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By Wolfgang Sliwka[*]
Microencapsulation is the enveloping of liquid droplets or fine solid particles to form microscopic capsules 1 to 5000 pm in diameter. For the fabrication of such capsules special techniques
have been developed which take into account the substance to be encapsulated and the intended
use of the capsules. The envelopes, consisting of natural or synthetic polymers, may be made
permeable, semipermeable, or impermeable. Thus, there are several possibilities for controlled
release of an encapsulated reactive substance, for example by destruction of the envelope
or by permeation : alternatively, reactions can be allowed to take place within the microcapsules.
Microencapsulation facilitates delivery of many substances to their site of utilization in a
novel form of preparation and novel mode of dosage, the solids being dispersed very finely
and having a very large surface area.
1. Introduction
Microencapsulation is the name given to a novel technique
for the preparation of substances, the development of which
began about 20 years ago.
Numerous processes and their products-microcapsuleshave been described, largely in patent literature. A few surveys
In what follows an attempt is made to
review the field of microcapsules, their preparation, their properties and their uses and potential applications.
Since life began nature has been utilizing the envelopment
of systems for their protection or for providing particular
reaction spaces, the enveloping wall displaying in addition
specific membrane functions. The abundance of examples
available is quite overwhelming and extends from arboreal
against light and oxygen. Release of the active principle is
postponed until the capsule has entered the organism, for
example, after dissolution of the capsule wall within the stomach or the intestine.
The technique of microencapsulation aims at enveloping
gases, liquids, or solids present in finely dispersed form. In
general, the mean particle diameters can be varied between
about 1 and 5000pm; natural or synthetic polymers are used
for the walls of the capsules. The external form of the capsules
depends on the core material and the deposition of the material
of the wall. Thus, microcapsules may appear as smooth spherical globules, as grape-like clusters, or as irregular structures
with a smooth or folded surface. They can be readily investigated by means of scanning electron microscopy (SEM) (Fig.
Fig. 1. a) Polyacrylate capsules prepared by a phase-separation technique. b) Complex coacervate capsules on a paper base. c) Polyamide
capsules prepared by rapid interfacial condensation (despite the folds the capsules are impermeable). SEM photomicrographs.
fruits and plant seeds to spores, from the hen's egg and its
shell to the cell and its cell wall. The principle is found in
nature from the macroscopic down to the microscopic range.
In the macroscopic range the enclosing of active ingredients
in capsules, for example of medical preparations in the familiar
gelatin capsules, has long been practised. Powdered active
principles are offered in sausage-shaped hard capsules, liquid
or pasty ones are brought between two soft gelatin ribbons
which are then shaped and welded together by special machines
to form spherical capsules. Encapsulation improves the dosability, but principally it serves to protect the active principles
[*I Dr. W. Sliwka
Kunststomaboratorium der BASF A G
67 Ludwigshafen (Germany)
Angew. Chem. internal. Edit.
1 Vol. 14 (1975) 1 N o . 8
The nature of the polymers and the wall thickness determine
the ability of the microcapsule (the capsule envelope) to isolate
the contents and to release them selectively. Some examples
of the possibilities are given below.
The capsule wall seals off the capsule contents from the
external surroundings, and to release them it must be opened.
This may be effected mechanically from outside, i. e. by shearing or crushing, or from inside e.g. by heating above the
boiling point of the core material, and by dissolution, melting,
or burning of the wall material (Figs. 2a and b).
The capsule wall can be semipermeable, for example impermeable to the core material but permeable to low-molecular
[*I Thisand thefollowing SEM photomicrographs were taken by Dr. Hendus
in the Hauptlaboraiorium, BASF A G (Ludwigshafen. Germany).
Fig. 2. a ) Polyacrylate microcapsules on a paper base: mechanically opened, bj opened by melting at 220 C . c) with dents formed as a result of
the loss of \olatile solvent as core material. ( S E M photomicrographs.)
liquids coming in from outside. Provided these liquids exhibit
no tendency to mix with the core material, the contents remain
enclosed. Otherwise the liquid entering by diffusion builds
up an osmotic pressure which threatens to burst the capsule
from within. Microcapsules which resist the osmotic pressure
can be used as exchangers. They take up substances from
the environment and release them again on being introduced
into a different medium. Microcapsules which do not resist
the osmotic pressure burst and release the capsule contents.
The capsule wall can be permeable to the core substance.
Release of the core material is regulated by the thickness
and pore width of the wall (Fig. 2c). In contrast to the case
of destruction of the capsule, the contents do not emerge
all at once but slowly (sustained release). In this way a certain
concentration of core material can be maintained in the surroundings for a prolonged period, which is often desired,
e.y. for therapeutic purposes.
The permeability of the capsule wall also depends on the
surrounding medium. Thus, if an impermeable microcapsule
is introduced into a liquid in which the wall material will
swell, then the polymer network expands. As a result the
capsule may become permeable to the core material, and
in this way the core constituents-for example, fertilizers and
drugs-are dissolved out of the capsules.
Such properties open up many possible uses for microcapsules.
2.1. Capsule Dimensions
For the sake of simplicity we shall confine our discussion
here to spherical microcapsules, such as are normally formed
during the encapsulation of liquids.
During the encapsulation operation a definite ratio by
weight of the core material k to the wall material w is weighed
out and the capsule diameter is then adjusted in a dispersing
stage. Assuming that all capsules display this ratio, the capsule
diameter then unambiguously establishes the wall thickness.
