ORGANIC

CHEMISTRY
Cyclohexanone

Members XI-4:
1. Alaina Amalia (02)
2. Bagus Fikri S. (06)
3. M. Mauludi Edwin (14)
 PREFACE
Praise and Gratitude we prayed to Allah SWT, because thanks to the abundance of
grace and the gift of his so that we can arrange this paper properly and timely. In this paper we
present about Cyclohexanone.

This paper is made from a variety of sources and some assistance from various parties
to help resolve the challenges and obstacles during work on this paper. Therefore, we thank
you profusely to all those who have helped in the preparation of this paper.

We realize that there are still many fundamental flaws in this paper. Therefore, we invite
readers to give suggestions and criticisms which we can build. Constructive criticism from
readers so we expect to further refinement of paper.

Bogor, March 16th2015,

Writer

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 CONTENTS

Prepace ……………………………………………………………………………………. 1

Definition ……………………………………………………………………………………. 4

Isomers ……………………………………………………………………………………. 5

Nomenclature ……………………………………………………………………………………. 6

Properties ……………………………………………………………………………………. 7

Quantitative Analysist …………………………………………………………………………… 8

Quanlitative Analysist …………………………………………………………………………… 8

Preparation ……………………………………………………………………………………. 11

Used In Daily Life …………………………………………………………………………… 18

Related Research …………………………………………………………………………… 19

References ……………………………………………………………………………………. 22

Attachment ……………………………………………………………………………………. 23

Page 2 of 23
Page 3 of 23
 DEFINITION

Cyclohexanone is the organic compound with the

formula (CH2)5CO. The molecule consists of six-carbon cyclic
molecule (A cyclic compound is an organic compound that
contains one or more closed rings of carbon atoms) with a
ketone functional group. Cyclohexanone having two alpha-
carbons in the ring provides four alpha-hydrogens which can
be substituted depending on the reaction conditions with
remaining six hydrogens unreact. This colorless oil has an
odor reminiscent of peardrop sweets as well as acetone.

Cyclohexanone is slightly soluble in water, but miscible with common organic solvents.
Cyclohexanone is used to produce Nylon (Nylon is a generic designation for a family of
synthetic polymers known generically as aliphatic polyamides). It is a clear oily liquid with an
acetone like odor. It is used as an industrial solvent and activator in oxidation reactions. It is
used in the production of adipic acid, cyclohexanone resins, cyclohexanone oxime, caprolactam
and nylon 6.

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 ISOMERS

The examples above is the one between 117 isomers from Cyclohexanone

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 NOMENCLATURE
1. IUPAC Name

Cyclohexanone is a family of ketones, ketones are name by dropping the final –e from the
name of the hydrocarbon that has the same number of carbon atoms, and adding the ending –
one. The position of the carbonyl group is indicated by the number of the carbonyl carbon atom
as it is positioned in the carbon chain. The chain numbering is done from the end that results in
the lowest number for the carbonyl group. And because cyclohexanone is a cyclic compound,
place the prefix cyclo before the name of the straight-chain alkane that has the same number of
carbon atoms in the ring.

2. Common Name

Common name of ketones are obtained by simply naming the two alkyl groups attached to
the carbonyl group arrange alphabetically and adding the word “ketone”.

IUPAC name = Cylohexanone

Common name = -

Synonyms = 3-cyclohexanone; cyclohexyloxide; Methanone,cyclohexyl-1H-

imidazol-2-yl; 2-cyclohexanone; cyclo-hexanone; 2-Cyclohexancarbonylimidazol

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 PROPERTIES

Properties
Molecular formula C6H10O
Molar mass 98.15 g/mol
Appearance Colorless liquid
Odor Peppermint or acetone-like
Density 0.9478 g/mL, liquid
Melting point −47 °C (−53 °F; 226 K)[5]
Boiling point 155.65 °C (312.17 °F; 428.80 K)
Solubility in water 8.6 g/100 mL (20 °C)
Solubility in all organic solvents Miscible
Vapor pressure 5 mmHg (20°C)[3]
Refractive index (nD) 1.447
Viscosity 2.02 cP at 25 °C[4]

The great majority of cyclohexanone is consumed in the production of precursors to

Nylon 6,6 and Nylon 6. About half of the world's supply is converted to adipic acid, one of two
precursors for nylon 6,6. For this application, the KA oil (see above) is oxidized with nitric acid.
The other half of the cyclohexanone supply is converted to the oxime. In the presence of sulfuric
acidcatalyst, the oxime rearranges to caprolactam, a precursor to nylon 6.

