7620 J . Am. Chem. SOC.

1981,103, 7620-1629
then boiled briefly, cooled to room temperature, and acidified with 20% indicating a mixture of compounds. Gradually the spectrum of this
DCI. The amino anhydride 3 that crystallized was removed by centri- region became less complex; after 30 min most of the spectrum appeared
fugation. The supernatant was again made basic with NaOD; during the to be due to a single compound. By then two new doublets (6 6.68, J =
addition, more anhydride crystallized and was removed by centrifugation: 12 Hz; 6 7.12, J = 11 Hz) had appeared.
NMR (of supernatant) 6 2.50 (3 H, s), 6.89 (1 H, d of d, J = 2 Hz, J Reaction of 10 with H20, Ethanolamine, and Mercaptoethanol. A
= 8 Hz), 7.17 (1 H, d, J = 8 Hz), 7.37 (1 H, d, J = 2 Hz). Two singlets, 60-MHz ‘H NMR spectrum of a 10% (w/w) solution of 10 in D 2 0 was
at 6 2.78 and 7.54, were attributed to 4-methylaniline-3,5-disulfonate obtained immediately after the compound was dissolved; this spectrum
(about 12 mol %). Two multiplets at 6 7.79-8.00 and 8.59-8.75, at- was the same as that subsequently obtained after the solution had stood
tributed to residual naphthalimide impurities, integrated to a total of 0.78 at room temperature for 6 h, 30 h, 10 days, and 75 days. Compound 10
H. was distinctly less stable in weak base. The NMR spectrum of a freshly
5-Amiw-2-toluenesulfoNcAcid (Eastman): NMR (D20/OD-) 6 2.49 prepared 10% (w/w) solution of 10 in 0.1 M Na+/D+ carbonate buffer
(3 H, S, CH3), 6.86 (1 H, d ofd, J = 2.5 Hz, J = 8 Hz, 4-H), 7.14 (1 in D20 was very similar to the spectrum of 10 in D20. After 1 day at
H, d, J = 8 Hz, 3-H), 7.34 (1 H, d, J =I 2.5 H, 6-H). rwm temperature, the pD 9.1 spectrum was not noticeably different, but
6-Amlno-3-tolwnesulfonicAcid (Aldrich): NMR (D20/OD-) 6 2.24 after 9 days at room temperature the intensity of the vinyl protons was
(3 H, S, CHS), 6.84 (1 H, d, J = 8 Hz, 5-H), 7.17 (1 H, d of d, J = 2 reduced, and a new peak had appeared at 6 5: 3.50. It was estimated
Hz, J = 8 Hz, 4-H), 7.49 (1 H, d, J = 2 Hz, 2-H). that between 20% and 50% of the compound had been converted, pre-
Reaction of 5 with Propionaldehyde and Formaldehyde. Equal volumes sumably to the lithium salt of 7.
of 0.2 M propionaldehyde and 0.2 M 5 in D20 were mixed at room The NMR spectrum of 52 mg of 10 in 0.4 mL of D20 and 0.1 mL
temperature, and the NMR spectrum was recorded as soon as possible. of 0.5 M Na+/D+ pD 9.1 carbonate buffer was obtained. To the sample
Within 120 s the aldehydic proton (6 5: 9.67) was greatly reduced; a new tube was added 14 WLof ethanolamine, and within 120 s the NMR
triplet (6 7.52, J = 5 Hz) had appeared. A similar experiment with spectrum of the vinyl region was recorded. No signals were seen, indi-
formaldehyde was complicated by the fact that the resonance from the cating that at least 90% of compound 10 had reacted. The complete
formaldehyde protons at 6 4.82 was too close to the HDO peak for spectrum showed the presence of two multiplets at 6 N 3.0 and 6 = 3.7.
adequate observation. A rapid reaction, however, seemed likely, since A similar experiment was performed with 2-mercaptoethanol with
the first obtainable spectrum of the naphthalimide region was complex, virtually identical results.