Starting from a wall and core material of the same density
(p, =pk) we obtain the relationship between the wall thickness
dw=r2-rl and the ratio of the weight of the wall material
Wwto that of the core material W,:
which, after rearranging, gives
2. Influencing the Properties of Microcapsules
According to Fick’s diffusion law, the quantity dm/dt [mole!
s] that diffuses through the wall of a microcapsule is proportional to the surface area A of the capsule shell, the concentration gradient dc/dw (dc is the concentration drop across the
wall thickness dw), and the diffusion coefficient D [cmZ/s]:
Fig. 3. Cross-section of an idealized microcapsule. r,=capsule radius, r , =radius of core material, k=core material, w = w a l l material.
The diffusion coefficient D embraces the specific properties
of the envelope material, such as its physicochemical constitution, its interaction with the surroundings (e.g. the swelling
power), and the temperature dependence of these interactions.
D/dw is the permeability coefficient or the permeability [cmjs].
On the basis of this equation, the capsule surface area,
the wall thickness, and the physicochemical constitution of
the wall material in relation to the physicochemical constitution of its environment are the important parameters.
For the usual Wk/(W, + W,) ratios of 0.50 to 0.95 the linear
increase in wall thickness with increasing capsule diameter
shown in Fig. 4 is obtained.
In practice the results will be affected by the capsule diameter
distribution that is always present, and by the percentage
wall material distribution on individual capsules.
The linear dependence of release of diffusible core material
on the thickness of the capsule, expected according to eq.
(I), has essentially been confirmed by experiment (examples:
phenobarbital/gelatin‘61; eprazinone/gelatinr’]).
Angrw. Ckem. intrmut. Edit.
Vof. 14 ( 1 9 7 5 ) 1 No. 8
Table I . Storage characteristics of some hqulds in gelatin microcapsules (after [I]).
As fraction of
Mean capsule
total capsule
Storage time
I'X 1
Carbon tetrachloride
0 70
0 80
0 85
0 90
0 95
Table 2. Hildebrand's solubility parameter 6 [(cal/~m'))"~]
for some solvents
and polymers [S]. As a rule two solvents are miscible if their solubility
units. For polymers the
parameters 6 d o not differ by more than 2-3
6 range is given: 0 denotes insolubility in solvents of this group.
0. I
Llquid loss
at 25°C
and 50 R H
d, [ p l -
Fig 4. Wall thickness dw as a function of capsule diameter d , for various
M/, + W,)ratios.
With the small diameter of the microcapsules, and the consequently limited thickness of the capsule wall, complete impermeability with respect to gases or liquids, and especially solvents, cannot be obtained. However, the durability of the
core material can be optimized by suitable choice of the
capsule dimensions and the wall materials (cf. Table 1).
2.2. Capsule Wall Material
The wall material is as decisive for the permeability properties of the capsule wall as are the capsule dimensions. In
the selection of a suitable wall material it is helpful to refer
to Hildebrand's solubility parameters[*] (Table 2). For the
preparation of impermeable capsules a wall material with
a solubility parameter as different as possible from that of
the core material should be chosen. In this way it is possible
to carry out a preliminary selection, also taking into consideration, the diffusion coefficients of the core material and of
the substances surrounding the wall.
Results of investigations on the permeability of wall materials are reproduced in Figures 5---7["3 "I. As expected the permeability decreases with increasing molecular weights of the
permeating materials[101. The state of the polymeric wall
material also influences the permeability. Thus the rate of
release of sulfamerazine from gelatin microcapsules diminishes
sharply with increasing degree of crosslinking in the gelatin" 'I.
Solvents with poor H-bonding
9.3 2 1.3
9 . 6 i 1.5
10.2 20.9
10.8k 1.2
Nylon 8
Ethylcellulose, N 22
Vinyl chloride-vinyl acetate copolymer
Polymethyl methacrylate
Nitrocellulose SS 0.5 s. dry
Solvents with moderate H-bonding
Nylon 8
Diethyl ether
n-Butyl acetate
Ethylcellulose N 22
Ethyl acetate
Dibutyl phthalate
Vinyl chloride-vinyl acetate copolymer
Polymethyl methacrylate
11.9+0.8 Nitrocellulose SS 0.5 s. dry
Propylene carbonate
Ethylene carbonate
9.0 k0.9
10.6i 2.8
10.9k 2.4
11.5 k 1.6
Solvents with strong H-bonding
12.6F 1.6
Polymethyl methacrylate
Ethylcellulose N 22
Nylon 8
Ethylene glycol
Nitrocellulose SS 0.5 s, dry
ing powder. The suitable form will always depend on the
subsequent use. The surrounding medium is of decisive importance as regards the stability of the capsules and especially
of their contents.
2.3. Mode of Preparation of the Microcapsules
3. Microencapsulation Techniques
Capsules may be prepared in dispersion, for example in
water, or as dry capsules, for example, in the form of a free-flow-
Microencapsulation can be carried out in two ways: (i)
physicomechanically and (ii) chemically.
. 4 n q e ~ .Chivn.
inrernar. Edir. / Vol. I 4 ( 1 9 7 5 ) 1 No. 8
3.1. Physicomechanical Microencapsulation Techniques
3.1.1. Spray Drying
Pi@. 5. Reciprocal permeability ( t , ) of nylon microcapsules as a function
of the molecular weight ( M W ) of the permeating substance. 1 =acetone.
2=urea. 3=ether, 3=thiourea. 5=creattnine. 6=L-cysteine. 7=DL-methionine. X = D-dextrose. 9 =[>-sucrose (after [9]).