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 QUANTITATIVE AND QUALITATIVE ANALYSIS

1. Quantitative Analysis

 Spektrofotometri


2. Qualitative Analysis

 Tollen Test

 Identification of unknown
 Lucas test
 Chromic Acid Test (Jones Reagent)
 2,4- Dinitrophenylhydrazine test
 Oxidation of Aldehydes
 2,4 – Dinitrophenylhydrazin (2,4- DNP) test for aldehyde or Ketones

A role for solvents in the toxicity of agricultural organophosphorus pesticides.

Organophosphorus (OP) insecticide self-poisoning is responsible for about one-quarterof

global suicides. Treatment focuses on the fact that OP compounds inhibit acetylcholinesterase
(AChE); however, AChE-reactivating drugs do not benefit poisoned humans. We therefore
studied the role of solvent coformulants in OP toxicity in a novel minipig model of agricultural OP
poisoning. Gottingen minipigs were orally poisoned with clinically relevant doses of agricultural
emulsifiable concentrate (EC) dimethoate, dimethoate active ingredient (AI) alone, or solvents.
Cardiorespiratory physiology and neuromuscular (NMJ) function, blood AChE activity, and
arterial lactate concentration were monitored for 12h to assess poisoning severity.

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 Poisoning with agricultural dimethoate EC40, but not saline, caused respiratory arrest
within 30 min, severe distributive shock and NMJ dysfunction, that was similar to human
poisoning. Mean arterial lactate rose to 15.6 [SD 2.8] mM in poisoned pigs compared to 1.4
[0.4] in controls. Moderate toxicity resulted from poisoning with dimethoate AI alone, or the
major solvent cyclohexanone. Combining dimethoate with cyclohexanone reproduced severe
poisoning characteristic of agricultural dimethoate EC poisoning. A formulation without
cyclohexanone showed less mammalian toxicity. These results indicate that solvents play a
crucial role in dimethoate toxicity. Regulatory assessment of pesticide toxicity should include
solvents as well as the AIs which currently dominate the assessment. Reformulation of OP
insecticides to ensure that the agricultural product has lower mammalian toxicity could result in
fewer deaths after suicidal ingestion and rapidly reduce global suicide rates.Copyright © 2012
Elsevier Ireland Ltd. All rights reserved

A method for rapid screening of ketone biotransformations: detection of whole cell Baeyer-
Villiger monooxygenase activity.
1. A method for screening of ketone biotransformations was developed and applied to the
identification of Baeyer-Villigermonooxygenase (BVMO) activity. The method was based
on the formation of a purple coloured product on reaction between an enolizable ketone
and 3,5-dinitrobenzoic acid in an alkaline solution. Absorbance of the colour decreased
with the size of the cycloketone ring. Stoichiometric ratio between cycloketone and 3,5-
dinitrobenzoic acid was 1:1 at maximum absorbance. The method was applied for
monitoring the consumption of cyclohexanone by bacteria under aerobic conditions, and
was found to be potentially useful for both screening assays and quantitative
measurements of BVMO activity. Compared to other existing methods, this method is
faster, cheaper and amenable for whole cell assays.Copyright © 2011 Elsevier Inc. All
rights reserved.