“Wolf and Lamb” Reactions: Equilibrium and Kinetic

Effects in Multipolymer Systems
B. J. Cohen,* M. A. Kraus, and A. Patchornik
Contribution from the Department of Organic Chemistry, Weizmann Institute of Science,
Rehovot, Israel. Received April 8, 1981

Abstract: Two reagents reacting avidly with each other in solution are rendered mutually inactive by attaching each to a separate
batch of insoluble polymer. Two-stage reactions in which a soluble reagent reacts first with one polymeric reagent and the
product with the second polymeric reagent afford advantages over analogous reactions in solution. In acylation reactions of
carbon acids, the simultaneous use of a polymeric strong base and a polymeric acylating reagent proved to be superior to the
use of soluble reagents, both for bringing about quantitative acylations and for coping with undesirable side reactions. New
polymeric strong bases were prepared: polymeric trityllithium, para-substituted trityllithium polymers, and polymeric lithium
diisopropylamide. Active esters of polymeric o-nitrophenol and N- 1-hydroxybenzotriazole were used as acylation reagents.
The scope and limitation of these reactions and their application to general multiphase systems are discussed.

Polymeric reagents-reactive, low molecular weight molecules A t present, few examples exist in which more than one poly-
bound to a polymeric backbonehave been widely used in organic meric reagent is used in a particular reaction. Pittman and
chemistry during the past two decades. The most significant Smith,I5 for instance, described a reaction involving the simul-
advantages of these reagents over their soluble counterparts are taneous use of two polymeric organometallic catalysts for con-
the ease of their separation from the reaction mixture and their secutive isomerization and hydrogenation of olefins. Use of two
possible recycling. Polymeric catalysts, polymers for specific insoluble polymers or a mixture of a soluble and an insoluble
separations, carriers for sequential synthesis, polymeric blocking polymeric reagents for peptide synthesis has also been
groups, and polymeric transfer reagents in general organic syn-
thesis, all have utilized these advantages. Use has also been made
of the fact that chain fragments within a crosslinked polymeric (4) Patchornik, A.; Kraus, M. A. Pure Appl. Chem. 1975,13, 503-526.
backbone have restricted mobility. Active species attached to the (5) Neckers, D. C. J . Chem. Educ. 1975, 52, 695-702.
polymer can thus be effectively isolated from each other a t rel- (6) Weinshenker, N. M.; Crosby, G. A. Annu. Rep. Med. Chem. 1976,11,
atively high concentrations, providing the advantages of high 261-270.
(7) Mathur, N. K.: Williams, R. E. J . Mucromol. Sci., Rev. Macromol.
dilution and specificity, along with rapid kinetics. In other cases, Chem. 1976, CIS,117-142.
properties of the backbone itself such as polarity, pore size, and (8) Crowley, J. I.: Rapoprt, H. Acc. Chem. Res. 1976, 9, 135-144.
chirality were utilized to achieve unique reactions, the polymer (9) Heitz, W. Adv. Polym. Sci. 1977, 23, 1-23.
providing a specific microenvironment for the reaction. These (10) Leznoff, C. C. Acc. Chem. Res. 1978, 11, 327-333.
(11) Kraus, M. A.; Patchornik, A. CHEMTECH. 1979, 118-128.
aspects of polymeric reagents have been extensively reviewed.’-14 (12) Kraus, M. A.; Patchornik, A. Macromol. Rev. 1980, I S , 55-106.
(13) Mathur, N. K.; Narang, C. K.; Williams, R. E. “Polymers as Aids
(1) Pittman, C. U.; Evans, G. 0. CHEMTECH. 1973, 560-566. in Organic Chemistry”: Academic Press: New York, 1980.
(2) Leznoff, C. C. Chem. SOC.Reo. 1974, 3, 65-85. (14) Hodge, P., Sherrington, D. C., Eds. “Polymer Supported Reactions
(3) Overberger, C. G.;Sannes, K. N. Angew. Chem., Int. Ed. Engl. 1974, in Organic Synthesis”; Wiley: New York, 1980.
13, 99-104. (15) Pittman, C. U.; Smith, L. R. J. Am. Chem. Soe. 1975,97,1749-1754.

0002-7863/8 1/ 1503-7620$01.25/0 0 198 1 American Chemical Society

Equilibrium in Multipolymer Systems J . Am. Chem. SOC.,Vol. 103, No. 25, 1981 7621

Scheme I Scheme 111

+ B
A - products S 2 SA* SAB

@-A + Q-B - no reaction \ ;!de product;