One microencapsulation process of very general application
consists in the spraying of an emulsion or dispersion in a
stream of hot inert gas. A film-forming polymer is dissolved
in the continuous phase which surrounds the core material
particles inside the sprayed droplets. The drying process causes
this solution to shrink into a pure polymer envelope firmly
enclosing the core material. The resulting capsules are obtained
as free-flowing. dry powder.
For the preparation of capsules containing dye solutions
and pigment dispersions for copying papers, for example.
a dispersion of carbon black in oil is emulsified in a large
excess of a solution of film-forming polymer, e. 8. hydroxyethylcellulose in water. The emulsion is then atomized and the
water volatilized. Free-flowing microcapsules 1 to 10 pm in
diameter are obtained’l2]. A wide range of solid particles
have been encapsulated by means of this procedure from
an organic solution of a film
Preformed microcapsules can be obtained as powder by
spraying from their dispersion. This procedure is also used
for putting a second or third wall layer around the capsules
and thus for altering the wall permeability[“].
3.1.2. Dipping or Centrifuging Techniques
MWFig. 6. Permeabilit) of microcapsulea (wall materials : o 0 ethylcellulose.
- 0 cellulose acetate and x
x polyinylformal) as a function of the
molecular weight ( M WI of the permeating substances methylene blue. tuberactinomycin. polymyxin B, insulin. lysozyme. a-chymotrypFin, semi-alkaline
protease. pepsin. ovalbumin. serum albumin. and y-globulin: measured a5
their relative adsorption on activated charcoal as core material (after [ 101).
t [hl-
Fig. 7. Rate of release of sulfamerazine from microcapsules made of gelatin
with various degrees of crosslinking: gelatin,sulfamerazine 8 : 4 ; solution
medium : acid pepsin solution B.P.; temperature 37°C. o Sulfamerazine crystals, 0 noncrosslinked gelatin envelope. Gelatin envelope treated with formaldehyde for a 15 min, m 1 h, v 3 h, 6 h ; after [ I l l .
In the physicomechanical procedures liquid and solid particles are encapsulated in the gas phase. The chemical encapsulation techniques make use of the liquid phase, i. e. the process
is carried out in emulsion or dispersion. Deposition of the
wall material on the interface between the liquid core material
and the liquid surrounding medium represents the chief problem here. Not only must a third phase be precipitated, but
it must also appear in the right place, namely at the boundary
between the two other phases.
The principle of these techniques is based on passing the
core material particles or droplets at high speed through
a thin film ofthe liquid envelope material. The particles entrain
the wall material and are enveloped by it. Microcapsules
are formed when the wall material film sets, for example
in a hardening bath. The technique gives relatively large capsules. with diameters of up to 8 mm, and the size uniformity
is very good.
A special embodiment is the centrifuge process proposed
by Sommercille~15*
The core material atomized from a rotating disk strikes
a row of the numerous orifices on the periphery of the centrifuge bowl. A film of the wall material is stretched over the
orifices and is constantly renewed by fresh wall material solution.
In one example kerosene as core material is enveloped
with a solution of polyvinyl alcohol and sodium alginate
in water/glycerol. The wall material is hardened in 20 ”/, CaCI,
3.1.3. Multiple Nozzle Spraying
In multiple-nozzle processes the core material emerges from
an inner nozzle and the wall material from a concentric ring
nozzle slit. When the stream tears outside the nozzle, droplets
consisting of core and envelope are formed. Water or aqueous
solutions are enveloped in a shell of paraffin and other waxes.
The capsule diameters vary from fractions of a millimeter
to a few millimeters.
The capsule wall is hardened either by cooling and allowing
it to set or in a hardening bath[16-’81.
3.1.4. Fluidized Bed Coating
Finely divided solid core material is held suspended by
a vertical current of air and sprayed with the wall material
A n g a r . Chem. internut. Edit. i tb/. 14 11975) II N o . X
solution. Following evaporation of the solvent a solid skin
of the wall material is deposited around each particle.
This technique lends itself to coating solid particles with
diameters from 40pm up to tablet size. Smaller particles agglomerate. Pharmaceuticals, chemicals, seeds, and foodstuffs
above all are encapsulated in this way. The list of wall materials
used stretches from sugar through gelatin, resins, and waxes
to cellulose derivatives and synthetic polymers.
A special embodiment is the process known as the Wurster
process in the American Ijteraturel'" "I, I t is carried out
in chambers with batches of up to 450kg. The chambers
are fitted with a fixed vertical pipe. around which the core
material carried by the ascending air current is made to circulate. It moves upward through the interior of the vertical
pipe section while being sprayed and descends outside the
pipe section while the coating dries. Each time the particles
pass through the encapsulating zone they receive an extra
coating. This process is repeated until the desired thickness
of the coating is achieved. depending on the intended use
of the capsule.
3.1 3. Electrostatic Microencapsulation
Liquids can be encapsulated by atomizing the core material
and molten wall material and charging the two kinds of droplets with opposite polarity. The droplets are then mixed in
a collision chamber where they combine. To obtain the capsule
shape the particles are allowed to dwell as a suspension in
a thermostated space and are then cooled to give capsules
in powder form"'].
3.1.6. Vacuum Encapsulation
The principle of this process consists in enveloping solid
nonvolatilecore materials under high vacuum. The wall material is volatilized in vacuum and condensed on the colder
particles. which are in rotary motion. Paraffins, waxes. metals,
oxides. and the like are used as the wall materials.
Various types of apparatus can be used for this purpose.
