Preparation, properties and conformational analysis of the diastereomers
of 3,3,5-trimethylcyclohexanol
Signature:_____________________________
CHEM 3880
9 September 2013
Abstract:
The goal of this experiment was to reduce a ketone with sodium borohydride to form a
diastereomeric mixture of alcohols in order to separate the mixture by gas chromatography and
analyze it by Proton Nuclear Magnetic Resonance spectroscopy (1H NMR) and Infrared
spectroscopy (IR) to determine the abundance of isomers1. The goal was attained by first
preparing cis and trans-3,3,5-trimethylcyclohexanol from 3,3,5-trimethylcyclohexanone using
sodium borohydride (NaBH4) as the reducer in the presence of ethanol2. This was done in order
to study the solvent effects on stereochemistry of the product composition. The 1H NMR spectra
of the isomers was used to determine the abundance of isomers. Gas chromatography was then
used to confirm the results obtained from NMR anlysis. For NMR, the pentet pattern is for trans
which is at peak 3.5 and triplet of triplet pattern is for cis which is at peak 3.2. In GC, the two
peaks – one with retention time 4.021 and the other with retention time around 4.134 stand for
trans and cis isomers respectively. For NMR the trans % was 78.26% and the cis % was
21.74%. For GC the trans % was 81.6% and the cis % was 18.4%. Finally, NMR and GC were
successfully used to analyze the alcohol mixture. Both these analytic methods gave roughly the
same results and are powerful tools to analyze diastereomeric mixtures.
Introduction:
The objectives of this experiment were to: (1) to prepare cis and trans-3,3,5trimethylcyclohexanol from 3,3,5-trimethylcyclohexanone, (2) to study solvent effects on the
stereochemistry of the product composition, (3) to obtain 1H NMR spectra of the isomers, (4) to
determine the relative abundance of the isomers by NMR and gas chromatography and (5) to
apply conformational analysis to the interpretation of the 1H NMR spectra of the
diastereoisomers1.
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Gas chromatography (GC) is a tool to separate, quantify and identify unknown organic
compounds and permanent gases. The principle of GC requires a sample solution to be injected
into the gas chromatography (GC) inlet where it is vaporized. The carrier gas then moves the
vapor onto a chromatographic column. The sample flows through the column and the
compounds are separated by their interaction with the stationary phase (column coating) and the
mobile phase (carrier gas). Finally, the last part of the column passes through a heated transfer
line and ends at the entrance to ion source. From there compounds eluting from the column are
converted to ions and detected according to their mass to charge m/z ratio. The gas
chromatograph uses a capillary column in which the stationary phase consists of silica. The CG
consists of a carrier gas, gas controls, column, injector, detector and oven. A detector at the end
of the column records the amount of time required for a given compound to elute off of the
column. This allows similar compounds to be separated by GC such as isomers of
dichlorobenzene, racemic cyclic ketone, or cis- and trans- fatty acids. So the amount of peak
separation determines the analyte molecules (e.g. cis and trans isomers). GC used in conjunction
with 1H NMR and infrared spectroscopy (IR) confirms the structure of organic compounds.
Different groups show differences in energy between the axial and equatorial conformers. The
differences in energy represent a measure of the steric bulk of the substituents. Single atoms are
known to have little steric bulk. It is recognized that functional groups in an axial orientation are
sterically more impeded than equatorial orientation. Literature shows that the trans isomer is
represented a quintuplet and cis isomer is present as a triplet of triplets3.
DO I NEED to SHOW Sodium Borohydride REDUCTION And Proposed mechanism of
methanol
ARE 2a and 2b trans and 3e and 3b cis isomers
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2a
2b
3e
3b
Materials and Methods:
Protocol was titled Preparation and properties of the diastereoisomers of 3,3,5trimethylcyclohexanol: conformational analysis and was obtained from CHEM 3880-A1 There
were no deviations from the suggested procedure. The deuterated solvent was chloroform for
NMR and the solvent was methanol for GC.
Results:
The integration value is the area under the peak. In GC, the area of a peak is proportional to
amount of the compound that is present. The percent composition of the NMR analysis and GC
analysis for trans and cis are listed in Table I. The average for methanol was calculated and is
listed in Table II. The percent deviation of the methanol average to experiment 6 is shown in
Table III. Experiment 17 did not have valid results and experiment 18 resulted in no product.
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Table I: Percent composition of the NMR analysis and GC analysis for trans and cis.
Experiment #
1
2
3
4
5
6
7
7
9
10
11
12
13
14
15
16
17
18
Rxn.
Solvent
methanol
methanol
methanol
methanol
methanol
methanol
ethanol
ethanol
ethanol
ethanol
ethanol
ethanol
2-propanol
2-propanol
2-propanol
2-propanol
2-propanol
2-propanol
NMR
analysis –
trans (%)
97.1
87.0
84.6
76.9
69.5
78.3
78.6
76.9
74.1
73.5
71.4
60.0
71.4
62.5
55.0
NMR
analysis
– cis (%)
2.9
13.0
15.4
23.1
30.5
21.7
21.4
23.1
25.9
26.5
28.6
40.0
28.6
37.5
45.0
GC
analysis –
trans (%)
81.2
89.0
78.1
81.0
72.0
81.6
69.9
70.4
70.4
67.0
65.6
68.9
61.0
63.3
57.3
55.8
GC
analysis –
cis (%)
18.8
11.0
21.9
19.0
28.0
18.4
30.1
29.6
29.6
33.0
34.4
31.1
39.0
36.7
42.7
44.2
invalid results
no product
Table II: Percent composition of methanol for NMR analysis and GC analysis for trans and cis
with average.
