R R

OH ))) O

R R NO2
O2N
O

O
O
Br Br R
Zn/Cu
R R O
O
)))
R

O CH2I2
Zn, )))
R R R R

SONOCHEMISTRY: ULTRASOUND APPLICATIONS IN ORGANIC

SYNTHESIS

RICHMOND SARPONG
STOLTZ LITERATURE MEETING
THURSDAY, 03/13/03
9AM

SONOCHEMISTRY - A TIME LINE

Broadly defined, describes a subject in which sound energy is used to affect chemical processes.
Nonelectromagnetic radiation is used to accelerate and execute chemical reactions

Potential of sonochemistry first identified by Loomis (Wood, R.W.; Loomis, A.L. Phil. Mag. 4, 1927, p414 and
JACS 1927, 49, 3086). Sonic waves of great intensity (100 kHz to 500 kHz) were produced and led to "clear
accelerating effects" e.g., explosion of NI3 and "atomization" of glass fragments from container walls.

Up until ca. 1940, large amount of pioneering work in polymers and chemical processes

1955 - 1970 ..."doldrum years"..."period of neglect"

Since early 1970s, increase in research with ultrasound due to the general availability of commerical ultrasound
equipment

National groups devoted to sonochemistry in UK, Germany, Romania, Japan and China

This presentation in mostly limited to the application of ultrasound in Organic Synthesis

 SOUND RANGES

7 8
O 10 102 103 104 105 105 10 10
Hz

Human Hearing Conventional Power Ultrasound

16 Hz - 18 kHz 20 kHz - 100 kHz
20 kHz - 2 MHz
Diagnostic
Ultrasound
5 MHz - 10 MHz
SOME USES OF ULTRASOUND

Field Application

Biology, Biochemistry Rupture biological cell walls to isolate cell contents

Release contents of selected cells --> Achieves enzymatic transformations
without purification
Ships SONAR. High frequency, low power sound waves to measure distance

Engineering Assist drilling, grinding, cutting. Processing glass and ceramics. Welding
(plastics/metals). Dentistry.

Industrial Dispersing pigments and solids in paint, inks, resins. Cleaning and degreasing
materials. Acoustic filtration, drying, atomization, precipitation, degassing,
electroplating

Medicine Ultrasonic imaging (2-10 MHz). Physiotherapy; treatment of muscle strains

Plastics and Polymers Radical polymerization initiation. Welding of thermoplastics. Degradation of

preformed plastics

SONOCHEMISTRY EQUIPMENT

The transducer is the key device for any ultrasonic device; converts one form of energy to another
Three types: liquid driven, magnetostrictive and piezoelectric
Liquid-Driven Transducers - useful for industries where
emulsification/homogenization is important
Magentostrictive Transducers-based on ferromagnetic
materials which change dimension when a magnetic field
is applied. Rapid on/off application leads to vibrations
and sound energy
Piezoelectric Transducers - Most common
Piezoelectric effect - instantaneous generation
of electric charge between opposite faces of certain
materials when a sudden pressure is applied across
them; transducers use opposite of this effect by either
expanding or contracting when an electric charge is
applied. Usually charges alternating at 20KHz is applied.
Piezoelectric materials are ceramics dispersed with
BaTiO3 , PbNb2 O6 and lead zirconate titanate.

Reaction Mixture Water+Detergent

Back Mass Bolt w/ Electrical

Contact btwn
masses
Heater

Piezo Eectrical
Elements Contacts
Stainless
Steel Tank
Front
Mass
Transducers
Bonded to Base

"CLEANING BATH" PIEZOELECTRIC SANDWICH TRANSDUCER

 TRANSMISSION OF ULTRASONIC ENERGY

Sound travels through a medium as a series of compression and rarefaction motions of molecules

Equal vibrational motion occurs at half wavelength distances( i.e., a full wavelength comprises a compression and
rarefaction). Therefore, it is the half wavelength of sound in a medium that governs the design of sonochemical
equipment

Emitting face of a transducer is at the maximum point of vibration

Wavelength of sound in a medium depends on the velocity and freqeuncy of sound in that medium
sound velocity = wavelength X frequency

Titanium or titanium alloy is often used as a waveguide; 12.7 cm length (half wavelength) waveguide or multiple of this
number is required to get 20 kHZ (velocity of sound in titanium ~ 5080 ms-1 )

Higher frequency ultrasound provides less power and penetration and usually requires a probe delivery

CAVITATION

Acoustic vibrations are many orders of magnitude below molecular vibrations. Thus ultrasonic irradiation
cannot be directly absorbed by molecules

Ultrasound is propagated via a series of compression and rarefaction waves induced in molecules of the media

At high power, rarefaction cycle may exceed attractive forces between molecules and "cavitation" (think cavtiy)
bubbles will form