@-A + S + @-E
Scheme IV
SA -!-- S A B desired product

Scheme I1
C 6 H 5 C H z C N 4- ( C 6 H 5 ) 3 C CsH5CHCN
CBH~CH‘CN
S SA SAB C~HSCHCN
I
COC6H5 OCOC6H5
However, beyond the convenience of facile separation of products,
no additional advantages over the use of the corresponding soluble “messenger” reagent S: it will react first with @-A leading to
reagents were presented in those reactions. a soluble product SA, the latter moving to @-B and reacting with
In a series of studies, mainly by Rebek and his co-workers18-z2 it to give the end product SAB. It is impossible to carry out the
and also by our it has been discovered that two insoluble corresponding reaction with soluble reactants because A and B
polymeric reagents in the same reaction mixture can provide some will interact, and the overall reaction must be separated into two
unique capabilities. Such mixtures, for example, have been used steps: first, a reaction of S with A, followed by a reaction of SA
in mechanistic studies to establish the existence of highly reactive with B.
free species in solution. These species which were generated by We examined the advantages of the polymeric reagent approach
one polymeric reagent reacted with the second to yield a product in reactions, both a t equilibrium conditions and under kinetic
attached to the latter. control. In either case, the two-polymer system proved to be
W e have studied the possibility of using a mixture of two superior to a two-stage conventional reaction carried out with
insoluble polymeric reagents for synthetic purposes. We hoped soluble reagents.
that such an undertaking would eventually provide benefits beyond At equilibrium, the system in solution may be described as
those described above and that this approach could even be used shown Scheme 11.
to modify the usual course of reactions. Indeed, our initial resultsz4 The reaction of 1 equiv of A with 1 equiv of S will not lead
showed that these assumptions were correct. The present work quantitatively to SA. Equilibrium concentrations of the three
provides the theoretical basis as well as additional experimental components S, A, and SA will depend on the equilibrium constant.
evidence for the advantages in using a multiplicity of polymeric The same is true for the reaction of SA with B. If an excess of
reagents in organic synthesis. A is used to promote SA formation, this excess should be removed
prior to the introduction of B, otherwise an ensuing reaction
“Wolf and Lamb’ Reactions-Theoretical Considerations between A and B will lower the yields and complicate the sepa-
Multipolymer systems of insoluble polymeric reagents are ration process. With polymeric reagents, on the other hand,
unique in that reactions can only take place within the matrix of excesses of @-A and @-B may be used simultaneously, without
the polymeric reagent. This spacial localization of various reaction polymer interaction. S will react with the excess of @-A and will
steps to their respective polymeric phases can lead to advantages lead to quantitative formation of SA, which will further react with
not found in conventional reactions in solution, where all com- the excess of @-B, yielding the desired final product. Excess @
ponents can interact s i m u l t a n e ~ u s l y . ~ ~ -A and @ -B are easily separated out by filtration, eliminating
We investigated twestage reactions in which a starting material laborious workup procedures.
is modified successively by two polymeric transfer reagents. The Under kinetic control the following scheme may be presented
analogous soluble reagents react with each other rapidly in so- (Scheme 111).
lution, but they are rendered mutually inactive upon their at- The reaction of S and A leads to an active species SA* whose
tachment to the respective polymeric phases. These reactions were reaction with B gives the desired product SAB. However, SA*
accordingly termed “Wolf and Lamb” reactions (after Isaiah may also react with unchanged starting material S or undergo
11:6). spontaneous decomposition, to give side products. In solution,
A general scheme for these reactions is as shown in Scheme a certain reaction time is needed to complete the transformation
I. of S to SA*. If B is introduced before quantitative formation of
A and B react with each other in solution. @-A and @-B are SA* has taken place, an undesired reaction will occur between
the corresponding insoluble polymeric reagents, which cannot B and unreacted A. During this time, however, side reactions
interact whenmixed. An indirect reaction between @-A and @ involving SA* molecules already formed may occur. The extent
-B is possible only through the mediation of a third, soluble of these will depend on the various reaction rate constants. Here
again, utilization of a two-polymer system with excesses of @-A
and @-B may be helpful: any SA* molecule formed can im-
(16) Stern, M.; Kalir, R.; Patchornik, A.; Warshawsky, A.; Fridkin, M. mediately undergo a reaction with @-B, already available in the
J. Solid-Phase Biochem. 1977, 2, 131-139. reaction mixture, and unlike the reaction with soluble reagents,
(17) Heusel, G.; Bovermann, G.; Gohring, W.; Jung, G. Angew. Cbem., there is no need to wait for a quantitative formation of SA*.
Int. Ed. Engl. 1977, 16, 642-643.
(18) Rebek, J.; Brown, D.; Zimmerman, S . J. Am. Chem. SOC.1975,97, In the following sections, these two schemes are illustrated with
454-455. acylations of carbanions, and the advantages in the simultaneous
(19) Rebek, J.; Gavina, F. J. Am. Cbem. SOC.1975, 97, 3453-3456. use of two polymeric reagents are confirmed. In these examples,
(20) Rebek, J.; Gavina, F. J . Am. Chem. SOC.1975, 97, 3221-3222. the “A”’s are strong bases, “B”’s are acylation reagents of the
(21) Rebek, J.; Gavina, F.; Navarro, C. J . Am. Cbem. Soc. 1978, 100,
8 1 13-8 1 17.
active ester type, and “S”’s are ketones, nitriles, esters, etc.,
(22) Wolf, S.; Foote, C. S.; Rebek, J. J. Am. Cbem. SOC.1978, 100, possessing a-hydrogens abstractable by A.
7770-7771,
(23) Warshawsky, A.; Kalir, R.; Patchornik, A. J . Am. Cbem. SOC.1978, Results and Discussion
100,4544-4550. Polymeric Trityllithium la. When acylating carbon acids such
(24) Cohen, B. J.; Kraus, M. A,; Patchornik, A. J. Am. Cbem. SOC.1977,
99,4165-4167. as nitriles, esters, or ketones, having two or three a-hydrogens,
(25) Kraus, M. A. Ph.D. Thesis, Weizmann Institute of Science, Israel, the monoacylated product has a-hydrogens more acidic than those
1975. in the starting material. In the benzoylation of phenylacetonitrile,
1622 J. Am. Chem. SOC.,Vol. 103, No. 25, 1981 Cohen, Kraus, and Patchornik

