Large-scale synthesis and purification of trans-4-tert-butyl-1- phenylcyclohexanol, an organic gelation agent

Full text of DOI:10.1080/00304948.2013.743767

This article was downloaded by: [UNIVERSITY OF KWAZULU-NATAL]
On: 09 March 2013, At: 03:11
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Organic Preparations and Procedures
International: The New Journal for
Organic Synthesis
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/uopp20
Large-scale Synthesis and Purification of
trans-4-tert-Butyl-1-Phenylcyclohexanol,
an Organic Gelation Agent
Lisa Alvarez-Jordan a & Charles M. Garner a
a Department of Chemistry & Biochemistry, Baylor University, Waco,
TX
Version of record first published: 16 Jan 2013.
To cite this article: Lisa Alvarez-Jordan & Charles M. Garner (2013): Large-scale Synthesis and
Purification of trans-4-tert-Butyl-1-Phenylcyclohexanol, an Organic Gelation Agent, Organic
Preparations and Procedures International: The New Journal for Organic Synthesis, 45:1, 75-80
To link to this article: http://dx.doi.org/10.1080/00304948.2013.743767
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Organic Preparations and Procedures International, 45:75–80, 2013
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2013.743767
OPPI BRIEF
Large-scale Synthesis and Purification
of trans-4-tert-Butyl-1-Phenylcyclohexanol,
an Organic Gelation Agent
Lisa Alvarez-Jordan and Charles M. Garner
Department of Chemistry & Biochemistry, Baylor University, Waco, TX
A relatively small number of organic compounds can be used to convert organic liquids
into gels1,2 and are referred to as low-mass organic gelators, distinguished from polymeric
gelling agents. The gelling properties of such materials are typically discovered inadver-
tently; even now, it is difficult to design molecules with this behavior. Scheme 1 gives some
examples of known organic gelators (1–5). Structurally, they tend to have long unbranched
alkyl chains (1,3 24) and/or significant degrees of hydrogen bonding (2, 3,5 4,6 57). These
Scheme 1
Representative Organogelators.
materials exhibit a wide range of gelation behavior, with some compounds useful for
gelling only very non-polar liquids and others effective for immobilizing a wider range
of fluids. The gelled state is achieved by first dissolving the gelator in the appropriate hot
liquid, followed by cooling. The gelation resembles crystallization in that there is often an
Received May 2, 2012.
Address correspondence to Charles M. Garner, Department of Chemistry & Biochemistry, Baylor
University, Waco, TX 76798-7348. E-mail: Charles garner@baylor.edu
75

76
Alvarez-Jordan and Garner
irreproducible delay between cooling and the onset of gel formation. These molecules
function through the same general mechanism, namely by aggregation primarily in one
dimension, yielding long fibers that overlap extensively. Depending on the cross-sectional
diameter of the aggregates, the resulting gels may be clear or cloudy, the latter ones being
more common.
trans-4-tert-Butyl-1-phenylcyclohexanol (6) is perhaps the smallest and most rigid
molecule known8–10 to gel organic solvents, and one of the simplest structurally. This com-
pound has been known for several decades11,12 before its gelation abilities were recognized.
Low concentrations (0.5–1 wt%) can be used to convert a wide variety of saturated hydro-
carbons to transparent gels that resist gravity indefinitely and give sharp, concentration-
dependent melting points. For example, a mineral oil gel containing 1 wt.% of 6 exhibits
a melting point of 52–53◦C. Aromatic hydrocarbons and even halocarbons, ethers and es-
ters can be immobilized at higher concentrations (2–5%). Protic solvents (e. g., methanol,
ethanol) are entirely resistant to gelling, the compound simply precipitating upon cooling
instead. The gels are technically metastable, and precipitation of the gelling agent can occur
if seeded, mechanically agitated, and/or warmed somewhat, etc. Very slow evaporation of
a dilute hexane solution of 6 can yield fibers up to several centimeters in length. However,
mineral oil gels are very resistant to precipitation, generally being stable for months or even
years at room temperature.