Curcumin and synthetic analogs induce reactive oxygen species and decreases specificity
protein (Sp) transcription factors by targeting microRNAs.
2. Curcumin inhibits growth of several cancer cell lines, and studies in this laboratory in
bladder and pancreatic cancer cells show that curcumindownregulates specificity protein
(Sp) transcription factors Sp1, Sp3 and Sp4 and pro-oncogenic Sp-regulated genes. In
this study, we investigated the anticancer activity of curcumin and several synthetic
cyclohexanone and piperidine analogs in colon cancer cells.The effects of curcumin and
synthetic analogs on colon cancer cell proliferation and apoptosis were determined using
standardized assays. The changes in Sp proteins and Sp-regulated gene products were
analysed by western blots, and real time PCR was used to determine microRNA-27a
(miR-27a), miR-20a, miR-17-5p and ZBTB10 and ZBTB4 mRNA expression.The IC50
(half-maximal) values for growth inhibition (24 hr) of colon cancer cells by curcumin and
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 synthetic cyclohexanone and piperidine analogs of curcumin varied from 10 μM for
curcumin to 0.7 μM for the most active synthetic piperidine analog RL197, which was
used along with curcumin as model agents in this study. Curcumin and RL197 inhibited
RKO and SW480 colon cancer cell growth and induced apoptosis, and this was
accompanied by downregulation of specificity protein (Sp) transcription factors Sp1, Sp3
and Sp4 and Sp-regulated genes including the epidermal growth factor receptor (EGFR),
hepatocyte growth factor receptor (c-MET), survivin, bcl-2, cyclin D1 and NFκB (p65 and
p50). Curcumin and RL197 also induced reactive oxygen species (ROS), and
cotreatment with the antioxidant glutathione significantly attenuated curcumin- and
RL197-induced growth inhibition and downregulation of Sp1, Sp3, Sp4 and Sp-regulated
genes. The mechanism of curcumin-/RL197-induced repression of Sp transcription
factors was ROS-dependent and due to induction of the Sp repressors ZBTB10 and
ZBTB4 and downregulation of microRNAs (miR)-27a, miR-20a and miR-17-5p that
regulate these repressors.These results identify a new and highly potent curcumin
derivative and demonstrate that in cells where curcumin and RL197 induce ROS, an
important underlying mechanism of action involves perturbation of miR-ZBTB10/ZBTB4,
resulting in the induction of these repressors which downregulateSp transcription factors
and Sp-regulated genes

Hydromorphone metabolites: isolation and identification from pooled urine samples of a cancer
patient.
3. 1. Hydromorphone-3-glucuronide, dihydromorphine, dihydroisomorphine,
dihydromorphine-3-glucuronide and dihydroisomorphine-3-glucuronide were isolated
from a cancer patient's urine and identified as metabolites of hydromorphone by
comparison with synthetic standards using LC/MS/MS with gradient elution. 2. The
relative urinary recovery of dihydroisomorphine-3-glucuronide was estimated to be 17-
fold higher than previously reported. 3. Three new metabolites, including
hydromorphone-3-sulphate, norhydromorphone and nordihydroisomorphine, were
tentatively identified.

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 PREPARATION
1. Oxidation Reactions of Alcohols

Simple 1º and 2º-alcohols in the gaseous state lose hydrogen when exposed to a hot copper
surface. This catalytic dehydrogenation reaction produces aldehydes (as shown below) and
ketones, and since the carbon atom bonded to the oxygen is oxidized, such alcohol to carbonyl
conversions are generally referred to as oxidation reactions. Gas phase dehydrogenations of
this kind are important in chemical manufacturing, but rare to see in the research laboratory.
Instead, alcohol oxidations are carried out in solution, using reactions in which the hydroxyl
hydrogen is replaced by an atom or group that is readily eliminated together with the alpha-
hydrogen. The decomposition of 1º and 2º-alkyl hypochlorites, referred to earlier, is an example
of such a reaction.

RCH2–OH + hot Cu RCH=O + H2

RCH2–O–Cl + base RCH=O + H–Cl

The most generally useful reagents for oxidizing 1º and 2º-alcohols are chromic acid
derivatives. Two such oxidants are Jones reagent (a solution of sodium dichromate in aqueous
sulfuric acid) and pyridinium chlorochromate, C5H5NH(+)CrO3Cl(–), commonly named by the
acronym PCC and used in methylene chloride solution. In each case a chromate ester of the
alcohol substrate is believed to be an intermediate, which undergoes an E2-like elimination to
the carbonyl product. The oxidation state of carbon increases by 2, while the chromium
decreases by 3 (it is reduced). Since chromate reagents are a dark orange-red color (VI
oxidation state) and chromium III compounds are normally green, the progress of these
oxidations is easily observed. Indeed, this is the chemical transformation on which the
Breathalyzer test is based.