In one of them the core material particles are cooled in a
reservoir vessel and are allowed to fall onto a vibrating chute
under vacuum where they are struck by a jet of vaporized
wall material and coated. Capsules of 10 pm to 25 mm can
be produced'', 4. 2 3 ] .
In another type of apparatus the evaporator is situated
in the center of a drum, which rotates at a speed such that
the particles adhere to the inner wall. The particles are turned
by a scrabber. This arrangement is used predominantly for
the coating of acetate flocks, silicon carbides, ceramic compositions, and metal powders with a wide variety of metals'241.
solved in water, and this solution is covered with the solution
of the other component, for example, terephthalic acid dichloride in toluene. The result is the instantaneous formation
of a film of polyamide, insoluble in either phase. at the interface
between the mutually immiscible phases. R ~ u s l and
' ~ ~later
Vandegaer[2h]modified this process by dispersing a toluene
solution of terephthalic acid dichloride. with vigorous stirring,
in an excessof water containing polyvinyl alcohol as protective
colloid. An aqueous solution of ethylenediamine is then added
slowly to this emulsion. To neutralize the liberated acid, the
aqueous diamine solution contains an appropriate quantity
of caustic soda. The two monomers react at once on the
interface between the toluene droplets and water to form
solid polyamide. Capsules are obtained. which in this case
contain toluene as the core material (Fig. 8).
The procedure is very simple in principle. The reaction
very quickly affords a capsule wall whose thickness tends
to a limiting value determined by the resistance offered by
the wall to diffusion of the components. This process is especially suitable for laboratory encapsulations and for studying
the preparation of capsules in terms of capsule diameter,
wall permeability, and the charge on the capsule as a function
of the core materialsl''~ 251. The reactivity of the monomers
sets limits on the choice of the core material and the surrounding medium.
The properties of the polymers used for the capsule wall
can be varied by suitable selection of the diamines or acid
dichlorides, for example, hexamethylenediamine. sebacoyl
chloride, phosgene, and many others. Triamines lead to crosslinking and thus enable reduction of the permeability of the
capsule wall.
This technique can be used, for example. for the production
of capsules containing water as the core liquid by spraying
an aqueous diethyltriamine solution into a terephthalic acid
dichloride solution in petrol.
3.2. Chemical Encapsulation Techniques
Over the years many chemical encapsulation techniques
have been developed. The capsule wall can be formed by
polyreactions from monomeric or oligomeric starting materials, or from preformed polymeric wall material.
3.2.1. Wall Formation from Monomeric or Oligomeric Starting
Materials by Polycondensation and Polyaddition
A very well known encapsulation technique is based on
the principle of interfacial polyconden~ation[~~!One
monomer component, for example ethylenediamine, is disAnypit.
Chrm. inrernar. Edir. II
1 4 f 197.5) I No. K
Fig. 8. Encapsulation of toluene by the interface polycondensation technique.
1 =inner or core phase consisting of toluene and terephthalic acid dlchloride.
2=capsule envelope of polyamide, 3 =continuum consisting of water, pol)vinyl alcohol (PVAL), ethylenediamine, NaOH. and NaCl
Isocyanates, or polyisocyanates may be used for the encapsulation in place of the acid chlorides''*. 291. In some cases
they are used in combination with the acid chlorides.
A different procedure starts from urea-formaldehyde precondensates. The core material is dispersed in an aqueous solution
of the precondensate and curing of the precondensate is initiated by acidification. The resin, which becomes more and
more insoluble as the condensation progresses, precipitates
on the core material particles and microcapsules 1-500 pm
in diameter are
A procedure is also known in which monomeric styrene
dissolved in the core phase is insolubilized by polymerization
and subsequently forms an envelope around the remaining
water phase, and the wall material phase. The change in
the solvent composition produces separation of the wall material phase in highly viscous form. Distillation removes the
low-boiling components leading to solvent-free deposition of
the wall. The wall material may subsequently be crosslinked
with formaldehyde, dialdehydes, or diamines. A 16 to 30%
capsule dispersion is obtained, which consists for example,
of individual capsules 6-12 pm in diameter (cf. Fig. 1 a).
3.2.2.I . Coacervation
3.2.2. Wall Formation in the Presence of Polymeric Wall
Many microencapsulation techniques of this type are
known. Most of them have in common the fact that the
polymeric wall material is dissolved and the solution is added
to the core phase or, more frequently, to the continuous
phase. The core material is dispersed to the desired particle
size in the continuous phase and the polymeric wall material
is then deposited on the interface as a third phase by gradual
precipitation of the polymer. This is achieved either by the
use of precipitants, by changes in temperature, or by removal
of the solvent by dilution or distillation. The state of division
of the core material must not be altered. Thus, encapsulation
is achieved by phase separation, in special cases by coacervation or complex coacervation. Subsequently the wall material
is deposited on the core material/surrounding medium interface when its solubility parameter[*](cf. Table 2) lies between
that of the core material and the surrounding medium.
A water-soluble solid, e. g . ammonium dichromate powder,
may be encapsulated by dispersing it in a solution of ethylcellulose in toluene/ethanol (4: 1) and heating the whole to 70°C.
Slow addition of a petroleum fraction causes the ethylcellulose
phase to separate and deposit on the particles. After addition
of petroleum fraction in excess the capsules can be obtained
by decantation[321.
Further examples are the encapsulation of ammonium
nitrate with e t h y l ~ e l l u l o s eor~ ~with
~ ~ nitro~ellulose~~"~.