OH
O
1. PhMgBr
+
OH
2. H2O
H
H
H
6
7
Scheme 2
Preparation of trans- and cis-4-tert-Butyl-1-phenylcyclohexanol.
Gelling agent 6 is best prepared11,12 by reaction of the phenylmagnesium bromide
with 4-tert-butylcyclohexanone, both available in bulk quantities. The reaction inevitably
produces both trans (6) and cis (7) isomers of the product (Scheme 2), though (fortunately)
the trans isomer generally predominates (see below). Preliminary tests suggest that the
cis isomer does not interfere with the gelling ability of the trans isomer, but resistance to
crystallization under these conditions has not been evaluated. The isomers exhibit significant
differences in polarity on silica gel TLC, with the trans isomer being more polar (Rf 0.14 vs.
0.28 for the cis, using 10% ethyl acetate in hexanes). However, in addition to serious
limitations on scale, column chromatography is plagued by the tendency of compound 6 to
gel the solvent used to dissolve it for application to the column. For column chromatography,
dichloromethane proved to be the best solvent for the application and separation, but only
rather small amounts (< few grams) of 6 could be purified in this way. To provide samples
for industrial testing, we sought a relatively large-scale synthesis and purification of the
material.
In order to optimize the fraction of trans isomer formed, we studied various procedures
for the reaction. Optimization was studied on a one-mmol scale, with the results analyzed

Synthesis and Purification of trans-4-tert-Butyl-1-phenylcyclohexanol
77
by capillary gas chromatography, which easily resolved the isomers. The critical variables,
in decreasing order of importance, were (a) the use of phenylmagnesium bromide versus
phenyllithium, (b) the use of ether versus THF, and (c) the order of addition. We found
phenylmagnesium bromide to be much superior to phenyllithium, giving nearly always
better than 62% trans, while phenyllithium gave 50% or less of the desired trans isomer.
Diethyl ether was always superior to THF, especially when the ketone was added to the
Grignard reagent. In addition to poorer trans:cis ratios, THF always gave a larger amount
of unreacted ketone, presumably the result of enolization. The order of addition affected
mostly the amount of residual ketone, with the best results obtained from addition of the
ketone to the organometallic reagent. The predominance of the less stable trans isomer
was enhanced somewhat by the presence of magnesium bromide, prepared in situ from
magnesium and 1,2-dibromoethane. However, the simplest conditions that gave complete
conversion and a high trans:cis ratio were the addition of an ethereal solution of the ketone
to a 1 M ethereal solution of the Grignard reagent at −78◦C, and these were chosen for the
scale-up process.
The challenges for a large-scale synthesis are (a) to maximize production while avoid-
ing inconveniently large volumes of solvent, (b) to avoid if possible the necessity of an
aqueous work-up, and (c) to obtain the gel-active trans isomer essentially free of the in-
active cis isomer without chromatography. All of these goals were realized. We were able
to carry out the Grignard reaction on a > 2 mole scale in a 5-liter round bottom flask,
and quantitatively cause the precipitation of the magnesium salt by-product, and purify the
crude product by differential solubility/filtration.
After many smaller scale reactions, the following protocol was developed. On a 2.4
mole scale, commercial phenylmagnesium bromide (3 M in ether) was diluted to ∼0.7 M
with anhydrous ether in a 5-liter, three-neck round bottom flask equipped for mechan-
ical stirring and under a nitrogen atmosphere. Cooling this to −78◦C gave a stirrable
suspension of the Grignard reagent, to which was added a ∼2.5 M solution of 4-tert-
butylcyclohexanone (2.2 mol) in ether. The mixture was allowed to slowly warm to room
temperature overnight, and the resulting thick suspension was treated with water. As the
mildly exothermic hydrolysis was complete, there generally came a point where the ethe-
real solution would dramatically clear and all of the magnesium salts would coagulate on
the walls of the flask, but with no second liquid phase evident. This sometimes occurred
with as little as 80 mL of water (1.9 equiv. relative to Grignard used) but usually at closer
to 360 mL (8.4 equiv) of water. As long as the ethereal solution was warm (∼30◦C), the
organic products were completely soluble, and simple vacuum filtration through granular
sodium sulfate provided a slightly yellow solution. On one occasion, after addition of 8
equiv of water, the magnesium salts did not coagulate and a suspension was still present.
