Honors Cup Synthetic Proposal
Section: 220-2
Group Members: Justin Lomont, Koichi Murai, Lara Czabaniuk, Peter Horning
Title: Three Step Synthesis of 11-cycloheptylundecanoic acid
Introduction:
Recently, a fatty acid mixture was isolated from the lipids of the thermoacidophile
Alicyclobacillus cycloheptanicus. Subsequently, it was identified as a mixture of cycloheptyl fatty acids which are unique in this organism. It has been suggested that these
acids enable the organism to grow in acidic, hot media by providing a more dense cell
membrane. This has led to the important understanding of their biosynthetic relations.
However, owing to their very low natural abundance, it is necessary to synthesize these
fatty acids in order to obtain them in sufficient amount both for their structural
establishment and investigation of the involved biosynthetic pathway. One such
compound of this class is 11-cycloheptylundecanoic acid. (Reference 1)
11-cycloheptylundecanoic acid is a fascinating biological molecule. Its protective
capabilities become more relevant in light of all the environmental concern over acid rain.
Alicyclobacillus cycloheptanicus is a type of bacteria and due to its simple nature and
quick reproduction, much research can be done on the acids in its membrane.
In addition to its biological significance, this synthesis correlates with the material
studied in organic chemistry. The first step is an oxidation of a ketone to an alcohol, a
process studied in Chemistry 215. Cyclic compounds were studied in Chemistry 210, as
were substitutions. Syntheses involving concepts studied in lecture will reinforce and
solidify the concepts.
Overall synthetic reaction scheme:
OH
O
NaS2O4
DMF, H2O, NaHCO3
Br
Ph3P Br2
Pyridine
Br(CH2)10CO2Me
Mg, THF, Li2CuCl4
HO
O
Step 1
OH
O
NaS2O4
DMF, H2O, NaHCO3
Experimental 1
A solution of substrate (50 mmol) in dioxane (175 mL) or DMF for more difficultly
reducible substrates is added to water (175 mL) containing NaHC03 (27.5 9). (When
DMF was used as cosolvent, in some cases it was necessary to add some more water
during the reduction to prevent gel formation.) When no cosolvent is used, the substrate
is added neat. Sodium dithionite (12.5 g) is added and the reaction mixture refluxed for 4
h during which time three additional 12.5-g portions of Na2S204 are added. (A total of
three 12.5-g portions of Na2S204 sufficed for the reductions of benzaldehyde,
furfuraldehyde, 4-tert-b~-tylcyclohexanone, adamantanone, and norbornanone.) The
reaction is carried out under an atmosphere of nitrogen. After the mixture cooled to room
temperature, water is added until the solution becomes clear and thereafter the solution is
extracted with ether (furfuryl alcohol and y-valerolactone were isolated by continuous
extraction with ether for 7 and 72 h, respectively). When DMF is used as cosolvent the
ether extracts are backwashed twice with water to remove traces of DMF. After the
solution is dried (MgS04) and the ether is removed, the products are isolated by either
distillation or recrystallization. Identification is based on melting or boiling points,
infrared and 'H NMR spectra, and comparison with authentic materials.
All reductions were carried out on a 2-mmol scale and for purposes of isolation were also
done on a 50-mmol scale.
The reaction is also done in nitrogen at a temperature of 85 degrees Celsius.
Table I estimates 97% yield of cycloheptanol when reaction done in DMF. (48.5 mmol)
(From Reference #2)
Deviations from referenced experimental for 216:
We will be using DMF as the solvent as it produces a higher yield and is more readily
available.
A four hour reflux is not feasible given the time we spend in lab. We propose a two and
one half hour to three hour reflux in order to fit within the time constraints of 216.
Due to the decreased reflux time and any experimental error, we estimate the yield to be
80% instead of 97%.