The following equations illustrate some oxidations of alcohols, using the two reagents
defined here. Both reagents effect the oxidation of 2º-alcohols to ketones, but the outcome of
1º-alcohol oxidations is different. Oxidation with the PCC reagent converts 1º-alcohols to
aldehydes; whereas Jones reagent continues the oxidation to the carboxylic acid product, as
shown in the second reaction. Reaction mechanisms for these transformations are displayed on
clicking the "Show Mechanism" button. For the first two reactions the mechanism diagram also
shows the oxidation states of carbon (blue Arabic numbers) and chromium (Roman numbers).
The general base (B:) used in these mechanisms may be anything from water to pyridine,
depending on the specific reaction.

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Two structural requirements for the oxidation to carbonyl products should now be obvious:

1. The carbon atom bonded to oxygen must also bear a hydrogen atom. Tertiary alcohols
(R3C–OH) cannot be oxidized in this fashion.

2. The oxygen atom must be bonded to a hydrogen atom so that a chromate ester
intermediate (or other suitable leaving group) may be formed. Ethers (R–O–R) cannot be
oxidized in this fashion.

The fourth reaction above illustrates the failure of 3º-alcohols to undergo oxidation. The
second reaction mechanism explains why 1º-alcohols undergo further oxidation by Jones
reagent. The aqueous solvent system used with this reagent permits hydration (addition of
water) to the aldehyde carbonyl group. The resulting hydrate (structure shown below the
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aldehyde) meets both the requirements stated above, and is further oxidized by the same
chromate ester mechanism. Water is not present when the PCC reagent is used, so the
oxidationstops at the aldehyde stage.

Another chromate oxidizing agent, similar to PCC, is pyridinium dichromate, (C5H5NH(+) )2

Cr2O7(–2), known by the acronym PDC. Both PCC and PDC are orange crystalline solids that are
soluble in many organic solvents. Since PDC is less acidic than PCC it is often used to oxidize
alcohols that may be sensitive to acids. In methylene chloride solution, PDC oxidizes 1º- and 2º-
alcohols in roughly the same fashion as PCC, but much more slowly. However, in DMF solution
saturated 1º-alcohols are oxidized to carboxylic acids. In both solvents allylic alcohols are
oxidized efficiently to conjugated enals and enones respectively.

Characteristics of Specific Substitution ReactionsThe conditions commonly used for the

aromatic substitution reactions discussed in the table below.

Halogenation: C6H6 + Cl2& heat ——> C6H5Cl + HCl

FeCl3 catalyst Chlorobenzene

Nitration: C6H6 + HNO3& heat ——> C6H5NO2 + H2O

H2SO4 catalyst Nitrobenzene

Sulfonation: C6H6 + H2SO4 + SO3 ——> C6H5SO3H + H2O

& heat Benzenesulfonic acid

Alkylation: C6H6 + R-Cl & heat ——> C6H5-R + HCl

Friedel-Crafts AlCl3 catalyst An Arene

Acylation: C6H6 + RCOCl & heat ——> C6H5COR + HCl

Friedel-Crafts AlCl3 catalyst An Aryl Ketone

The electrophilic reactivity of these different reagents varies. We find, for example, that
nitration of nitrobenzene occurs smoothly at 95 ºC, giving meta-dinitrobenzene, whereas
bromination of nitrobenzene (ferric catalyst) requires a temperature of 140 ºC. Also, as noted
earlier, toluene undergoes nitration about 25 times faster than benzene, but chlorination of
toluene is over 500 times faster than that of benzene. From this we may conclude that the

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nitration reagent is more reactive and less selective than the halogenation reagents.
Both sulfonation and nitration yield water as a by-product. This does not significantly affect the
nitration reaction (note the presence of sulfuric acid as a dehydrating agent), but sulfonation is
reversible and is driven to completion by addition of sulfur trioxide, which converts the water to
sulfuric acid. The reversibility of the sulfonation reaction is occasionally useful for removing this
functionalgroup.

The Friedel-Crafts acylation reagent is normally composed of an acyl halide or anhydride

mixed with a Lewis acid catalyst such as AlCl3. This produces an acylium cation, R-C≡O(+), or a
related species. Such electrophiles are not exceptionally reactive, so the acylation reaction is
generally restricted to aromatic systems that are at least as reactive as chlorobenzene. Carbon
disulfide is often used as a solvent, since it is unreactive and is easily removed from the
product. If the substrate is a very reactive benzene derivative, such as anisole, carboxylic esters
or acids may be the source of the acylating electrophile. Some examples of Friedel-Crafts
acylation reactions are shown in the following diagram. The first demonstrates that unusual
acylating agents may be used as reactants.

