass spectrometry and the reaction progression under varying
conditions of pH, peroxide, and TAML concentration is being studied by means of
liquid chromatography.
HN
CH3
Initial conversion of the amine to the ketone was proven by GC-MS. Library match confirmed the suspected ketone reaction product. The
TAML reaction was carried out in aqueous conditions. Solid phase extraction was performed with methanol as the final elution step. The
initial product analysis showed a 98% match to the reference library.
N
N
Fe
H3C
N
CH3
N
CH3
H3C
Cl
12
8.0
160
49
30
9.0
160
58
36
10.0
160
67
42
11.0
160
61
38
Discussion
HPLC was used to track the reaction via time. Standards of both the amine and the ketone were run individually to determine the
corresponding retention times. Calibration curves were made for each standard based on the integration of the peaks. These calibration
curves were used to determine the molar amounts of both ketone formation and amine loss during the TAML reactions. LC-MS data
confirmed the retention times of both the amine and ketone.
HPLC
HPLC-MS
O
O
Cl
H3C
Sertraline
254 nm
CH3
700
Reaction Time
1 minute
600
FeIII-TAML-B*
(1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4tetrahydronaphthalen-1-amine
500
400
Time (min)
HN
CH3
O
300
200
What is TAML?
100
0
mVolts
TAMLs, created by Dr. Terrence Collins, have been inspired by enzymes that occur
in nature. Both oxygen and peroxides are implemented in nature for degradation
and require catalytic activation to carry out such processes on harmful materials.
While a typical enzyme in nature can be expected to be approximately 40,000
atomic mass units (amu), TAMLs are in the realm of 500 amu and are effective in
the degradation process. When TAML is combined with hydrogen peroxide, a
violent reaction occurs, allowing the degradation to take place. After catalyzing
reactions, TAMLs have been shown to self degrade on the scale of a few hours,
ensuring they themselves will not become a pollution problem once
implemented.3 TAMLs have been shown effective in various processes that
promote the development of green chemistry. The following research, based on
previous TAML work, explores the conversion of a methyl amine into a ketone.
1
2
3
HN
Reaction Time
7 minutes
750
500
CH3
4
Minutes
Future Work
Time (min)
0
-79
mVolts
1
2
3
4
Minutes
NH2
750
Reaction Time
13 minutes
500
250
0
mVolts
1
2
3
4
Minutes
O
Reaction Time
19 minute
500
Reaction Pathway
250
O
NH2
1,2,3,4-tetrahydronaphthalen-1-amine (Amine)
1,2,3,4-tetrahydronaphthalen-1amine (Amine)
3,4-Dihydro-1(2H)naphthalenone (Ketone)
Instrumentation
•Liquid chromatography (LC) –
•Varian Pro Star with a UV-Vis detector (254 nm)
•Column: Cosmosil π NAP column from Nacalai Tesque Inc. 4.6 x 150 mm
•Mobile Phase: 53% acetonitrile, 47% water, 0.5% phosphoric acid
•Liquid chromatography mass spectrometry (LC-MS)
•Waters Alliance HPLC with Thermo DSQ mass spectrometer
•Mobile Phase: 60% methanol, 40% water, 0.1% formic acid
•Gas Chromatography – Mass Spectrometry (GC-MS) –
•Agilent 5890 Series II with Agilent 5971A Mass Selective Detector
•Solid phase extraction (SPE) – Phenomenex Strata C18-U
Formation of the anticipated ketone structure was confirmed by GC-MS. LC
conditions were developed to achieve separation of the amine and ketone to
allow the effects of various pH conditions to be studied. As anticipated, the
reaction showed low efficiency near pH 7, but rapidly improved as pH increased
to near the optimum pH for this TAML system. All calculations were performed
referencing an external calibration curve created using standards of each
component in known concentrations. Data showed that pH 10 provided the best
reaction conditions for conversion of the amine to the ketone. The leveling off of
both ketone and amine molar amounts suggests that perhaps there is a limiting
reactant. While optimal reaction pH yielded a conversion of approximately 42%,
there is hope of improvement by varying the amounts of reagents used. This
work has shown that FeIII –TAML can be used as a benign pathway for
synthesizing ketones from methyl amines.
250
750
N-methyl-1,2,3,4tetrahydronaphthalen-1-amine
(Amine)
19
O
mVolts
HN
160
HPLC HPLC-MS
O
Percent
Conversion
7.0
H
H
O
CH3
pH
Starting µmol Ending µmol
Amine
Ketone
0
1
0
2
1
3
2
min
4
3
4
Minutes
5
Reaction Analysis
Conversion from the methyl amine to the ketone was tested under varying pH conditions. Quantitative data was taken for the amine,
ketone, and the suspected demethylated intermediate. The following graphs show the degradation of the amine and the formation of
the intermediate and ketone. As expected, increasing pH improved the efficiency of the reaction. This effect was most clearly observed
between pH 9 and 10. pH 10 resulted in both the greatest degradation of the amine and formation of the ketone. The suspected
mechanism involves the formation of the demethylated intermediate, which is then converted to the ketone. The lowest level of
intermediate was observed at pH 10. This point also supports the suspicion that pH 10 is the ideal pH for the reaction to reach
maximum efficiency.
Future work will involve keeping the reaction conditions at a constant pH while
varying other aspects of the reaction such as TAML and peroxide concentration.
The optimum pH, determined by the highest conversion rate to the ketone,
needs to be determined. One of the more pressing questions is if the
implementation of a higher hydrogen peroxide concentration will allow for
more extensive degradation of the amine along with greater formation of the
ketone. Another area to explore includes testing other amine structures to
determine if the anticipated ketone forms are created similar to those in this
work. Confirmation of the intermediate structure observed in the
chromatograms would be useful in determining the mechanism occurring
during the reaction. Anticipated work includes gathering fractions from the LC
run and analyzing by GC-MS to confirm tentative structures existing throughout
the reaction process. While peroxide concentration seems the most likely for
having a significant effect on the products formed, it is entirely possible that the
varying of both the sample or TAML concentration could also have a
noteworthy effect.
Acknowledgments
Acknowledgements
•Thanks to Dr. Dwight Tshudy,
Dr. Terrence Collins, and Longzhu Shen, for
providing the initial research which made this work possible.
•Thanks to Nacalai Tesque for the generous donation of the LC column.
•Thanks to Kristen Entwistle for continuous aid and contribution throughout the
duration of this project and being a supportive member of the research group.
References
1Shen,
L.; Tshudy, D. Carnegie-Mellon University, Pittsburgh, PA. Unpublished
work, 2009.
2Shen, L.; Tshudy, D.; Collins, T. Oxidative Degradation of SSRIs by FeIII –
TAML/H2O2 Activators. Presented at the Conference on Small Molecule Science
(CoSMoS), Boston, MA, 2009.
3Collins, T. J.; Walter, C. Little Green Molecules. Sci. Am. 2006, 294, 82-90.