The estimated yield is 48.5 mmol, which is 5.472 g. We need 1.316g for step two of the
synthesis, so the materials used in this step need to be scaled down. After taking the new
estimated yield into account, we found that scaling reagents and solvents down by a
factor of 3.45 would produce an adequate amount of product. The new masses and
volumes of reagents and solvents are as follows:
14.5 mmol of cycloheptanone (1.624 g) in 50.73 mL DMF and 50.73 mL water with
7.971 g NaHCO3 dissolved in it
3.623 g Na2S2O4 added to the mixture four separate times.
The times given for extraction are not feasible given the time constraints of Chem 216.
We suggest extraction with ether 3 times and then recrystallization or distillation for
further isolation. The possible impurity of the product was also taken into account when
the new yield was estimated.
Expected yield:
80% 1.322g
Safety, disposal and green issues 1:
Though this experimental uses a large amount of Na2S2O4, the material is much safer to
use than metal hydrides to reduce ketones. It will not explode. Using water as a solvent
enables us to reduce use of toxic solvents. The experiment will of course need t o be
done under a fume hood, especially since sodium dithionite will emit a toxic gas if it
comes into contact with an acid. Sodium dithionite is sensitive to the air, and we must
perform the transformation in nitrogen. DMF is a skin irritant and direct contact with it
should be avoided.
(From MSDS)
Step 2
OH
Br
Ph3P Br2
Pyridine
Experimental 2
To a cooled ( 0̊C) and stirred solution of triphenylphosphine ( 7.86 g, 0.03 mol) in
CH2Cl2 (50 mL) was added Br2 (1.6 mL) in CH2Cl2 (50 mL) dropwise over a period of
30 min. To the resulting white suspension was added a solution of cycloheptanol (3.42 g,
0.03 mol) in pyridine (2.6 mL) over a period of 1 h while cooling was maintained
externally. After stirring the mixture for 3 h, the solvent was removed under reduced
pressure. The residue was chromatographed on a silica gel column, eluting with
petroleum ether. The evaporation of the solvent furnished Cycloheptyl bromide (3.7 g,
69.8%): b.p. 82̊C/10 mm; IR: 2928, 1458 cm-1; 1H-NMR: 1.5 (m,12H, 6 x CH2), 3.4
(m, 1H, CHBr).
(From reference #1)
Deviations from referenced experimental for 216:
The 3 hour stirring time is very hard to accomplish within one lab period. We propose
stirring the mixture for two hours in order to complete the synthetic step within one fourhour lab period.
Due to the decreased stirring time and any experimental error, we estimate a 55% yield
instead of 69.8% yield.
We will want to adjust the scale of the experimental step to produce the amount of
product we need for the third step. We calculated the yield given the new estimated yield
of 55% and then found that we would need to reduce everything by a factor of 2.6 to get
the 1.122 grams of product, enough for step three. The new masses and volumes of
reagents and solvents are as follows:
3.023 g triphenylphosphine in 19.2 mL CH2Cl2
0.62 mL Br2 in 19.2 mL CH2Cl2
1.316 g cycloheptanol in 1mL pyridine
Reduce drop wise adding times to 15 and 30 minutes respectively due to scaling down of
the experimental.
Expected yield: 55% 1.122 g
Safety, disposal and green issues 2:
Triphenylphosphine is harmful if inhaled so the experimental step must be done under a
fume hood. It is also harmful to the environment, especially to aquatic animals. Special
care must be taken to ensure that this chemical is disposed of correctly. It is not
compatible with acids. Bromine causes severe burns and is very toxic by inhalation. Any
container containing bromine must be covered at all times and contact with skin must be
avoided. Pyridine is harmful if inhaled or absorbed through the skin.