The second makes use of an anhydride acylating reagent, and the third illustrates the
ease with which anisole reacts, as noted earlier. The H4P2O7 reagent used here is an anhydride
of phosphoric acid called pyrophosphoric acid. Finally, the fourth example illustrates several
important points. Since the nitro group is a powerful deactivating substituent, Friedel-Crafts
acylation of nitrobenzene does not take place under any conditions. However, the presence of a
second strongly-activating substituent group permits acylation; the site of reaction is that
favored by both substituents.

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 A common characteristic of the halogenation, nitration, sulfonation and acylation
reactions is that they introduce a deactivating substituent on the benzene ring. As a result, we
do not normally have to worry about disubstitution products being formed. Friedel-Crafts
alkylation, on the other hand, introduces an activating substituent (an alkyl group), so more than
one substitution may take place. If benzene is to be alkylated, as in the following synthesis of
tert-butylbenzene, the mono-alkylated product is favored by using a large excess of this
reactant. When the molar ratio of benzene to alkyl halide falls below 1:1, para-ditert-
butylbenzene becomes the major product.

C6H6 (large excess) + (CH3)3C-Cl + AlCl3 ——> C6H5-C(CH3)3 + HCl

The carbocation electrophiles required for alkylation may be generated from alkyl halides (as
above), alkenes + strong acid or alcohols + strong acid. Since 1º-carbocations are prone to
rearrangement, it is usually not possible to introduce 1º-alkyl substituents larger than ethyl by
Friedel-Crafts alkylation. For example, reaction of excess benzene with 1-chloropropane and
aluminum chloride gives a good yield of isopropylbenzene (cumene).

C6H6 (large excess) + CH3CH2CH2-Cl + AlCl3 ——> C6H5-CH(CH3)2 + HCl

Additional examples of Friedel-Crafts alkylation reactions are shown in the following diagram.

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 The first and third examples show how alkenes and alcohols may be the source of the
electrophilic carbocation reactant. The triphenylmethyl cation generated in the third case is
relatively unreactive, due to extensive resonance charge delocalization, and only substitutes
highly activated aromatic rings. The second example shows an interesting case in which a
polychlororeactant is used as the alkylating agent. A four fold excess of carbon tetrachloride is
used to avoid tri-alkylation of this reagent, a process that is retarded by steric hindrance. The
fourth example illustrates the poor orientational selectivity often found in alkylation reactions of
activated benzene rings. The bulky tert-butyl group ends up attached to the reactive meta-
xylene ring at the least hindered site. This may not be the site of initial bonding, since
polyalkylbenzenes rearrange under Friedel-Crafts conditions (para-dipropylbenzene rearranges
to meta-dipropylbenzene on heating with AlCl3).

A practical concern in the use of electrophilic aromatic substitution reactions in synthesis

is the separation of isomer mixtures. This is particularly true for cases of ortho-para substitution,
which often produce significant amounts of the minor isomer. As a rule, para-isomers
predominate except for some reactions of toluene and related alkyl benzenes. Separation of
these mixtures is aided by the fact that para-isomers have significantly higher melting points
than their ortho counterparts; consequently, fractional crystallization is often an effective
isolation technique. Since meta-substitution favors a single product, separation of trace isomers
is normally not a problem.

2. The preparation of cyclohexanone from cyclohexanol.

This preparation shows that a ketone can be prepared by the oxidation of a secondary
alcohol. In a similar way, an aldehyde can be prepared from a primary alcohol, but since
aldehydes are easily oxidised further to carboxylic acids, they must be distilled off from the
reaction mixture as formed.

RCH2OH  RCHO  RCO2H

(primary alcohol) (aldehyde) (acid)

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Procedure:

