Proceedings of The National Conferences
On Undergraduate Research (NCUR) 2016
University of North Carolina Asheville
Asheville, North Carolina
April 7-9, 2016
Isomerization of Vicinal Dibromides in Conformationally Rigid Cyclohexane
Systems
Ryan Acocella
Chemistry
King’s College
Wilkes-Barre, Pennsylvania 18711 USA
Faculty Advisor: Dr. Anne Szklarski
Abstract
Previous studies by Barton et al. have shown that vicinal bromine atoms in rigid cyclohexane systems can undergo an
interesting isomerization via a diatropic shift.1 In this 1,2 interchange, the bromine atoms rearrange from the diaxial
positions to the diequatorial positions when heated. The goal of this project was to determine if this reaction could be
developed into an undergraduate laboratory experiment to demonstrate the concept of kinetic and thermodynamic
products. To that end, the reaction time, the extent of isomerization, ease of analysis, and safety were evaluated. The
substrate, 1,2-dibromo-4-tert-butylcyclohexane, was prepared via bromination of 4-tert-butylcyclohexene at 0 ºC to
give a 9:1 mixture of diastereomers. The major diastereomer, which is the kinetic product, contains diaxial bromine
atoms, whereas the minor, thermodynamic product has both bromines in the equatorial positions. This 9:1 mixture of
diastereomers was heated at temperatures ranging from 100 ºC to 175 ºC in a sealed vial for approximately 3 hours.
The isomerization was completed under polar and non-polar conditions by heating the substrate neat or in d6-DMSO.
Samples from each reaction were analyzed by GC-MS every 30 minutes in order to monitor the change in the ratio of
diaxial and diequatorial isomers, and the final reaction mixtures were analyzed by 1H NMR spectroscopy. From these
experiments it was determined that the thermal rearrangement of 1,2-dibromo-4-tert-butylcyclohexene is relatively
slow and stops at a 1:1 ratio of diastereomers. However when heated in d6-DMSO, there is a significant change in the
ratio of diaxial to diequatorial isomers, but the analysis is complicated by a previously undescribed side reaction.
Keywords: bromination, isomerization
1. Background
The halogenation of alkenes is a widely used reaction in organic synthesis.2 Controlling product distributions is critical
for the synthesis of complex molecules, especially halogenated natural products. 3 Previous research has shown that
the bromination of conformationally rigid cyclohexenes at low temperatures favors the formation of the kinetic
product, which has both bromine atoms in the axial positions.4 However, when the reaction is heated, the bromine
atoms can undergo an isomerization to form the thermodynamic product, which has both bromine atoms in the
equatorial positions. It is known that the isomerization can occur through two possible mechanisms (Scheme 1).4 The
isomerization can go through either a polar intermediate, as seen in mechanism 1, or through a diatropic shift as seen
in mechanism 2.4 If the reaction proceeds through mechanism 1, a bromonium ion forms with the loss of a bromide
leaving group, which can then attack the neighboring carbon and break open the bromonium ion. Overall this
mechanism results in the exchange of the two bromines from the diaxial to the diequatorial positions. If the reaction
proceeds through mechanism 2, a diatropic shift occurs in which the C–Br bonds break and form simultaneously, and
no charged intermediate is formed. It is unclear which mechanism will be favored for the isomerization of 1,2dibromo-4-tert-butylcyclohexane, but it was hypothesized that the polar mechanism would be favored in a polar
solvent, such as DMSO, and the diatropic shift mechanism would be favored under nonpolar conditions.5
Scheme 1. Possible mechanisms for the isomerization of vicinal dibromides
When conformationally rigid cyclohexenes are brominated, the kinetically favored diaxial isomer is formed
preferentially (Scheme 2).1 The kinetic product forms faster because it has a lower activation energy, but with the
large atomic radii of the bromine atoms in the axial positions, it is less stable than the thermodynamic product. The
thermodynamic product, which has both bromines in the equatorial positions, is more stable and lower in energy than
the kinetic product. In order to form the thermodynamic product, the reaction must be heated to overcome the higher
activation energy. The general concept of kinetic and thermodynamic control of product distributions is usually
covered during the second semester of undergraduate organic chemistry, and is often demonstrated in the context of
elimination reactions to form alkenes. This project aims to broaden student understanding of the scope and
applicability of this fundamental principle using a halogenation reaction. Since the intention is to develop this reaction
into an undergraduate laboratory experiment, a few limitations were set. First, the heating of the product was limited
to 175 °C because it can be safely maintained in an undergraduate laboratory using a hot plate and a thermometer. In
addition, the product was only heated for 2 hours so that the experiment could be completed in a 3-hour laboratory
period, including time for instructions, set-up, and clean up.