But vacuum filtration of the warm (30◦C) ethereal solution to remove the rather granular
magnesium salts was still easily performed, followed by rinsing with a little ether to make
sure that the salt did not retain any of the desired product. In either case, evaporation of
the filtrate gave essentially a quantitative yield (96–99%, 490–505 g) of the crude cis/trans
mixture (∼62–68% trans), free of unreacted ketone by capillary GC analysis.
Since chromatography could only provide small amounts of pure trans or cis isomer,
we studied crystallization. Of some of the common solvents (aliphatic and aromatic hydro-
carbons, ethers, ethyl acetate, alcohols), crystallization was possible only from alcohols;

78
Alvarez-Jordan and Garner
for all others, cooling of a warm solution resulted in a gel. We found that hot (60◦C) 85:15
ethanol:water would dissolve the mixture of isomers readily, but upon cooling the fibrous
trans isomer precipitated in such a way that the solvent could not be efficiently removed
from the solid. It was later learned that the cis isomer (7) could often be crystallized from
> 60% cis-enriched samples, as discussed below.
Since the trans isomer was more polar than the cis (based on TLC observations), it
was decided to measure the solubility of each in hydrocarbon solvents at room temperature.
As long as the mixtures were not heated, gelation was avoided, and the cis isomer was
significantly more soluble. For example, in hexanes the cis isomer was much more soluble
(22 mg/mL) than was the trans isomer (5.2 mg/mL). A variety of hydrocarbons (pentane,
cyclopentane, 2-methylbutane, cyclohexane, 2,3-dimethylbutane) were also studied, but the
relative solubilities were nearly the same as observed for hexanes. Thus, a simple method to
obtain highly pure trans isomer was to simply stir the powdered crude product with sufficient
hexanes (14.5 mL per gram) to dissolve all of the cis isomer. This inevitably washed away
some of the trans isomer as well, but the operation was simple if not entirely efficient. On
the largest scale attempted, 100 g of powdered crude product in a 2 L Erlenmeyer flask
was suspended and stirred with 1450 mL of hexanes for ∼20 min, then collected in vacuo
on a 600 mL coarse fritted funnel until dripping stopped; then the solid was broken up
and suspended again in 620 mL more hexanes, stirred and filtered as before to give 50.7 g
(∼82% recovery) of the trans isomer, >99% pure by capillary GC analysis. Thus, on the
2.2 mole scale described above, the yield of pure trans isomer was 248–256 g, or 49–50%
yield overall.
The hexanes were easily recycled by distillation. The resulting cis-enriched mixture
(>60% cis) could be recrystallized from 85:15 ethanol:water to yield the crystalline cis
isomer; however, filtration must be done before the trans isomer begins to precipitate
(evident as fibrous rather than crystalline material). In theory, the resulting trans-enriched
filtrate could then be concentrated and treated with hexanes to obtain more of the pure trans
isomer, but we did not study that level of recovery.
Experimental Section
Phenylmagnesium bromide (3 M in ether) and 4-tert-butylcyclohexanone were obtained
from Aldrich Chemical and used as received. Anhydrous ether was obtained from Mallinck-
rodt and used as received. The Grignard reagent and anhydrous ether were transferred by
cannula under nitrogen or argon. Hexanes (VWR) were ACS grade and distilled before use.