1. Dissolve sodium dichromate dihydrate (12.5 g) in water (60 mL) in a 100 mL beaker and
with continuous stirring with a glass rod (Do not stir the mixture with your thermometer),
carefully and slowly add concentrated sulfuric acid (11 g, 6 mL). Allow the mixture to
cool.
2. Place cyclohexanol (6 g, density 0.96 g cm-3) in a 100 mL conical flask and add the
dichromate solution to it in one portion, with swirling to ensure thorough mixing.
3. When the temperature rises to 55 C, cool the flask in cold water; sufficient external
cooling should be applied to keep the temperature between 55 and 60 C.
4. When the mixture no longer heats up, allow to stand, with occasional swirling, for 1 hour.
5. Pour the mixture into a 250 mL round bottom flask, add water (60 mL).
6. Set up a distillation apparatus (but with a stopper instead of a thermometer and a 100
mL graduated cylinder to collect the distillate).
7. Distil the mixture using a Bunsen burner until about 30 mL of distillate (two layers) has
been collected.
8. Transfer to an Erlenmeyer flask and saturate with salt (about 7 g).
9. Separate the layer of cyclohexanone in a separatory funnel.
10. Extract the aqueous layer twice with ethyl acetate (10 mL). Combine the ethyl acetate
extracts with the cyclohexanone layer. Dry with anhydrous magnesium sulfate (5 min)
and filter into a pre-weighed dry 50 mL RB flask.
11. Distil off the ethyl acetate, b.p. 77 C, using a distillation apparatus set up on a steam
bath.
12. This leaves the cyclohexanone (b.p. 153 - 156 C) in the flask. Determine the weight of
the product.
13. Before discarding your dark green chromium (III) sulfate solution down the sink, add 2
mL ethanol and swirl.

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 THE USEFULNESS IN DAILY LIFE

The great majority of cyclohexanone is consumed in the production of precursors to

Nylon 6,6 and Nylon 6. About half of the world's supply is converted to adipic acid, one of two
precursors for nylon 6,6. For this application, the KA oil (see above) is oxidized with nitric acid.
The other half of the cyclohexanone supply is converted to the oxime. In the presence of sulfuric
acid catalyst, the oxime rearranges to caprolactam, a precursor to nylon 6.

Industry Application
Industry Application
Synthetic Fibre Most important raw material in manufacture of
Caprolactam and adipic acid
Coating As solvent and thinner for lacquers containing
NC, methacrylate ester and PVC polymers
Polymer As solvent in phenolic resins mfr
Agrochemicals Preferred solvent for DDC and formulations of
organophosphorous agrochemicals
Aviation As sludge solvent in air-turbine fuel
Pharma Key raw material in manufacture of
monomethylcyclohexylamine,
dimethylcyclohexylamine (which are
intermediates for ibuprofen)
Wax As solvent in manufacture of waxes and shellac
Waxes
Process and Manufacturing In mfr of 2,4-Dinitrophenylhydrazone

Page 18 of 23
 RELATED SEARCHES

1. Catalyst promotes the air oxidation of olefins to ketones.

A catalytic air oxidation of an olefin directly to a ketone would be an important development

for the petrochemical industry. Whereas oxidizing ethylene to acetaldehyde via the Wacker
process is a well-known direct catalytic oxidation process, similar methods for directly
manufacturing ketones in one step from the corresponding olefin have eluded
commercialization.

R. Glaser and colleagues found a catalyst system that can convert olefins to ketones in
good conversion and selectivity. The model used by the inventors is the conversion of
cyclohexene to cyclohexanone, a precursor to adipic acid and caprolactam. The conventional
routes to cyclohexanone are cyclohexane oxidation and phenol hydrogenation. The
cyclohexane route is not very selective, and the phenol route uses a costly starting material.

The disclosed catalyst system is based on a mixture of Pd(OAc)2 and a heteropolyacid

encapsulated in mesoporous silicate MCM-41. In one example, the catalyst consists of 10 wt%
Pd(OAc)2 and 15 wt% ammonium molybdovanadophosphate in MCM-41). A mixture of 2 mmol
cyclohexene, 4.5 mL MeCN, 0.5 mL H2O, 38 mg p-toluenesulfonic acid, and 100 mg of the
catalyst mixture is charged into a glass tube that is inserted into an autoclave. The autoclave is
pressurized with 2 MPa of air at 50 °C for 6 h. Cyclohexene conversion is 96.7%, and selectivity
to cyclohexanone is 94.0%.

One of the challenges for this route to cyclohexanone will be to find a cost-effective way to
convert benzene to cyclohexene. (Sumitomo Chemical [Tokyo]. US Patent 7,939,692, May 10,
2011; Jeffrey S. Plotkin)

2. Use less catalyst to make a commercial fungicide.

Azoxystrobin (3) belongs to a group of fungicides known as strobilurins that, ironically, are
found in the wood-rotting fungus Strobilurus tenacellus. A published method for preparing 3
uses as much as 20% DABCO (diazabicyclo[2.2.2]octane) as the catalyst. Inventors A. J.
Whitton, E.C. Boyd, and J. Vass note that this reagent is expensive and that an improved
process would be desirable.