Activated ~harcoa1""~and
phenobarbital[351have also been encapsulated in this way.
Water or glycerol droplets can be encapsulated with a partially saponified ethylene-vinyl acetate copolymer. A stirred
solution of the wall material in toluene is warmed and treated
with a solution of polydimethylsiloxane in toluene (1 : 1) and
with the glycerol to be encapsulated. Three phases are formed:
the continuous phase with polydimethylsiloxane in toluene,
the glycerol phase as the microcapsule core, and a solution
of the wall polymer in toluene. After cooling and crosslinking
of the wall material the microcapsules are separated with
toluene dii~ocyanate[~~!
In a technically reliable microencapsulation technique[37]
a copolymer is used consisting of hydrophilic and hydrophobic
monomer units. It is insoluble both in the core material (for
example hydrocarbons) and in water. The copolymer of various
acrylic and methacrylic acid derivatives is dissolved in a lowboiling solvent, e. g. chloroform and isopropyl alcohol, and
added to an emulsion of the core material in water with
vigorous stirring. The water as the external phase contains
a protective colloid, for example polyvinylpyrrolidone. On
dispersion the polymer solution is distributed over and around
the core material droplets. Depending on solubility, the organic
solvents at once become distributed over the core phase, the
During conversion of a lyophilic colloid from the sol state
into that of a solid precipitate by insolubilization an intermediate state can arise. This state is characterized in that the
previously uniformly distributed colloid or polymer precipitates in a second, still liquid, solvent-containing phase. Bungenberg de Jong and K r ~ y t [ called
~ ~ l this process coacervation
(Latin "acervus", heap).
The coacervation, triggered off by the addition of a salt
or precipitant, by dilution, or by a change in pH, begins
with the precipitation of very fine coacervate droplets accompanied by clouding of the previously almost clear sol (microcoacervation).
As the coacervation continues the fine coacervate droplets
coalesce into larger ones (macrocoacervation), until a coherent
coacervate phase is formed which contains practically all of
the polymer. The coacervate droplets display a tendency toward enclosing solid particles, such as dyes, present in the
used this phenomenon for microencapsulating
very finely dispersed dye precursor solutions, which he divided
and dispersed in the polymeric solution before carrying out
the coacervation (Fig. 9).
Fig. 9. Schematic representation of microencapsulation by coacervation. a)
Dispersed core material droplets in gelatin/gum arabic solution; b) beginning
of coacervation by precipitation of fine-particle mlcrocoacervate from the
solution; c) gradual precipitation of the microcoacervate on core material
droplets; d ) coalescence of the microcoacervate of the wall material phase. Encapsulation by Complex Coacervation
Complex coacervation is the mutual precipitation of two
oppositely charged sols or polymers in solution to form a
complex coacervate. A gelatin solution is mixed with a gum
arabic solution at, for example, pH 4.5 and is then diluted
(Fig. lo), or the pH of the diluted solution is slowly adjusted
to pH 4.5. Gelatin is an amphoteric polymer with an isoelectric
A n y i w . Chrm. intrmat. Edit.
/ Vbl. 14 ( 1 9 7 5 )
No. (I
point at pH 8. On acidification of the solution the polymer
becomes positively charged and interaction with the always
negatively charged gum arabic takes place. Since gelatin solutions gel at room temperature, the complex coacervation is
carried out above the gelation temperature of 37 “C.
100 ‘lo H20
50’6 Gel
50% G a.
Fig. 10. Three-component diagram for complex coacervation of gelatin (Gel.)
and gum arabic (G. a,) by dilution with water at pH 4.5; dilution proceeds
along the line from A to B; K=complex coacervate region (both polymers
arein thecoacervate); H = homogeneoussolution region; P=phase separation
region in which the two polymers are present in different phases (after [39]).
Industrial scale microencapsulation is carried out as follows:
The solution of the gellable hydrophilic polymer gelatin is
placed in a stirred vessel and the core material, e. g. the solution
of dye precursor, is emulsified in it until the desired particle
size of say 2-5 pm has been obtained. Gum arabic solution
is then added. Coacervation occurs, the system being constantly stirred. Subsequently the composition is cooled from
50°C to 5-10 “C and the gelatin-gum Brabic complex coacervate which has precipitated around the core phase is allowed
to gel. It is hardened by the addition of glutaraldehyde or
formaldehyde and slow adjustment of the pH to 9-10 with
caustic soda.
This process is used, for example, for the production of
microcapsules used in the manufacture of carbonless copy
paper (Sections 4.1.1 and 4.1.2). The microcapsules obtained
by this method are to a greater or lesser extent cluster aggregates (cf. Fig. 1 b). By taking suitable measures the agglomeration can be Encapsulation by Chemical Reaction of the Polymer
The solution of hydrolyzable cellulosederivative is dispersed
in the core material, e.g. a solution of the aniline dye Ceres
Blue GNR in a mixture of 68 parts of cyclohexanone and
25 parts of diphenoxyethylformal in water containing caustic
soda and some dispersant. The dissolved cellulose derivative
is saponified, which leads to the precipitation of a waterand core-material-insoluble cellulose film on the core material
as a third phase. Capsules 30-50 pm in diameter are formed
and can be isolated after washing with water‘411.
4. Applications of Microcapsules
4.1. Capsules with Impermeable Envelopes
4.1.1. Carbonless Copy Paper
In the past copies of writing were produced solely by inserting a sheet of carbon or copying paper between the original
Angew. Chem. internat. Edit.
