Reduction of CamphorSynthetic FFR #2

Kevin Chen12/5/13

Chem 213Section #101

TA: Michael Banales

Introduction

This synthesis is significant because of both the compounds and the reactions that it

involves. The starting material, camphor, has been used for centuries in religious ceremonies as a

symbol of consciousness and in traditional Chinese medicine to help reduce pain.1 Research has

focused on camphor’s mechanisms of action and safety.

One of the most notable effects of camphor in lotions is its cooling effect, which is

similar to menthol. Researchers have attributed this effect to its action on transient receptor

potential melastatin 8 (TRPM8), a Ca+ activated receptor responsible for sensation of cold.2 In

addition, camphor appears to block the irritant receptor, TRPA1, and the pain receptor, TRPV1,

which explains its anti-itch and analgesic effects.3

Recent studies of camphor have also determined its toxicity. Pediatric journals report

severe neurotoxicity after accidental camphor ingestion by small children.4 Symptoms include

nausea, dizziness, hallucinations, and seizures, with neurotoxic effects occurring after 50mg/kg

oral ingestion. Hepatic and renal damage can also occur. Because of these negative health

effects, the FDA limits concentration of camphor in products to 11%, and recommends

alternative products for medicinal purposes.5

Camphor is also incredibly significant to the plastics industry because it is used as

starting material for creating celluloid, which is considered the first thermoplastic.

Thermoplastics are easily molded at high temperatures and become solid upon cooling, making

celluloid a historical step in materials science. Camphor has continued to be used as a plasticizer

for cellulose nitrate and laquers.6

Borneol and isoborneol are much less prevalent compounds, but they still have

significant uses in biology and chemistry. Researchers are still trying to determine the biological

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activity of borneol. Borneol seems to increase the activity of blood-brain barrier transporters,

making it easier for substances to enter and leave the brain.7 After oral administration to mice,

concentrations of excitatory neurotransmitters increase, although the effects of this are

unknown.8 Because of the difference in chirality between borneol and isoborneol, the compounds

are commonly used as ligands in asymmetric synthesis.9 This makes them and reactions that

produce them useful to organic chemists.

Oxidation and reduction reactions are an essential step in many, if not most, organic

syntheses. Many biochemical processes, such as metabolism and photosynthesis, rely on redox

reactions, as do industrial processes, such as running battery cells and extracting pure metals

from ores.

In this case, conversion to the desired secondary alcohol is done through reduction of a

ketone. The two most popular reducing agents are lithium aluminum hydride, and sodium

borohydride. This reaction utilizes the less reactive, safer reagent, sodium borohydride. Sodium

borohydride can react with only ketones and aldehydes, while lithium aluminum hydride can

react with esters, aldehydes, ketones, amides, and carboxylic acid. The mechanism of reduction

of sodium borohydride to borneol/isoborneol using sodium borohydride is shown in Scheme 1.

Scheme 1: Mechanism of sodium borohydride reduction of camphor to borneol and isoborneol.

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First, a hydride from sodium borohydride attacks the carbonyl carbon of the ketone,

driving the double bond electrons to become an oxygen lone pair and giving the oxygen a

negative charge. The hydride can attack from two different directions, forcing the oxygen atom

towards either the 3-carbon or 4-carbon ring. This results in the production of two isomers. The

exo isomer, isoborneol, has its oxygen closer to the 3-carbon ring, while the endo isomer,

borneol, has its oxygen closer to the 4-carbon ring. Electrons on the oxygen bond with a proton

from methanol, resulting in the desired alcohol.

The purpose of this lab was to synthesize and purify borneol and isoborneol through the

use of the sodium borohydride reagent. Products from this synthesis were then analyzed using

melting point determination, IR, NMR, GC, and GC-MS. Organic chemists could find this

reaction useful because camphor and borneol are important components of drugs and chemical

processes. They both have potent biological effects and merit further research.

ExperimentalIsoborneol/Borneol. Camphor (200mg), methanol (5 mL), and sodium borohydride (.120g)

were combined. The mixture was refluxed for 30 minutes. Ice water (3.5 mL) was added to the

beaker and the white, solid product was then removed using vacuum filtration. The product

(47mg, 23.26%) was allowed to dry for several days.

Melting Point: 210-213°C

GC (40-250°C, 10°C/min) GC, from GC-MS (40-250°C, 10°C/min)RT % Composition

9.27 55.53%

9.38 9.32%

18.11 9.55%

19.72 10.94%

22.91 14.67%

MS

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RT % Composition

13.30 88.64%

13.45 11.36%

Compound Major Peaks Molecular Mass (literature)Borneol 40.93, 66.95, 94.95, 109.95,

153.97154.249 g/mol

Isoborneol 40.99, 66.99, 94.95, 109.91 154.249 g/mol

IRPeak Position (cm-1) Functional Groups3335.99 R - OH

2946.81, 2875.44 R3 - CH

1452.89 R2 – CH2

1366.58 R – CH3

1302.01 R2 – C(CH3)2

1105.99 CO - H

NMRPeak Position (PPM) Integral Value

.8 7.27

1.1 3.00

1.7 5.15

3.6 0.50

Results/DiscussionThe synthesis of borneol and isoborneol was achieved by reacting sodium borohydride

with camphor. The carbonyl carbon of camphor was attacked by a hydride from sodium

borohydride, ultimately resulting in conversion of the ketone to an alcohol. The two directions of

attack created products of differing chirality, with isoborneol as the endo isomer and borneol as

the exo isomer. Because of steric hindrance from the two axial C-C bonds and two methyl

groups, the exo isomer, borneol, is less common. The identities of the products were confirmed

with melting point, IR, NMR, GC, and GC-MS.

