香精香料英文资料

The Chemistry of Perfumes:

From Discovery to Synthesis

Literature Seminar

Lensey Hill

April 18th, 2006

Introduction:

One of the most interesting aspects of fragrance chemistry is its ability to incorporate

several different areas of chemistry in its investigations.1 Most perfumists can be considered

artists in the preparation of fragrances, combining an almost fantastical creativity with the

knowledge found in areas such as analytical, synthetic, and physical chemistry. With the advent

of new technologies, the fragrance industry has developed in the last 100 years towards a highly

synthetic area of industrial chemistry.2 With interruptions of extraction natural products

including weather, disease, politics, and economics, synthetic products in industry are much

more favorable.3 A comprehensive review of this subject could in fact fill volumes of books and

a large portion of this information will not be presented. The purpose of the paper is to explore

the mechanism for sensing fragrant molecules in the body, the use of gas chromatography and

mass spectrometry in determining fragrant components, and several examples of synthesizing

popular fragrant molecules.

Historical Significance:

One of the most prolific discoveries in the antiquity era that led to what today is known

as fragrance chemistry, was the burning of natural salves and oils to produce incense. This act

was preformed as a token of esteem to gods through out many years from the Egyptian to Greek

periods.2

The use of natural products to produce aromas has escalated from worship practices to

a booming industry still in use today. The transformation of incense has evolved as the

knowledge from alchemists to chemists has evolved. From the antiquity era to the renaissance

era, perfumes were composed strictly of uncharacterized aromatic compounds of flowers and

barks of trees. The first synthetic fragrant compounds were developed in the mid 1800’s.2 When

chemists discovered that compounds could be synthesized in the lab, the art of perfumery took

2

on a whole new perspective. In the mid to late 20th century, the use of gas chromatography and

mass spectrometry led to the structural characterization of many fragrant components. With this

technology, chemists could synthesize the products which would eliminate natural product

extraction and reduce cost for certain fragrant components.2 Recently an interesting focus has

been placed upon the mechanism by which odorant molecules are recognized in the brain.

Scientists hope that by understanding this biological process, new advances in the fragrance

industry can be brought about.2

It wasn’t until the last several decades that the actual mechanism for the sense of smells

in the human body began to be investigated.4 Though still not completely understood, the

olfactory system has led to the resolution of many new biological compounds and their functions

in many mammalian species.

The Olfactory System:

The olfactory system is located in the nose of humans on the roof of the two nasal

cavities and is responsible for the recognition of over a thousand different odorant molecules.4

The purpose of this system is to bind odorant molecules to receptor sites that upon bonding

release information that is ultimately carried to the brain to trigger the sense of smell. Odorant

molecules must exhibit several properties for this process to occur. They must exhibit high

vapor pressure, low polarity, surface activity, water solubility, and lipophilicity.4 The strength of

this system allows for many odorants to be detected and distinguished at relatively low

concentrations. The size of the olfactory region in humans is approximately 2.5 cm2 and

encompasses roughly 50 million primary sensory receptor cells. Figures 1 and 2 represent the

locations and composition of the olfactory system, respectively.

3

Figure 1: Location of the Olfactory System in the Human Brain

: Picture taken from

reference 4.

Figure 2: The Olfactory System: Picture taken from reference 4.

The mechanism by which the odorant molecules activate the recognition to the brain is

still currently under investigation. The suggested pathway will be discussed in the seminar to

follow. Now that the olfactory system has been introduced, several types of fragrant molecules

and their synthesis can be discussed.

4,5

4

Common Types of Fragrant Molecules:

Since the structural discovery of fragrant compounds, several classes of molecules have

emerged. Ironically, not all compounds making up perfumes are pleasant smelling. Often times

the molecules have wood and musk-like odors, but when combined with other fragrant

components a pleasant fragrant perfume is developed. The compounds are divided into roughly

twenty categories of aromas.2 Listed in Table 1 are just are several classes of molecules used in

perfume synthesis.1

The volatility of many of the components are used to create the fragrance by

way of layers or notes.2 Most perfumes consist of three notes; the top, heart, and base. Top

notes are essentially responsible for the initial smell of perfumes and are typically the most

volatile compounds. The heart note contains the common components that have some volatility

and are responsible for the main aroma of the fragrance, generally lasting several hours. Base

notes contain the least volatile compounds and have aromas lasting most of the day.6