Cavitation bubbles collapse in succeeding compression cycles generating the energy for chemical and mechanical
effects

CAVITATION IS FACILITATED
- in systems containing dissolved gases
- when small particles acting as nucleation sites are present
- by vapor pressure increase or volatile components

**** THE LOWER THE POWER TO PRODUCE CAVITATION, THE LOWER THE ENERGY RELEASED ON BUBBLE
COLLAPSE

Typically bubble collapse corresponds to energy gained from 5000K or pressures of 500 bars in terms of the
vibrational energy it imparts to molecules (Science, 1992, p248)

Cavitation effects depends on the system: homogenous liquid phase --> radical formation in media; heterogenous
liquid phase --> high level emulsification. A direct result is that phase transfer reactions are greatly improved. In
solid-liquid phase --> impinging/jet impact -->particles ejected from surface react more efficiently or surface is
'cleaned'

Current efforts to delineate the true effect of cavitation is focused on the use of sonoluminescence and
ESR spectroscopy
 DEFINING THE LAWS OF SONOCHEMISTRY

A specific nature of sonochemistry is suggested Ando etal JCSCC, 1984, p439

KCN/Al2 O3
Br CN
83% 76%

+ regioisomers
STIRRED SONOLYSED

Sonication seems to obey some rules of its own

An empirical systemization of sonochemistry has been published (Luche, J.L. Advances in Sonochemistry, Vol3,
1993, p 85 and TL, 1990, 4125)

Effects are both chemical and mechanical

RULE 1
Reactions that proceed via radical or radical ion intermediates are most likely to be sonochemically influenced

RULE 2
In heteregenous systems, reactions proceeding via ionic intermediates can be stimulated by mechanical effects.
Usually the effect is comparable to efficient mixing

RULE 3
Heterogenous reactions with mixed mechanisms (radical and ionic). These may be enhanced in a convergent way
(chemically for the radical and mechanical for the ionic) or a switch may occur where the radical pathway is enhanced
and "change" the reaction products

Factors affecting sonochemical reactions: frequency, power, reaction temperature (low temperature can lead to
higher reaction rates!), overpressure, solvent

SONOCHEMICAL REACTIONS IN ORGANIC SYNTHESIS

HOMOGENOUS REACTIONS - Have received less attention for sonochemical activation

Kinetic Studies

O
N C O
)) )
N3 Porter etal. JACS, 1938, 1497

Enhanced initial rate

Hydrolysis

O R OH
)) ) O
O + Kristol etal . TL, 1981,907
+ H2O
O2 N 35 oC R OH O2 N

14-15% enhancement
independentof R group

H2 O/ Ethanol
(CH3 )3 C-Cl (CH3 )3 C-OH + HCl Mason etal. Ultrasonics Int. '85
Proc., Butterworth, U.K., 839
)) )
Effect of ultrasound increased with EtOH content with a maximum effect at 50% w/w
Rates of reaction under sonolysis increased as temp was reduced from 20 oC to 10 o C
Sonolysis of some solvents may occur: H2 O, CCl 4 , CHCl3 . We can take advantage of this in synthesis

Sonoisomerization

CO2 Me CO2 Me MeO2 C

R X - X Elpiner etal. Nature, 1965, 945

CO2 Me )) ) X CO2 Me CO2 Me

R-X

A Variation of the Hunsdiecker Reaction (Dauben etal. JOC, 1989, 6101)

Cl 3C X X
S SCCl 3 + CO2 + R R-Cl
N R N
)) )
O o
10 - 15 min, 33 C
O
Cl 3C-X

Cleavage of the Tin Hydrogen bond

OH

Ph R3 SnH O2
O Ph Nakamura, E. JACS, 1991, 8980
O
I )) ) 0-20 o C
84%

The radical nature of some reactions is compromised by attached R groups

O R' O
R' )))
P OR R' P Hubert C. etal
+ N OR
H JOC, 1995, 1488
OR R' R' R'HN OR

>90% yield in 1.5 h w/ R = Et

No rate enhancement w/ R = C16H31
Sonolysis of Iron Carbonyls
O
(OC)3Fe 60 atm CO
Fe2(CO)9 ))) O O
Ley, S.V etal.
O J. Organomet. Chem.
OH 23 oC, 30 min O 1985, C17, 285

70%

Milder Conditions, Enhanced Rates for the Heck Reaction (Cheng, J etal. Bull. Inst. Chem. Acad. Sin. 1989, 9)

Pd(PPh3), NEt3
CH3CN, C6H6 50 oC, 6h, 76% (sonication)
80 oC, 24h, 71% (thermal)
I
CO2Me CO2Me

Pauson-Khand Annulation is Accelerated by Sonication (J. Organomet. Chem. 1988, 233)