/ Vol. I 4 ( 1 9 7 5 ) / No. 8
and the intended copy. The impression was obtained through
the transfer of carbon, by virtue of the writing pressure, from
the layer on carbon paper onto the sheet underneath. This
technique is simple but has certain drawbacks. The inserted
carbon paper makes the paper assembly thicker. Parts of
the assembly shift readily out of register and the whole is
therefore difficult to manipulate. The carbon paper tends to
soil the fingers and the copy. The copy itself is not rubproof.
Environmental problems arise during destruction of the
These adverse factors soon prompted a search for an
improved, “cleaner” method of copying. The work undertaken
to this end led to a number of novel mechanically and chemically reacting copying paper. The latter has become known
in the English-speaking countries as carbonless copy paper
or simply carbonless paper. It is estimated that 500000 tons
of carbonless copy paper was used in 1974 in the Western
hemisphere, including Japan: this corresponds to 50000 tons
of microcapsules. The proportion of carbonless paper in the
copy paper market varies between 7 and 40
In these carbonless papers the carbon is replaced by a
solution of dye precursor which is transferred to a specially
prepared surface of the copying sheet underneath, on which
the dye develops.
Initially, the back of the top sheet was for this purpose
provided with a type of foam coating, in the voids of which
the dye precursor solution was located. However, this arrangement was not very successful[431.It was not until Green[391
produced microcapsules by successfully enveloping very fine
droplets of dye precursor solution with gelatin by means
of coacervation that the breakthrough for carbonless copy
paper arrived. Microencapsulation began to develop at the
same time.
4.1.2. Makeup and Mode of Action of Carbonless Copy Papers
How are carbonless copy papers made today? Let us take
a look at a simple set of invoice forms, or a transfer requiring
two copies. The top or CB (coated-back) sheet carries the
microcapsule layer on the back. Underneath lies a middle
or CFB (coated front and back) sheet, carrying the developer
layer on the front and the capsule layer on the back. Below
this is the bottom or CF (coated front) sheet with the developer
layer on top.
The individual layers can be reproduced with the aid of
scanning electron microscopy (SEM). Fig. 11a shows the surface of untreated paper, Fig. 11b the same paper coated with
the active adsorbent, the developer or acceptor layer (78 g/m*). The developer layer consists of activated inorganic
pigments such as attapulgite, Fuller’s earth, silica gel, and
sodium aluminum
which are fixed together with
a binder, e. g. a polymer dispersion. Recently, organic substances such as phenolic
and salts of salicyclic acid
derivatives have been used as developers.
Fig. l l c shows a layer of microcapsules on the back of
the top or CB sheet (5 g capsules/m2).The botryoidal aggregation of gelatin capsules is embedded in a binding material.
The cellulose cuttings, which are added to the layer of capsules
as a spacer, prevent premature destruction of the capsules.
Starch and other powders have recently been employed as
Fig. 11d shows a layer of single microcapsules on the back
of a top or CB sheet. The wall of the capsules manufactured
I +O
Fig. 13. Development of color from N-benzoylleukomethylene blue (top)
by slow hydrolysis to leukomethylene blue (center) and its rapid photooxidation to the pigment ion on the developer layer (bottom).
to activated pigment, any site where the capsules are destroyed
at once produces a mark caused by the color former developing
on adjacent pigment. Thus, these papers furnish copies even
when used in combination with unprepared paper.
4.1.3. Additional Uses of Microcapsules with Impermeable
Liquid crystals of the cholesterol ester type are protected
from UV light, moisture (hydrolysis), and impurities by microencapsulation in capsules 1&30 pm in diameter[”]. In
this form they can be easily utilized. Their property of changing
color with temperature is used in medical diagnosis for determining skin temperature characteristicsr’*.5 3 1 and in other
For producing lightweight papers an attempt was made
to use hollow spheres with a diameter of 25-28 pm as lightweight
They are manufactured by emulsion polymerization[’61of vinylidenechloride and subsequent formation
of hollow microcapsules by expansion of the polymer particles
containing isobutane as a blowing agent.
The irritant action of flame-retardant substances on the
skin and mucosa, above all of halogenated organic compounds,
can be reduced substantially by microencapsulation. The compatibility of the encapsulated substances with polymeric systems is increased, thus improving their blendability. In case
of fire the capsule opens as a consequence of the rise in
temperature and releases the flame-retardant‘’ ’I.
Microencapsulation of adhesives, above all two-component
adhesives, also offers many advantages. In the case of unsaturated polyesters, and especially epoxides, the liquid components
Angew. Chem. inrernat. Edit. J Vol. 14 ( 1 9 7 5 )
No. 8
are encapsulated[’*! The capsules (25-150 pm in diameter)
are processed together with the binder and the second component. In aircraft‘“] and automobile[611construction e. g.
they are applied onto screws[591or rivets; the capsule contents
are released on riveting or screwing,and the result is a metal-tometal bond plus an anticorrosive effect.
After the encapsulation of liquid curing agents such as
triethylenetetramine and hexamethylenetetramine and mixing
with epoxides, a slow outward diffusion and reaction cannot
be avoided. All the same, the time needed for setting to take
place after mixing increases to 10 days to 8 weeks. The contents
are released by heating[621.
The use of microencapsulated flavors, leaveners for bakery
goods, fermentation agents, oils, and fats has become widespread in the food industry, especially where liquid substances
must be converted into solids for dry mixes or where an
improved durability or reduced volatility is desired. The active
content of the capsules is 50-90%. Release is by heat, by
pressure (chewing gum) or by dissolution of the wall (above
40°C). Natural or synthetic polymers tested and approved
by the American FDA are used as wall materials. Examples
are gelatin, gum arabic, and cellulose derivatives.