Table 1

Odorant

Amber

H

(-) -Ambrox

Woody

OSide Product of Iso E Super

TimberolExample 1

OExample 2

OOKaranalOH

5

Sandlewood

OHOH(Z)-(-)-ß-santalol

PolysantolNO2

Musk

OMuscone

O2NNO2

Musk xylolOFloral

ß-damascenone

ORose Oxide

Fragrance compounds may be placed into three categories, natural, identical, and

artificial. Most often artificial compounds mimic those of their natural product counterparts.2

Some of the first synthetic components were developed in the 19th century, among these were

vanillin, coumarin, and salicylaldehyde.1 It was later discovered that replacing the methoxy

group of vanillin (Figure 3) with an ethoxy group increased the strength of the odor, allowing for

a decrease in the amount used in perfumes also resulting in a lowering of cost.1 Many small

changes in the structure of components like the one mentioned above may result in odor

intensification by several orders of magnitude.2 These findings helped escalate the synthetic

industry and are the current basis for research in the fragrance industry today. The next section

shows several examples of synthetic routes used in current research.

6

CHOHOOMeVanillinHOOEtCHOEthyl-Vanillin

Figure 3

Synthesis of Fragrant Molecules:

Because synthetic products are used in fragrances today just as much as natural products,

synthetic chemistry will be the main focus of attention of this literature review. Referring back

to Table 1, it may be noted that many of the fragrant molecules have multiple stereocenters. The

synthesis of one isomer has proven to be a very difficult task to overcome with the generation of

multiple products resulting from several stereocenters. However, in 1991 Paquette synthesized (-)-9-epi-Ambrox (Scheme 1), a stereoisomer of Ambrox found in Table 1. Though not a

fragrance chemist, Paquette was interested in the use of the oxy-Cope rearrangement and current

synthetic methods to isolate a single isomer.7 To generate the rearrangement active species, the

bicyclic ketone

1 was treated with dihydrofuranyl lithium to afford the oxy-cope starting material

2. This compound then rearranged to give the corresponding enolate that reacted with

phenylselenyl chloride to give

3. Product

4

was generated by the removal of the phenyl

selenium group to provide the desired double bond followed by alkylation with methyl iodide

and LDA. NaBH4 was then used to reduce the ketone to alcohol

5. The metal catalyst palladium

was used to reduce all double bonds in the molecule to afford product

6, which was

dehydroxylated to afford the desired

epi-Ambrox

7.7

7

O1OHOTHF-7866%LiHOO21. KH, THF2. PhSeCl-78OOPhSeOO3OOH1. NaIO42. LDA3. MeIOH6OHNaBH4CeCl3MeOH5OSePh45% Pd-CH2, EtOAc1. NaH, CS2; CH3I2. (Me3Si)3SiH AIBN , C6H6OH7(-)-9-epi-Ambrox

Scheme 1: Synthesis of (-)-9-epi-Ambrox

Another interesting molecule (Figure 4) that has drawn much attention in the synthetic

industry is Galaxolide (1,1,2,3,3,8-hexamethyl-1,2,3,5,7,8-hexahydro-6-oxacyclopental[b]naphthalene).8 It is observed that the molecule has two possible stereogenic

centers. Frater and co-workers were able to develop synthetic routes to four different

stereoisomers.9 They also determined that the (8S,2S)- and (8S,2R)- diastereomers were

responsible for the strong musky odor and that the other two isomers gave no smell. The major

disadvantage of the synthesis was that it was not applicable on an industrial scale. Scrivanti and

co-workers developed a synthetic route to the desired diastereomers that was more industrially

friendly (Scheme 2).10

82GalaxolideFigure 5

8

O

To begin, KBrO3 is added to pentamethylindane

1 to afford the brominated product

2. A

cross coupling reaction of the brominated product with a palladium catalyst and CuI resulted in

the protected alkyne containing the tertiary hydroxyl substituent

3. Addition of KOH resulted in

the deprotection of the alkyne

4. Next, Pd(OAc)2 was used in conjunction with CO and water to

hydrocarbonylate the alkyne

5. A Ru-Binap catalyst is then used to asymmetrically hydrogenate

the double bond adjacent to the carboxylic acid group

6. The enatioselectivity of the product is

due to the (S)-Binap ligand on the ruthenium metal center. Sodium borohydride and iodine were

used to reduce the carboxylic acid to an alcohol

7. Paraformaldehyde along with an acidic

workup allowed for the ring closed products of (8S,2R)- and (8S,2S)-Galaxolide.10