The experimental melting point compares favorably with the literature value. The value

recorded was 210-213°C, while the literature value is 205-210°C for borneol and 214°C for

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isoborneol. The small discrepancy in melting point could imply small amounts of contaminants,

but melting point determination may also have been inaccurate because isoborneol decomposes

instead of melting. This characteristic was reproduced in the lab, as the sample turned brown and

lost mass.

The IR provides strong evidence that the intended product was created. The most

significant peak of this spectrum appears at 3335.99 PPM. The major change of the reaction is

conversion of a ketone to an alcohol, and this peak’s downfield position and broad shape are

characteristic of an alcohol. Importantly, there is no peak at 1715 PPM corresponding to a

ketone, meaning that the collected solids are free of starting material. Other peaks agreed with

the structure of borneol/isoborneol, including peaks at 2946.81, 2875.44, 1452.89, and 1366.58

PPM corresponding to various C-H bonds, a peak at 1366.58 PPM corresponding to a C(CH3)2

group, and a peak at 1105.99 PPM corresponding to the hydroxyl’s C-O bond.

NMR data supports correct product formation, but is less convincing. A weak, .5 integral

value peak appears at 3.6. This would not be possible if the alcohol were not formed. Remaining

peaks at .8, 1.1, and 1.7 appear to mostly correlate with the structure, but the sheer number of

chemically distinct hydrogen atoms made interpreting the spectrum difficult.

The two GC analyses varied widely, with one implying major impurities and the other

finding the sample almost completely pure. The initial GC obtained values that did not align with

the compendium, but did agree relatively. Isoborneol accounted for 55.53% with a peak at 9.27

and borneol accounted for 9.32% with a peak at 9.38. Unknown contaminant peaks at 18.11,

19.72, and 22.91 accounted for the remaining 35.16%.

However, this data appears to be in error because the second, more accurate GC finds a

completely pure sample with an isoborneol peak 13.30 and 88.64% and a borneol peak at 13.45

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and 11.36%. In addition, the IR spectrum found no contaminants. One possible error that could

have occurred while running the first GC was inadequate cleaning of the microliter syringe. This

would have introduced several contaminants into the sample which would not have appeared in

the second GC. However, both GC’s ultimately indicate that at least some desired product was

synthesized, and that isoborneol was formed in greater concentrations, which was expected.

The MS confirms the identities of the compounds. Software utilized the MS data to

identify the two compounds as isoborneol and borneol. Manual assignment of MS peaks also

found structures fit spectrums well. Key peaks for isoborneol included a three carbon chain of

the containing the two methyl groups at 40.93 m/z, the three carbon ring plus the two methyl

groups at 66.95 m/z, the half of the molecule containing alcohol at 94.95 m/z, the other half of

the molecule at 109.95 m/z, and the molecular ion at 153.97 m/z. Because the structures are

almost identical, borneol produced a MS analysis with the same peaks.

Compared to literature values, the percent yield was low, at 23.26%. However, one

literature value did fall close at 24.55%.10 Other values ranged from 72% to 80.58%.11,12 This

data implies that the percent yield for this reduction is highly variable, but also that the approach

could have been flawed. The percent yield would likely have improved if work-up had followed

an extraction/evaporation strategy, as opposed to precipitation/filtration. Keeping the product

solid was difficult, and a significant amount could have been lost in solution during filtration.

Redox reactions are common within the human body, meaning that this reaction is of

biological significance. In addition, camphor and borneol have several biological and industrial

applications. This synthesis was successful at producing pure product, but was inefficient.

References1. Congren, J. Faming Zhuanli Shenqing. 2013, Peop. Rep. China Patent 103393776.

2. Selescu T. et al. Chem. Senses. 2013, 38, 563-75.

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3. Vetter, I. et al. The Journal of Neuroscience. 2013, 33, 16627-16641.

4. Michiels E.; Mazor S. Pediatr Emerg Care. 2010, 26, 574-5.

5. Sahana K.; Rajiv D. Indian Pediatr. 2012, 49, 841-2.

6. Reilly, J. Journal of the American Institute for Conservation. 1991, 30, 145-162.

7. Chen, Z. et al. Int. J. Pharm. 2013, 456, 73-9.

8. Li, W. et al. Eur J Drug Metab Pharmacokinet. 2012, 37, 39-44.

9. Chen Y. et al. Organic Syntheses, 2009, 82, 87-92.

10. Wang, N. et al. Huaqiao Daxue Xuebao, Ziran Kexueban, 2006, 27, 89-91.

11. Zhao, P. et al. Huaqiao Daxue Xuebao, Ziran Kexueban, 2010, 31, 671-673.

12. Zhao, P. et al. Huaqiao Daxue Xuebao, Ziran Kexueban, 2011, 32, 188-190.

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