In the marine feedstuffs sector efforts are being devoted
to developing feeds sufficiently finely divided for freshly
hatched fish; however, no suitable composition has as yet
been discovered[63! Feeding of encapsulated unsaturated vegetable fats to cattle leads to the production of milk containing
a higher proportion of unsaturated fats. The capsule walls
protect the unsaturated fats from enzymatic hydrogenation
during the passage through the stomach and open only later,
in the acidic intestinal portion of the digestive tract, where
the fats hydrolyze[64! The encapsulation of vitamins and hormones to protect them against oxidation and degradation
is also known in the feedstuffs industry.
Brighteners in household detergents have been encapsulated
(to provide protection against bleaching agents), as have also
bleaching agents and odoriferants[6’!
An attempt is being made to encapsulate certain rodenticides
in order to neutralize their taste. The amounts ingested by
rats are indeed increased, but the mortality rates achieved
give conflicting results. It is probable that the release
mechanism has not yet been adequately mastered[661.
To combat fire ants Mirex capsules have been developed.
By encapsulating the insecticide the applied dose is reduced
to one-half or o n e - q ~ a r t e r [681.
4.2 Microcapsules with Controlled Release of the Contents
The enveloping of readily soluble fertilizers[691has long
been of interest to agriculture. Waxes, resins, asphalt, and
also plastics made of urea-formaldehyde resins, polystyrene,
polyethylene, and even polyepoxides and polyurethanes, have
been employed for enveloping. A uniformly diminished dissolution rate is obtained both by multiple coating-e.g. of
ammonium nitrate, aiming at a decrease in the hydrophilic
properties of the wall material toward the outer
and by single coating of compound fertilizers. Fig. 14 demonstrates the release of the nitrogen component of a compound
fertilizer encapsulated with 1-10
by weight polybutadiene,
which is active up to a complete growth period of 6-9
months[711.The combination of aminoplast resins with a very
wide range of polymers gives similar results[72! Urea envel547
oped in sulfur[731and a wax-capsulated fertilizer solution[741
intended for small gardens have recently been developed.
'oar I
0 48 96 144 192 240
Fig. 14. Fertilizer release (in
nitrogen) with time f following the water
immersion of a compound manure (13 N/13 P205/21 K 2 0 ) particle size
2-4mm, enveloped in 1-10 wt-% polybutadiene (after [71]).
Encapsulation avoids a high local fertilizer concentration
and reduces the number of applications required. With small
amounts of the coating material, for example less than about
1 % polybutadiene on 2-4 mm fertilizer grains, nondusting
and noncaking materials are obtained[751.
Encapsulation of the sown crops retards germination to
such an extent that summer grain can be sown as early as
the fall. The result is a very early appearance of the crops
in the spring[76!
The insecticide methyl parathion has been encapsulated
with polyamide[261,whose degree of crosslinking determines
the rate of release. Methyl parathion [O,O-dimethyl-0-(pnitropheny1)thiophosphatel has a short persistence of several
hours to some days and is very toxic. Encapsulation to give
a diameter of 30-50pm
allowed the persistence to be
increased and the toxicity to be reduced to 1/9th. The slow
release by diffusion and the greater persistence allow smaller
doses and fewer applications to be used177*
681. This type of
product has been approved for cultures of cotton, lucerne,
and sweet corn by the FDA in the United States since 1974.
Copper sulfate is encapsulated to act as a water herbicide
(algicide)[68! The capsules, 1600pm in diameter, cannot be
sprayed. They sink to the bottom in water and slowly liberate
the copper sulfate by diffusion through micropores or after
biological degradation of the capsule wall. Field trials are
being conducted on encapsulated insect sexual stimulants and
In pharmacology an attempt is being made to achieve a
depot effect by slow release of the therapeutic agent from
the microcapsules and to prevent an overdose immediately
6* 351.
Here masking the
after administration[78*
tastefsO. protection against oxidation[821are also of vital
importance. Gelatin, gum arabic, hydroxystearyl alcohol, glyceryl monostearate, sodium alginate, ethylcellulose, and carboxymethylcellulose are used as the capsule wall materials.
In the cosmetic industry, the release of deodorants, perf u m e ~ [831,
~ ~and
anti trans pi rant^[^^] can be controlled by
microencapsulation, i. e. their action can be sustained.
4.3. Microcapsules with a Semipermeable Envelope
Semipermeable microcapsules offer a sound prerequisite
for separating substance systems. As packings in columns
they are simple and clean in use. Their very small dimensions
give them an extremely high area-to-volume ratio, while their
very thin membrane-like envelope is very stable. Thus, they
allow a high rate of exchange.
Kondo et dLS5]
have determined the permeability constants
of 24 different, encapsulated electrolytes. The capsule walls
were prepared by interfacial condensation from diethylenediamine and terephthaloyl dichloride. The permeability constant
of the 2pm capsules was very small (10-8cm/s). Diffusion
obeyed Fick's law.
Thies et al. used water-containing microcapsules for the
liquidfliquid extraction of monoethylamine, triethanolamine,
and triethylenetetramine in chloroform or toluene[86! The
capsules were prepared by a special
with walls
of partially hydrolyzed ethylenevinyl acetate copolymers and
were crosslinked with isocyanate. They were used in a normal
chromatographic column. Up to a certain limiting value the
capsules absorb the amines completely.