KBrO3NaHSO31OHKOH3H2Ru-(S)-Binap5(CH2O)nH2SO464COOHCOOHNaBH4/ I2Pd(OAc)2/PyPPh2/H+CO, H2O (THF)2BrPd(OAc)2/PPh3/CuI piperidineOHOH7OGalaxolide

Scheme 2: Synthesis of Galaxolide

Also to be noted is the use of metal catalysts in the preparation of odorous compounds.

With the advent of cross coupling reactions, many synthetic schemes have been reduced to as

few as half the number of steps required.11 Generally the catalysts are used in small amounts

9

relative to starting material, allowing for reduced costs that are favorable to fragrance companies.

Several examples of metal catalyzed reactions will be mentioned in the literature seminar to

follow.

The field of fragrance chemistry encompasses many areas of chemistry from

biochemistry to synthetic organic chemistry shown above. The last area of this discussion is

analytical chemistry, more specifically, the use of gas chromatography and mass spectrometry to

determine the fragrant components of perfumes.

Methods of Analysis:

Often times, several methods of analysis are employed for structure elucidation,

degradation of the fragrant components, effect of packaging, and quantification of the

components in the fragrance.3 Many perfume compounds contain as many as fifty fragrant

components, but quantifying their ratios is very difficult. The concentrations of these

components may vary between 0.10-30%. With the quantitation of these chemicals being

problematic, the use of gas chromatography has been employed along with several other

methods.12 Several attempts using GC-flame ionization detection (FID) and GC-MS monitoring

of specific ions have been investigated with low success rates. For FID, the difficulty lies in the

large number of components resulting in low resolution of the peaks. The specific ion case

proves challenging when isobaric ions are released. Chaintreau and Debonneville reported the

success of using a comprehensive GC coupled with a quadrupole MS. Scheme 3 is a depiction

of the GC/MS used in the above study. They were able to report linear calibration curves of area

sums along with low analysis time.12

10

Figure 6: Scheme of GC x GC-MS system taken from Reference 12.

Conclusions:

As shown in the paper, fragrance chemistry encompasses a vast array of chemical fields.

From biochemistry to analytical chemistry, the future of this area of chemistry seems far

reaching and abundant. With a better understanding of the mechanism by which the odorants

bind to the receptor sites in the olfactory system, molecules can be created that contain functional

groups that increase binding capabilities. Newly developed GC/MS methods will help quantify

the amount of fragrant components in perfumes which allows for reduced cost and quicker turn-around-time for fragrances to be developed. Finally, with the discovery of new odorous

compounds and their derivatives, the artists better known as perfumists have an array of “colors”

to create their “works of art.”

References:

1.)

Frater, G.; Bajgrowicz, J.A.; and Kraft, P.

Tetrahedron.

1998. 54, 7633-7703.

2.)

Bauer, K; Garbe, D.; and Sturburg, H.

Common Fragrances and Flavor Materials. 4th ed.

Wiley, VCH,

2001.

11

3.)

Frey, C. and Rouseff, R. Natural Flavors and Fragrances: Chemistry, Analysis, and

Production. ACS, Washington DC,

2005.

4.)

Leffingwell Reports, Vol. 2(No. 1), May,

2002.

5.)

Firestein, S.

Nature.

2001.

413.

211-218.

6.)

7.)

Maleczka, R.E.; Paquette, L.A.

J. Org. Chem.

1991,

56, 6538-6546.

8.)

Galaxolide® is a trademark registered by International Flavour and Fragrances.

9.)

Frater, G.; Muller, U.; Kraft, P.

Helv. Chim. Acta. 1999,

82,

1656.

10.)Scrivanti, A.; Matteoli, U.; Ciappa, A.

Tetrahedron: Asymmetry 2002, 13,

2193-2195.

11.)Chapuis, C.; and Jacoby, D.

Applied Catalysis A: 2001. 221,

93-117.

12.) Debonnville, C.; and Chaintreau, A.

J. Chromatogr. A 2004, 1027,

109-115.

12