O
Co(CO)3 Bu3PO, hexane
H + O Ph
Co(CO)3 )))
 CARBON-CARBON BOND FORMATION

Horner-Wadsworth-Wittig
O SO2CH3
O OR
H3CO2S P
OR El Fakih etal. TL, 1992, 4909
CH3
CH3
))) THF, 23 oC
70-80%
<10% (without sonication)

Non-stabilized ylides can proceed through a single electron transfer mechanism and so
these reactions should be enhanced sonochemically. However, stabilized ylides should proceed
through a more polar mechanism. So this enhancement cannot be rationalized very well

ANY REACTION IN WHICH A SINGLE ELECTRON TRANSFER MECHANISM IS CLEARLY DEFINED

SHOULD BE SONOCHEMICALLY ENHANCED

O AgOBz (0.1 eq)

R OH
R N2
Muller etal. Synthesis, 1998, 837
))) 23 oC FmocHN O
FmocHN
65-82% yield

Hydroboration of hindered substrates is greatly facilated by sonication

B
))) Crimmins, M.T. etal. TL, 1989, 5993
HB
Neat, 23 oC, 1h
99% (Thermally, 99%, 5h, 65 oC)

HETEROGENOUS REACTIONS WITH NON-METALS

Heterogenous systems appear to behave in a reasonable predictable manner when sonicated

Reactions normally run with phase transfer reagents are especially susceptible to acceleration by
ultrasound

A phase transfer catalyst is often necessary under thermal conditions

CO2 Me SynLett, 1991, 907

NO2
CO2 Me 23 oC, 2h, )))
NO2

Sonication also induces a partial reoxidation of the Mn salt ...potential catalysis?

CN
CN Mn(OAc)3, KOAc
Trogolo etal. Tetrahedron, 1993, 10705
O
AcOH, ))), O
COOH
0-10 o C, 2h, 65 %

Wittig reactions are often enhanced under sonication (Yang etal. Synlett, 1992, 799)

PPh3 Br O LiOH, H2 O/CH2Cl2

+

PPh3 Br O ))), 4h, 43%

Stirring at 23 o C, 24%
Saponifications in Aqueous Solutions are Enhanced by Ultrasound; Sonochemical Emulsification

O
O
10% aq. NaOH
OH
OMe TL, 1979, 3917

Reflux, 90 min, 15%

Sonication, 23 oC, 96%

Formation of anions from heterogenous bases facilitated by sonication

NaH,)))
S 50 oC, 1h S TL, 1966, 6383
Na
O O

Br
CN Br K2CO3, ))) CN Chin. Chem. Lett. 1991, 517
Chem. Abstr. 1992, 116, 193753t
CO2Et PEG-600, ClCH2CH2Cl CO2Et
85%

Nitrogen Protection (Under Phase Transfer Catalysis) Is Enhanced. This is also true for indole protection.

COOt-Bu
NH (t-BuOCO)2O, NaHCO3 N
Luche, J.L. etal. Synlett, 1991, 37
MeOH, ))), 3h
OH OH

>80% yield

A Case for "C-H Functionalization"? (JCSCC, 1994, 1425)

NaNO2, AcOH [O] +

Ce(NH4)2(NO3)6 Si Si Si N
Si NO2
O2
CHCl3, 23-75 oC
NO2 H
))), 4h

REDUCTION REACTIONS

LAH, DME
Br Boudjouk etal. TL, 1982, 1643
MeO MeO
))), 35 oC, 7h
70%

LiAlD4, C6D12
TL, 1984, 1415
Si O Si
O ))), 25 oC, 2h
OMe D

The usual reductive protocols involving heterogenous systems are also facilitated
(e.g., nitro to amine, aldehyde to alcohol etc)

Generally, sonochemical reduction chemistry is underexplored

 OXIDATION REACTIONS

OH
Perfluoroalkyl
O2, Sulfonate salt Mokryi, E.N etal. Akad. Nauk Ukr. 1993, 7, 99
Chem. Abstr. 1994, 121, 107751
)))

KMnO4, H3O+
JCS Perkin Trans. II, 1988, 375
PhH,450 torr
))) O

R
R
R
R TL, 1991, 3201
TPAP, NMO
O
HO 25 oC, 90 min
>90% O

PCC/SiO2
JOC, 1989, 5387
20 min, )))
OH O

ORGANOMETALLIC SONOCHEMISTRY

This has seen the greatest impact in terms of sonochemical applications

Usually, the influence of ultrasound is to remove passivating coatings on metals (oxides, carbonates, OH etc) -->
Depassivation and also to aid in single electron transfer processes which constitute a crucial step in the formation of
organometallic compounds

Recently Reviewed: Luche, J.L.; Cintas, P. (Furstner, A. (ed.)), Activated Metals, VCH, Weinheim, 1997.