Scheme 2. Synthesis and isomerization of 1,2-dibromo-4-tert-butylcyclohexane drawn flat (A) and in chair form (B)
2. Materials and Methods
2.1 Materials and Instrumentation
4-Tert-butylcyclohexene was purchased from Combi-Blocks. Bromine, chloroform, ethyl acetate, hexanes, and d6DMSO were purchased from Sigma Aldrich. Thin layer chromatography (TLC) was performed with glass-backed
silica gel plates (Merck EMD Millipore, 250 m) with fluorescent indicator (254 nm). A Bruker Avance 400 MHz
NMR spectrometer was used to collect 1H and 13C NMR data in deuterated solvents at 20 °C. Chemical shifts are
reported in ppm and are referenced to residual CDCl3 or d6-DMSO solvent peaks, at 7.26 ppm and 2.50 ppm,
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respectively. GC/MS data were collected using Agilent 5975C system with an Agilent 19091s-433 column (30 m x
250 m x 0.25 m).
2.2 Experimental Procedures
2.2.1 Synthesis of 1,2-dibromo-4-tert-butylcyclohexane
A 100-mL round bottom flask was charged with 4-tert-butylcyclohexene (1.20 mL) and chloroform (24.0 mL) then
cooled to 0 ºC in an ice bath. While stirring, a 1 M solution of Br2 in CHCl3 (8.0 mL) was added dropwise. The solution
was stirred for an additional 5 minutes while monitoring by TLC. Hexanes were used as the TLC developing solvent
and KMnO4 stain was used to analyze the TLC plates (Rf (diaxial) = 0.74, Rf (diequatorial) = 0.37). The reaction was
quenched with a saturated, aqueous solution of sodium thiosulfate (~8 mL), and the mixture was stirred to quench any
excess Br2. The solution was extracted twice with ethyl acetate (~10 mL each), and then combined organic layers were
washed with water (~10 mL), then with brine (~10 mL). The combined organic layers were dried over magnesium
sulfate and concentrated in vacuo to give a pale yellow oil (2.078 g, 96% yield). The crude mixture was analyzed by
GC/MS (Figure 1) and 1H NMR, and resulted in a diaxial to diequatorial ratio of approximately 1:0.13. The crude
mixture was used in subsequent reactions, but a portion of the mixture was purified by flash chromatography (silica
gel, 100% hexanes) to obtain NMR data for each diastereomer.6
1,2-dibromo-4-tert-butylcyclohexane (diaxial bromines): 1H NMR (400 MHz, CDCl3) δ 4.76 (quin, J = 2.6 Hz,
1H), 4.67–4.65 (m, 1H), 2.49–2.40 (m, 1H), 2.21–2.14 (m, 1H), 2.01–1.92 (m, 2H), 1.71–1.56 (m, 3H), 0.89 (s, 9H);
13
C NMR (100 MHz, CDCl3) δ 54.7, 55.6, 41.1, 32.0, 29.3, 28.8, 27.3, 21.1.
1,2-dibromo-4-tert-butylcyclohexane (diequatorial bromines): 1H NMR (400 MHz, CDCl3) δ 4.11–3.96 (m, 2H),
2.54–2.47 (m, 2H), 1.93–1.76 (m, 2H), 1.71–1.62 (m, 1H), 1.25–1.09 (m, 2H), 0.86 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 58.6, 57.7, 48.58, 40.3, 38.4, 32.5, 27.7, 27.3.
a)
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b)
c)
Figure 1: a) Gas chromatogram showing the kinetic product (retention time = 12.652 min.) and the thermodynamic
product (retention time = 13.596 min.). b) Mass spectrum for the kinetic isomer showing the molecular ion peak
(298 m/z). c) Mass spectrum for the thermodynamic isomer showing the molecular ion peak (298 m/z) and the
expected isotope pattern.
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2.2.2 isomerization of 1,2-dibromo-4-tert-butylcyclohexane
The crude mixture of 1,2-dibromo-4-tert-butylcyclohexene (100 mg) was heated in a sealed 1-dram vial either neat or
with anhydrous d6-DMSO (0.75 mL) under nitrogen atmosphere. The vials were heated at 100 °C, 125 °C, 150 °C, or
175 °C, and the isomerization was monitored using GC/MS. A GC/MS sample was prepared every 30 minutes for a
total of 2 hours. The final sample was also analyzed by 1H NMR spectroscopy.
3. Results
From the data collected, it was observed that heating 1,2-dibromo-4-tert-butylcyclohexane neat at 100 ºC, 125 ºC, or
150 ºC resulted in minimal changes in the diaxial to diequatorial ratio after 2 hours (Table 1). However, at 175 ºC the
rate of isomerization increased significantly, resulting in a 1:0.74 diaxial-diequatorial ratio after just 30 minutes of
heating. At the end of the 2-hour heating period, the ratio remained essentially the same at 1:0.76 diaxial to diequatorial
product (Figure 2). When subjected to longer heating times (4 hours or more) at 175 °C, the diaxial-diequatorial ratio
remained the same, suggesting that an equilibrium mixture was reached under these conditions.