Scheme V

-
Scheme VI

0 2 4 6 8 IO

TIME ( h r )
Figure 1. Loading of polymer I with anionic groups as a function of time.
I Ia
X = C1, OH; R = CH,, n-C,H, Table I
alkylation %
for example, treating 1 equiv of it (S) with 1 equiv of a strong starting material reagent product yield
base such as trityllithium (A) will produce 1 equiv of the anion
(CH,),CHCOC,H, CH,I (CH,),CCOC,H, 96
(SA). The anion will be formed quantitatively due to the large (CH,),CHCOC,H, C,H,CH,Br C,H,CH,C(CH,),COC,H, 98
difference between the pKa values of triphenylmethane and (CH,),CHCN C,H,CH,Br C,H,CH,C(CH,),CN 97
phenylacetonitrile. However, addition of 1 equiv of an acylation C,H,C=CH CHJ C,H,CsCH, 94
reagent such as an active ester of benzoic acid (B) will not lead
to the quantitative formation of the acylation product (SAB) 96
because of proton exchange between the product and anion
molecules not yet acylated (Scheme IV). I I
C H2C02E t
The result is an incomplete reaction and formation of mixtures.
The concentrations of the various species a t equilibrium depend
on the pKa values of A, SA, and SAB. The increased acidity of 98
the acylation product vs. that of the starting material makes proton I C,H,CH,Br I
interchange a common problem in acylations. It is impossible to
add an excess of trityllithium to promote the formation of the
product since this excess will reect competitively with the acylation
reagent.
Various ways to overcome this problem have been proposed:
inverse addition of a dilute anion solution to a concentrated solution
ro2 JNo2
of the acylation reagent, use of certain base-acylating reagent I