(From MSDS)
Step 3
Br
Br(CH2)10CO2Me
HO
Mg, THF, Li2CuCl4
O
Experimental 3
To a stirred suspension of Mg (1.44 g, 0.06 mol) in THF (15 mL) was added Cycloheptyl
bromide (8.85 g 0.05 mol) in THF (50 ml) at room temperature over a period of 1 h. The
mixture was cooled to -78̊C, Li2CuCl4 (3.5 mL, 0.1 M, prepared by dissolving 85 mg of
LiCl and 43 mg of CuCl2 in 10 ml THF) added and the mixture stirred over a period of
30 min. A solution of methyl 11-bromoundecanoate (12.6 g, 0.045 mol) in THF (50 mL)
was then added drop wise over a period of 1 h. Stirring was continued overnight at room
temperature. Saturated aqueous NH4Cl solution was added to decompose the Grignard
complex. The mixture was filtered and extracted with ether. The usual workup and
removal of solvent, followed by column chromatography of the residue, furnished Methyl
11-Cycloheptylundecanoate (6.68 g, 50 %): IR: 2942, 1745 cm-1; 1H-NMR: 1.3 (m,18
H, 9 x CH2), 1.4-1.7 (m,13H, 6 x CH2 and CH), 2.3 (t, J = 6 Hz, 2H), 3.7 (s, 3H, OCH3).
MS: 296 (19), 200 (M-C7H12) (23), 171 (2), 157 (9), 143 (22), 129 (8), 111 (12), 97
(C7H13) (68), 87 ( 90), 74 (C3H6O2) (100).
(From reference #1)
Deviations from referenced materials for 216:
Stirring overnight is a time issue that needs to be addressed. We suggest stirring the
mixture for two hours after the addition of the methyl 11-bromoundecoate and then
waiting until the next lab session (1 week later) to add the saturated NH4Cl.
Due to reduced stirring time and any experimental error, we estimate a 30% yield.
Scale will need to be altered because we only need 0.5 grams of the product, instead of
the 6.68 reported in the experimental. We calculated out new masses and volumes of
chemicals by assuming the 30% yield mentioned previously and then dividing by a factor
to get the goal of 0.5 grams. This factor turned out to be 8, and we scaled down all other
reagents and solvents appropriately. The new masses and volumes are as follows:
.18 g Mg in 1.9 mL THF
1.106 g cycloheptyl bromide in 6.25 mL THF
.44 mL of the Li2CuCl4 solution (prepare it the same way as the experimental due to the
already small scale)
1.575g Methyl 11-bromoundecanoate in 6.25 mL THF
When adding cycloheptyl bromide and methyl 11-bromoundecanoate drop wise, reduce
the time needed to add it from 1 hour to 15 minutes due to the scaling down of the
experiment. Stirring times will not be altered.
Expected yield:
30% 0.5g
Safety, disposal and green issues 3:
Magnesium and THF are highly flammable so extra care should be taken with them.
Lithium Chloride needs to be protected from moisture. If inhaled, fumes from cooper (II)
chloride are harmful. Keep samples covered and work under a fume hood.
(From MSDS)
Overall budget:
Chemical
Supplier
Cost
cycloheptanone
pfaltz & Bauer
$1.04/g
Na2S2O4
Alfa Aesar
$0.04/g
NaHCO3
pfaltz & Bauer
$0.03/g
Ph3P
Alfa Aesar
$1.55/g
Mg (powder)
Alfa Aesar
$0.15/g
Br2
pfaltz & Bauer
$0.29/g
LiCl
Alfa Aesar
$2.13/g
CuCl2
pfaltz & Bauer
$0.21/g
Br(CH2)10CO2Me
pfaltz & Bauer
$3.84/g
*Chemicals also available through Aldrich’s
Amt. Needed
1.624 g
14.492g
7.971g
3.023g
0.18g
0.62 mL/.1.934g
0.085g
0.043g
1.575g
Total
$1.69
$0.60
$0.24
$4.69
$0.03
$0.56
$0.18
$0.01
$6.05
Total costs per synthesis: $14.05
References
1. Hassarajani, S.; Mamdapur, V. Molecules. 1998, 3, 41-43.
2. Vries, J.G,; Kellog, R.M. J Org. Chem. 1980, 45, 4126-2129.