NMR analyses were performed in acetone-d6 at 500 MHz for 1H (referenced to TMS) and
at 125.7 MHz for 13C (referenced to solvent at 29.84 ppm). Quantitative GC analyses were
carried out using a 30 m × 0.25 mm HP-5 capillary column with helium carrier at 15 psi,
and FID detection.
trans- and cis-4-tert-Butyl-1-phenylcyclohexanol (6 and 7). To a two neck 5-L
round-bottom flask equipped with a mechanical stirrer and under nitrogen was added
phenylmagnesium bromide (800 mL, 3 M in ether; 2.4 mol) solution (viscous) using a
12 gauge cannula, followed by 2.8 L of anhydrous ether. The mixture was cooled to
−78◦C in a Dry Ice-acetone bath, resulting in a stirrable suspension. A solution of 4-
tert-butylcyclohexanone (340 g, 2.2 mol, 0.92 equiv. relative to Grignard) in anhydrous

Synthesis and Purification of trans-4-tert-Butyl-1-phenylcyclohexanol
79
ether (500 mL) under nitrogen was then introduced using a cannula over a 20–40 minute
period. The resulting very thick grey suspension was allowed to warm to room temperature
overnight with stirring. With the flask immersed in a room temperature water bath, water
was added using a cannula to the thick white suspension with stirring until the mixture
thinned considerably and the magnesium salts coagulated on the walls of the flask; this
typically occurred at somewhere between 80 mL and 360 mL (1.9–8.4 equiv) of water
added. The slightly yellow ethereal solution was filtered through a pad of anhydrous
granular sodium sulfate. On one occasion, the solution failed to become clear during the
addition of water (possibly because of more efficient stirring), in which case the suspension
was filtered through a pad of anhydrous sodium sulfate to remove the magnesium salts.
In either case, it is important that the ethereal solution be sufficiently warm (25–30◦C) to
keep the organic products soluble during the decantation/filtration process. Concentration
was carried out by atmospheric pressure distillation on a rotary evaporator followed by
pump vacuum (<1 Torr). This provided a nearly quantitative yield (490–505 g, 96–99%)
of a cis/trans mixture (62–68% trans), containing only traces of impurities by capillary
GC. It is important to maintain a clean injection port liner, as used liners may sometimes
cause significant amounts of dehydration (primarily of the trans isomer) during injection.
A temperature program of 100◦C to 240◦C at 10◦C per minute was used, and the observed
elution order (retention time) was: ketone (5.5 min), alkene dehydration product (11.8 min),
trans isomer 6 (12.3 min), and cis isomer 7 (12.8 min). On silica TLC, the trans isomer
exhibited Rf 0.14 vs. 0.28 for the cis, using 10% ethyl acetate in hexanes.
Pure trans-4-tert-butyl-1-phenylcyclohexanol (6). The vacuum-dried cis/trans mix-
ture was powdered using a mortar and pestle, and sifted through a 16-mesh wire gauze
to remove chunks (which were re-submitted for powdering). A weighed amount of the
powder was suspended in hexanes (14.5 mL per gram of powder) and the thick suspension
was magnetically stirred 15 minutes, then the solid was collected on a coarse fritted funnel
until dripping stops (important). Using a plastic spatula (to avoid damaging the frit), the
solid was then broken up in the fritted funnel (important), the solid was stirred with an ad-
ditional 6.2 mL of hexanes per gram (based on original weight) until a uniform suspension
resulted, and the filtration repeated (until dripping stops). The recovery is approximately
50% of the original weight, or 72–82% of the trans isomer present originally. On the
scale above, 248–256 g (1.07–1.10 mol, 49–50% overall yield) of trans-4-tert-butyl-1-
phenylcyclohexanol (6) was obtained, mp. 157.5–158.0◦C, lit 156.5–157.5,11 158–159.12
The purity is typically 99.3 0.1% trans by capillary GC analysis. 1H NMR (acetone-d6):
δ 0.78 (s, 9H), 0.96–1.08 (m, 2H), 1.14–1.22 (m, 1H), 1.66–1.76 (m, 4H), 2.48–2.56 (m,
2H), 3.75 (s, 1H), 7.22 (tt, J = 7.8, 1.2 Hz, 1H), 7.31–7.35 (m, 2H), 7.54–7.58 (m, 2H).