ALKALI METALS AND MAGNESIUM

Bogdanovic etal. ACIEE, 1983, 728

)) ) )) )
+ Mg*
+ Mg

Mg Activated Mg* is useful for

Grignard reagent prep
Acyloin Condensation (SynLett, 1990, 89)
SONICATION IS GENERALLY USEFUL
OSiMe3 FOR GRIGNARD REACTIONS, HALOGEN-
CO2 Et Me3SiCl, Na, THF METAL AND TRANSMETAL EXCHANGES

CO2 Et 0 oC, 2 h, ))), 82% OSiMe3

OH

90%, Thermal
O

NR2 TL, 1988, 2183

Li, THF O

90%, Sonochemical
 REACTIONS WITH ZINC METAL

Historically, the first metal to be used in organic chemistry

Zn-mediated reactions have been the most extensively studied in sonochemical organometallic chemistry

REDUCTIONS
The Zn(Ni) Couple (Luche, J.L. etal. JOC, 1989, 5313

Zn(Ni) (9:1)
O EtOH, H2O O Zn(Ni) (9:1) O
EtOH, H2O

NH3-NH4Cl
))), 3 h, 23 oC
pH 8,))), 1.5 h
23 oC
95 % 96 %
Thermal (12 h, 90 %) Thermal (24 h, 90 %)

TL, 1993, 1993, 357

O
O

Zn, AcOH, 25 oC

10 min, 100 %
O ))) H

5!:5" =1.5:1

ORGANOZINC REAGENTS

Improved Simmons-Smith Protocol (TL, 1982, 2729)

Zn, CH2I2, DME Unpredictable induction period suppressed

4h, 90 oC,)))
67% (12 % Thermally)

Hydroperfluoroalkylation/ Carbometallation (JACS, 1985, 5186)

Zn, CuI, THF

+ F3C OH
CF3I
HO
23 oC, 2 h, ))) 61 %

Barbier-Type Processes (Boudjouk etal. JOC, 1982, 751)

R Zn, Dioxane R
Br No Reaction Thermally!
Br )))
R' R
67-89%
R is electron withdrawing
 REFORMATSKY REACTION

Significant rate and yield improvements have been observed

Meyers, A.I. JOC, 1991, 2091

O
O
N Zn(Ag), THF N

N Br 40 oC, ))), 2 h N
R R NH2
NC 84 %

Jackson etal. JOC, 1992, 3397

Zn(Cu), ))) (Ph3P)2PdCl2, ))) NHBoc

NHBOC NHBOC
I IZn
DMA, PhH, 30 min N COOBn
COOBn COOBn

N Br

AQUEOUS ORGANOMETALLIC COUPLINGS

Sn and In seem to predominate

Whitesides, G.M. JOC, 1993, 5500

Sn, aq. NH4Cl-THF HO

Aq. CH2O + Br

23 oC, 1 h, )))
60 %

Binder etal. Tetrahedron, 1994, 749

AllylBr, Sn, ))) OH OH

O
HO OH
EtOH-H2O (10:1)
HO OH OH OH OH
60 - 65 %

O O OH
CHO AllylBr, In, )))
O O
EtOH, 1 h

60 %
 OTHER METALS FOR ORGANOMETALLIC SONOCHEMISTRY

Cu for Ullmann Couplings (Mason etal. Ultrasonics, 1986, 292)

NO2
NO2 Cu, DMF

NO2
I ))), 60 oC, 90 min
95 %

Al for Reduction Chemistry (TL, 1993, 353)

OH OH

O O
Al(Hg),
O 10 % aq. HCOONa
OH
EtOH, 23 oC, )))

HO HO

80 %
(Thermally 23 %)

CONCLUSIONS

Sonochemistry is gaining significance based on laboratory results and the availability of scale-up systems

Sonochemical applications can be envisaged in all types of systems, including homogenous reactions

Wide acceptance has been gained at a practical/empirical level, however, the theoretical understanding still lags
significantly behind

The usefulness of sonochemistry continues to expand into the arena of electrochemistry, photochemistry and
biotechnology

FOR THE ORGANIC CHEMIST: WHEN IN DOUBT, SONICATE!!!!!

Useful references

Price, G.J. (ed.)., Current Trends in Sonochemistry, Royal Society of Chemistry, Oxford, 1993

Mason, T.J. (ed.), Chemistry With Ultrasound, Elsevier Applied Science, London, New York, 1990

van Eldik, R.; Hubbard, C.D. (eds.), Chemistry Under Extreme or Non-Classical Conditions, Spektrum/Wiley, 1997

Abdulla, R.F. Adrichimica Acta 21, 1988, 31 - 42