Experiment #
1
2
3
4
5
6
Average
Rxn.
Solvent
methanol
methanol
methanol
methanol
methanol
methanol
methanol
NMR
analysis –
trans (%)
97.1
87.0
84.6
76.9
69.5
78.3
82.2
NMR
analysis
– cis (%)
2.9
13.0
15.4
23.1
30.5
21.7
17.8
GC
analysis –
trans (%)
81.2
89.0
78.1
81.0
72.0
81.6
80.5
GC
analysis –
cis (%)
18.8
11.0
21.9
19.0
28.0
18.4
19.5
Table III: Percent deviation of experiment 6 from the average methanol of the NMR analysis
and GC analysis for trans and cis.
Experiment #
6
Deviation
Rxn.
Solvent
methanol
methanol
NMR
analysis –
trans (%)
78.3
-4.8
NMR
analysis –
cis (%)
21.7
22.1
GC
analysis –
trans (%)
81.6
1.4
GC
analysis –
cis (%)
18.4
-5.7
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Calculations:
GC
The area of a peak is proportional to amount of the compound that is present. The area can be
approximated by treating the peak as a triangle. The area of a triangle is calculated by
multiplying the height of the peak times its width at half height.
To find the % of each isomer, the formula (Area/total area) x 100% was used.
Peak at retention time 1.007 trans
3203317569/3924845246 = 0.816264*100 % = 81.6%
Peak at retention time 4.021 & 4.134 cis
Area (of both peaks added together)/total area x 100%
(585993781+134228047)/3924845246 = 0.183503*100% = 18.3%
NMR
To find the % of each isomer divide the area by the total area.
The ratio for peaks at 3.5 = 0.47/1.69 x 1.23 = 0.34
The ratio for peaks at 3.2 = 0.15/1.69 x 1.23 = 0.11
Next, sum all areas to find total area = 1.23 + 0.34 + 0.11 + 0.94 + 1.65 + 6.16 + 17.03 = 27.46
% of trans = 1.23 / 27.46 = 4.48%
% of cis = 0.34 / 27.46 = 1.24%
The ratio trans: cis = 3.6: 1 therefore,
Trans % = 3.6 / 4.6 = 78.26%
Cis % = 1/4.6 = 21.74%
Discussion:
The resulting percentages for methanol were consistent with the average results of the other
experimenters as presented in Table II. The average NMR trans was 82.2% which was only 5|Page
4.7% deviation from my result. The NMR cis was significantly different at 22.1% but there was
an outlier with a reported cis value of 2.9%. GC analysis for both trans and cis showed
insignificant percent deviation of 1.3% and -5.72% respectively from my result. Both GC and
NMR analysis confirm that the major product is the trans isomer. Next, my results (experiment
6) compared to the average using other solvents, it suggests that the general result, that trans is
the predominant isomer still holds good. The ratio of trans : cis is quite different among the
solvents, suggesting that there is a solvent effect on the reaction outcome. There is a steady
decrease in the percentage of trans as you go from methanol to 2-propanol. The polarity
decreases as you go from methanol to 2-propanol.
Alcohol impacts reactivity and diastereoselectivity. As 2a is more stable than 2e for trans,
the trans isomer exists primarily in 2a form. When this ionizes, solvation will be sterically
hindered and hence the equilibrium will shift to the undissociated alcohol making this a weaker
acid. For the cis, 3e is preferred. When this ionizes, solvation is not hindered and hence
equilibrium is shifted to the dissociated alcohol. (Solvation will be hindered when the OH group
is axial due to 1,3-diaxial interactions). Hence the cis isomer is the stronger acid. Therefore in
reactions, the cis isomer would react more quickly in the presence of weak bases compared to the
trans. When considering steric bulk, the trans alcohol is bulkier coupled with the 1,3-diaxial
interactions with axial OH. Depending on reactions, this may react faster to relieve the diaxial
strain like in oxidation. Otherwise, it may actually react slowly if strain is not relieved. The
transition state for axial attack is hindered and less energetically less favorable. This is because
the top face is sterically hindered for attack by BH4- due to the presence of the axial methyl
group.
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The significance of the results suggests that NMR and GC were successfully used to analyze
the alcohol mixture. Both these analytic methods gave roughly the same results and are powerful
tools to analyze diastereomeric mixtures. The analysis gives insight into the possible mechanistic
pathways that the reaction occurs by.
References:
2. Haubenstock, H.; Davidson, E. J. Org. Chem., 1963, 28, 2772-2775.
3. Eliel, E. L.; Sshroeter, S.H. J. Am. Chem Soc. 1965, 87, 5031-5038.
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