Page 19 of 23
 The inventors describe a process that produces 3 by coupling o-cyanophenol (1) and
pyrimidine derivative 2 with <2% DABCO catalyst. K2CO3 is also present in the reaction mixture
to form the potassium salt of 1. The preferred solvent is DMF, but other solvents—such as
methyl isobutyl ketone, cyclohexanone, i-PrOAc, and EtN-i-Pr2—are also usable. The yield of
product 3, as a 43.6 wt% solution in toluene, is 98.7%; the inventors do not disclose the details
for recovering the pure material. The authors obtained pyrimidine 2 by using a process
described in WO 92/08703 (1992), but there are no details in the current patent.

The inventors give examples that show the effect of DABCO concentration on reaction
time and the recovered yield of 3. Without DABCO, the yield is 86.6%; it increases to 98.7%
with 1% DABCO catalyst, and it falls slightly to 97.5% with 2% DABCO. The reaction time is 8 h
without DABCO and decreases to 1 h with 1 or 2% DABCO. Experiments to assess the effect of
order of addition of the reagents showed that the yield improves if DABCO is the last
component added.

The inventors report that 3 can also be prepared by the reaction of 1 with acetal 4, as
shown in Figure 2. This example actually describes a reaction between 1 and a mixture of 2 and
Page 20 of 23
4 that produces a mixture of 3 and azoxystrobin derivative 5. The proportion of 3 in the mixture
is higher than might be expected from the relative amounts of 2 and 4 because 5 loses MeOH
to form 3. From a mixture of 2 and 4 that contains 12.4% 4, the product is a cyclohexanone
solution that contains 27% 3 and 73% 5. MeOH can be eliminated from 5 to give 3 by treating it
with methanesulfonic acid (MsOH) and Ac2O, but the inventors give few details.

Another option for preparing 3 is the reaction of cyanophenoxypyrimidine 6 and phenol

derivative 7 shown in Figure 3. Unfortunately, no examples in the patent describe this
procedure. The inventors do, however, describe the preparation of 7, also shown in Figure 3.

The starting material for 7 is 8, which the inventors prepared by a method reported in GB
Patent 2,291,874 (1996), but they do not include any details in the current patent. The first step
in preparing 7 is protecting the hydroxyl group in 8 with BnBr to give compound 9, recovered in
57% yield. Treating 9 with Ac2O in the presence of methanesulfonic acid (MsOH) eliminates
MeOH to produce compound 10. Mixing the product mixture with toluene isolates the product;
evaporating the toluene leaves crystalline 10 in 44% yield.

In the final step, catalytic hydrogenation over Pd/C removes the benzyl protecting group.
The product is an oil that crystallizes on standing; its yield is not reported. The inventors provide
1
H NMR data for compounds 5, 7, 9, and 10. (Syngenta [Guildford, UK]. US Patent 8,124,761,
Feb. 28, 2012; Keith Turner)

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 REFERENCES

http://en.wikipedia.org/wiki/Cyclohexanone

http://chemicalland21.com/industrialchem/solalc/CYCLOHEXANONE.htm

http://perpustakaancyber.blogspot.com/2013/09/pengertian-keton-sifat-kegunaan-isomer-
sintesis.html

http://wwwchem.uwimona.edu.jm/lab_manuals/c10expt21.html

http://www.acs.org/content/acs/en/patent-watch/2011-archive/may-23-2011.html

http://www.sigmaaldrich.com/catalog/product/fluka/68809?lang=en&region=ID

http://en.wikipedia.org/wiki/Nylon

http://www.irochemical.com/product/Solvents/CYCLOHEXANONE.htm

https://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/aldket1.htm

https://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/benzrx1.htm#benz7

https://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/alcohol2.htm#alcrx4

http://www.acs.org/content/acs/en/patent-watch/2012-archive/patent-watch-april-16-2012.html

Rusman, M.Si, RiandariDwika, M.Si, 2014, Organic Chemistry, Bogor; SMK-SMAK Bogor.

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