Table 1. Isomerization of 1,2-Dibromo-4-tert-butylcyclohexane at Various Temperatures
Diaxial : Diequatorial Ratio
Solvent
Temp (°C)
After 30 minutes
After 2 hours
Neat
100
1.0 : 0.18
1.0 : 0.21
d6-DMSO
100
1.0 : 0.22
1.0 : 0.28
Neat
125
1.0 : 0.23
1.0 : 0.32
d6-DMSO
125
1.0 : 0.42
1.0 : 1.10
Neat
150
1.0 : 0.51
1.0 : 0.71
d6-DMSO
150
1.0 : 1.27
Decomposition
Neat
175
1.0 : 0.74
1.0 : 0.76
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Figure 2: Gas chromatogram showing the kinetic product (retention time = 12.636 min.) and the thermodynamic
product (retention time = 13.609 min.) after heating neat in a sealed vial at 175 ºC for 2 hours.
To determine if the isomerization would be favored in a polar solvent, 1,2-dibromo-4-tert-butylcyclohexane was
initially heated in wet d6-DMSO, but a significant amount of side product was produced. The side product is thought
to be tert-butylbenzene, which could form through a Kornblum-type oxidation in the presence of water, based upon
the appearance of aromatic peaks in the crude 1H NMR data. More side product was produced as the temperature was
increased using wet DMSO. Therefore, anhydrous d6-DMSO was used fresh from ampules and kept under nitrogen,
which significantly reduced the amount of side product formed.
After heating the 1,2-dibromo-4-tert-butylcyclohexane in anhydrous d6-DMSO at 125 °C for 2 hours, the ratio of
diaxial to diequatorial product reached 1 : 1.10 (Table 1). This was the first time that the diequatorial isomer was
generated as the major isomer, and it formed at a much lower temperature than when heated neat. This result suggests
that the isomerization may proceed through a polar mechanism (see mechanism 1, Scheme 1), which is likely preferred
in polar solvents such as DMSO. Encouraged by this result, the temperature was increased to 150 °C, which increased
the ratio to 1 : 1.27 diaxial to diequatorial product after just 30 minutes (Figure 3). However, heating at 150 ºC for
longer times resulted in significant decomposition.
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Figure 3: Gas chromatogram showing the kinetic product (retention time = 12.604 min.) and the thermodynamic
product (retention time = 13.585 min.) after heating in a sealed vial in anhydrous d6-DMSO at 150 ºC for 30
minutes. The additional peaks that eluted at approximately 4.9 min. and 13.7 min. result from side products formed
at this temperature.
4. Conclusion
When a 9 : 1 mixture of diastereomers of 1,2-dibromo-4-tert-butylcyclohexane is heated at 175 ºC under nonpolar
conditions (neat), an isomerization occurs to form more of the thermodynamic isomer with diequatorial bromines.
Unfortunately, the change in the diaxial to diequatorial ratio stalled at 1 : 1.10, which is not enough of increase for use
in an undergraduate laboratory experiment. When d6-DMSO was used as the solvent, the largest increase in the
diequatorial isomer was observed after heating at 125 ºC for 2 hours. Unfortunately, increasing the temperature and/or
extending the heating times resulted in the formation of side products and eventually decomposition, despite the use
of anhydrous conditions. In future studies, other rigid cyclohexane systems will be examined to see if the isomerization
can occur more readily at a lower temperature without the formation of side products.
5. Acknowledgements
The authors would like to thank the Department of Chemistry at Wilkes University for use of their NMR facilities and
the Department of Chemistry and Physics at King’s College for funding.
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6. References
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2. Eissen, M.; Lenior, D. Chem. Eur. J. 2008, 14, 9830-9841.
3. Quinn, R. K.; Konst, Z. A.; Michalak, S. E.; Schmidt, Y.; Szklarski, A. R.; Flores, A. R.; Nam, S.; Horne,
D. A.; Vanderwal, C. D.; Alexanian, E, J. J. Am. Chem. Soc. 2016, 138, 696-702.
4. Barili, P. L.; Bellucci, G.; Marioni, F.; Morelli, I.; Marsilli, A. J. Chem. Soc. Perkin Trans. II 1972, 58-62.
5. Barili, P. L.; Bellucci, G.; Marioni, F.; Morelli, I.; Scartoni, V. J. Org. Chem. 1972, 37, 4353-4357.
6. Barili, P. L.; Bellucci, G.; Ingrosso, F.; Marioni, F.; Morelli, I. Tetrahedron. 1972, 28, 4583-4589.
7. Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W. J.; Larson, H. O.; Levand, O.; Weaver, W. M. J.
Am. Chem. Soc. 1957, 79, 6562.
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