13C NMR (acetone-d6): δ 25.6, 27.9, 32.7, 39.8, 48.7, 72.8, 127.4, 127.5, 128.8, 146.4. MS
(EI): 232 (M+, 7%), 133 (100%), 120 (8%), 105 (15%).
The alkene dehydration product gave the following GC-MS (EI): 214 (M+, 45%), 158
(33%), 143 (48%), 130 (100%), 115 (43%), 91 (80%).
Pure cis-4-tert-butyl-1-phenylcyclohexanol (7). The hexanes filtrate from the purifi-
cation of the trans isomer was concentrated by rotary evaporation or distillation, followed
by drying on the vacuum pump (<1 Torr), to give ∼260 g of cis-enriched material. This
material was dissolved in ethanol (1 L) with heating (∼70◦C) and water was added with
stirring until the mixture just clouded; approximately 230 mL was required. The mixture

80
Alvarez-Jordan and Garner
was allowed to cool to room temperature and stand overnight. The crystalline material was
collected and washed once with cold ethanol to give 90 g (0.38 mol, 17.6% yield, 47–57%
recovery of the cis isomer originally present) of cis-4-tert-butyl-1-phenylcyclohexanol (7),
mp. 117.5–118.0, lit 117–118,11 117.12 It was observed that sometimes the fibrous trans iso-
mer would begin to precipitate on prolonged standing, and it is important that the filtration
be performed before this occurs, but the difference is easily evident. 1H NMR (acetone-d6):
δ 0.92 (s, 9H), 1.1–1.2 (m, 1H), 1.62–1.70 (m, 4H), 1.76–1.82 (m, 4H), 3.66 (s, 1H), 7.17
(tt, J = 7.3, 1.2 Hz, 1H), 7.26–7.31 (m, 2H), 7.53–7.56 (m, 2H). 13C NMR (acetone-d6): δ
23.6, 28.0, 33.0, 40.3, 48.3, 72.6, 125.5, 126.8, 128.6, 151.8. MS (EI): 232 (M+, 8%), 133
(100%), 120 (8%), 105 (15%).
Acknowledgments
We would like to thank the Robert A. Welch Foundation (grant #AA-1395) for partial
support of this work, and the National Science Foundation (Award #CHE-0420802) for
funding the purchase of our 500 MHz NMR.
References
1. P. Terech and R. G. Weiss, Chem. Rev., 97, 3133 (1997).
2. M. George and R. G. Weiss, Acc. Chem. Res., 39, 489 (2006).
3. T. Brotin, R. Utermohen, F. Fages, H. Bouas-Laurent, and J.-P. Desvergne, J. Chem. Soc., Chem.
Commun., 416 (1991).
4. K. Hanabusa, M. Yamada, M. Kimura and H. Shirai, Angew. Chem. Int. Ed. Engl., 35, 1949
(1996).
5. E. A. Wilder, C. K. Hall, S. A. Khan and R. J. Spontak, Recent Res. Devel. Mat. Sci., 3, 93
(2002).
6. R. Mukkamala and R. G. Weiss, Langmuir, 12, 1474 (1996).
7. H. T. Stock, N. J. Turner and R. McCague, J. Chem. Soc, Chem. Commun., 2063 (1995).
8. C. M. Garner, P. Terech, J. J. Allegraud, B. Mistrot, P. Nguyen, A. de Geyer and D. Rivera, J.
Chem. Soc., Faraday Trans., 94, 2173 (1998).
9. P. Terech, J. J. Allegraud and C. M. Garner, Langmuir, 14, 3991 (1998).
10. C. M. Garner, “New Organic Gelation Agents”, US Patent 5,688,440; Nov. 1997; CAN127:20701.
11. E. W. Garbisch, and D. B. Patterson, J. Am. Chem. Soc., 85, 3228 (1963).
12. G. D. Meakins, R. K. Percy, E. E. Richards and R. N. Young, J. Chem. Soc. Sec. C, 1106 (1968).