Microencapsulated activated charcoal["] (see Fig. 6) has
been used, inter alia, for the preparation and purification
of kanamycin, tuberactinomycin from its mother liquor, lysozyme from protein, and decolorization of protease solution.
Microcapsules with semipermeableenvelopes are equivalent
to natural biological cells and mitochondria. Chang[9s871has
prepared a series of microcapsules of varying selectivity (see
Fig. 5) and reactivity ("artificial cells"). The envelopes were
generally obtained by interfacial condensation. Selection and
combination of a wide range of monomers enabled very different envelopes to be produced, capable of withstanding considerable internal pressures. Individual enzymes and enzyme
combinations were encapsulated. Urease, carboanhydrase,
trypsin, catalase, aspariginase, lipase, lactase, and the hemolyzate of red blood cells are active in the encapsulated form.
At high protein concentrations the stability of encapsulated
enzymes is better than that of free enzymes[87].
Chang is attempting to use the artificial cells for building
up artificial organs, for the treatment of liver and kidney
failure and in treating cases of drug poisoning. In order to
make the microcapsules compatible with blood they are
coated with albumin.
Microencapsulated urease selectively converts urea into
ammonia[881and blood urea can thus be transformed in an
exchange chamber located outside the body. The ammonia
formed must be bound by a special adsorbent[891.Microencapsulated asparaginase enables asparagine to be removed selectively and, in this way, the growth of asparagine-containing
tumors is suppressed. Uremic toxins can be removed with
microencapsulated activated charcoal. The adsorption is very
An artificial kidney has been developed which has been
in clinical use for the past 4 years. Inside the small apparatus
300 ml of large microcapsules (about 200 pm in diameter) have
a surface area of 2.25 m2, which is twice that of the membrane
of a standard artificial kidney (1 m'). As a result of the very
thin membranes (0.05pm) a 200 times faster transport rate
is obtained, and the patient-treatment time can be reduced
from 6-12 h to 2 hIE7].
Angeni Chem. inremar. Edit.
/ Vol. 14 ( 1 9 7 5 ) No. 8
5. Concluding Remarks
In the initial stages of the development of microencapsulation impermeability of the capsules was the main concern.
Under these circumstances the core substance can be released
and e.g. made available for a reaction only by destruction
of the capsule wall. This procedure has rapidly gained major
economic importance, notably for encapsulating color-former
solutions for carbonless copy papers. At first the encapsulation
was carried out by depositing gelatin envelopes onto liquid
droplets of an aqueous emulsion, but with the course of development new techniques and new natural and above all synthetic polymers began to be used as the wall materials. As a
result, the increasing variation in the possible core materials
was accompanied by a variation in the properties of the envelope.
At the present time envelopes making possible a slow release
of the core substance are being investigated. Drugs, fertilizers,
and plant-protection agents are being studied as the core
materials. The aim is to obtain a uniform release of the active
principle over a prolonged period and to avoid harmful overdoses at the commencement of use. The developing environmental consciousness has led to new tasks being posed in
respect of plant-protection agents for which microencapsulation too is being employed in various laboratories. Extensive
experiments are required to obtain oficial authorization to
use the encapsulated active principles. An encapsulated insecticide has already been approved for certain crops.
Microcapsules with semipermeable envelopes can be produced and used for separation processes. Their use in biochemistry and medicine is of special interest. Here enzymes
and enzyme systems in addition to adsorbents can now be
given a stable encapsulation. These microcapsules are the
equivalent of artificial cells. Packed in columns, they can
perform the function of organs; an artificial kidney of very
small dimensions (about the size of a football) is already
undergoing clinical trials.
Much work remains to be done in matching the properties
of thecapsules to the circumstances and to exhaust the possibilities offered by microencapsulation. Future development of
microencapsulation commands great interest.
Received: June 5. 1975 [A 77 IE]
German version: Angew. Chem. 87,556 (1975)
Translated by Express Translation Service, London
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C 0M M U N I C AT1 0 N S
pectation that even a cyclopropenyl radical with 3x-electrons
has antiaromatic characterf5!
By known methods[61we have prepared di-tert-butyl-(3,5-ditert-butylpheny1)cyclopropenylium perchlorate ( 1 1 and from
this by means of LiAIH4 1,3-di-tert-butyl-2-(3,5-di-tert-butylpheny1)cycloprepene (2). Photolysis of a solution of (2) in
di-tert-butyl peroxide['] at - 30°C affords a radical (3) whose
ESR Proof of the Antiaromaticity of a
Cyclopropenyl Radical"'
By Kurt Schreiner, Wilhelm Ahrens, and Armin Berndt"]
Dedicated to Professor K. Dimroth on the occasion of his 65th
The simplest representatives of previously known antiaromatic[*} compounds are the 4x-electron systems cyclobutadiene and the cyclopropenyl anions bearing substituents
that force the carbanion center to adopt a planar configuration.
Calculations by the electron gas method[31and MO calculations with consideration of overlap integralsc4]lead to the ex[*] Prof. Dr. A. Berndt, Dr. K. Schreiner, and Dipl.-Chem. W. Ahrens
Fachbereich Chemie der Universitat
355 Marburg, Lahnberge (Germany)
Fig. 1. ESR spectrum of the di-tert-butyl-(3,5-d1-tert-butl.lphenyl)cyclopropenyl radical (3) in di-tert-butyl peroxide at -30°C.
Angew. Chem. inrernar. Edit. / Vol. 14 ( 1 9 7 5 ) 1 No. 8
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