combinations such as ethoxide-ethyl ester, sodium hydride-ester I1 IIa, R = C,H,

or use of lithium diisopropylamide as the strong base, at very low b, R = OEt
temperatures. The results are not always satisfactory. According
to our suggested two-polymer approach, a strong polymeric base The structure of polymer I will be discussed later when para-
and a polymeric acylation reagent could be used to obtain the substituted tritylated polystyrenes are described.
desired product in high yield. Polymer Ia is very sensitive to moisture, oxygen, and carbon
Note that the acylation of carbanions does not exactly follow dioxide, as is its soluble analogue. Therefore, all manipulations
Scheme 11, and a more accurate description is according to Scheme involving this polymer were carried out under an inert atmosphere.
V. Polymeric trityllithium was shown to abstract acidic protons
Nevertheless, the use of polymeric reagents for this particular quantitatively from appropriate compounds. Excess of the polymer
example does not limit the validity of the considerations given was reacted with these compounds, followed by alkylation with
above for the use of polymeric reagents in reactions at equilibrium. an excess of soluble alkylating reagents in the same vessel.
To accomplish the “wolf and lamb” acylations we developed The alkylation products were obtained in excellent yields as
a strong polymeric base, polymeric trityllithium Ia (Scheme VI). Table I shows.
Polymer I, carrying triphenylmethane moieties, was prepared Although the excess of polymer Ia is also alkylated under these
by reacting polystyrene with benzhydrol or benzhydryl chloride conditions, this does not adversely affect the isolation of the desired
in a Friedel-Crafts reaction. With benzhydrol, lower loadings alkylation product, which is in solution. Workup of the reaction
(0.7 mmol/g) of trityl groups than with benzhydryl chloride (2.3 mixture was simple: the polymer was filtered and washed and
mmol/g) were obtained. The latter reaction also required less the excess of alkylating reagent was reacted with pyridine. The
catalyst. Therefore, polymer I obtained from the chloride was salts and excess pyridine were washed with dilute acid, and the
further used as our polymeric reagent. organic phase was evaporated to yield the pure product. The
The blood-red polymeric anion Ia was produced by reacting advantage of polymeric vs. soluble trityllithium was clearly dem-
polymer I with excess methyllithium or n-butyllithium in T H F onstrated by the fact that with the latter, chromatography was
or in 1,2-dimethoxyethane. The extent of ionization was deter- required to separate triphenylmethane from the product.
mined by washing excess reagents from the polymer, adding Using polymeric trityllithium, it was impossible to alkylate esters
ethanol, eluting the resulting ethoxide, and titrating with acid. having a-hydrogens. By the time proton abstraction was complete,
A typical loading vs. time graph is shown in Figure 1 . side reactions, probably condensations, had already occurred. This
In ordinary use, polymer l a with a loading of ca. 1.5 mmol/g will be discussed later.
of trityllithium groups was prepared by applying a 100% excess “Wolf and Lamb” Reactions. A special apparatus, described
of n-butyllithium in T H F for 2 h at 0 OC. in the Experimental Section, was designed for these reactions. In
Equilibrium in Multipolymer Systems J. Am. Chem. SOC.,Vol. 103, No. 25, 1981 7623

Scheme MI1 Scheme IX

Ia

Scheme X
this apparatus, the polymeric base Ia was prepared from polymer , - \
I by n-butyllithium in THF under inert atmosphere, while the
acylating polymer-an active ester of polymeric o-nitrophenol,
IIa or IIb26 (Scheme VI1)-was contained in a side arm.
After polymer Ia was prepared, excess n-butyllithium was
washed out and the side arm turned so as to add the acylating
polymer into the reaction chamber. The “wolf and lamb” effect
was clearly demonstrated, as the blood-red polymeric trityllithium
and the white polymeric active ester did not change their colors x
upon mkiig, whereas their soluble analogues reacted immediately 111, X = CH,
in solution. Color changes did occur, however, when molecules IV, X = OCH,
carrying an acidic hydrogen were introduced. The red polymer
Ia was converted to its white protonated from I, and the acylation
of the carbanion produced the orange polymeric o-nitrophenol I1
1
T H F n-BuLI

as its o-nitrophenolate salt (Scheme VIII).

In the benzoylation of phenylacetonitrile previously described,
the use of the two-polymer system offers a substantial advantage
over the reaction in solution. Molecules of phenylacetonitrile,
reformed at the acylating polymer as a result of proton interchange
between the product and anion molecules, can move back to the
polymeric base (present in excess), become deprotonated, acylated,
etc., until product formation is complete (Scheme VIII). The IIIa, X = CH,
stoichiometry of the reaction shows that 2 equiv of base are IVa, X = OCH,
required per 1 equiv of starting carbon acid (both polymer I1 and
the product will be ionized). We used a 150% excess of polymer Table I1 demonstrates the results of the “wolf and lamb” re-
Ia over that quantity and a 100% excess of the acylating polymer. actions vs. control reactions in solution.
Under these conditions, the reactions were complete within less The advantage of using polymers instead of soluble reagents
than 15 min. is impressive. The reaction solution has a light color and lacks
The mechanism just described implies that molecules of carbon the highly colored side products typical of many carbanion re-
acid may move repeatedly between polymeric reagents. Motion actions. The workup is very easy, mainly because of the insolubility
inside a polymer bead is diffusion-controlled and does not depend of the polymers. The high yields and purity of products are,
on stirring. Therefore, in order to shorten the residence time of though, unique to the two-polymer system. They stem from the
molecules within the polymer beads, and thereby shorten reaction fact that the two polymers constitute separate, noninteracting
times, the 20-50 mesh commercial polystyrene (XE-305, Rohm phases within the reaction system and the ensuing possibility of
and Haas) used for preparing the polymeric reagents in this work using excesses thereof.
was ground to beads of 100-150 mesh size. Considerable im- The above described reactions result in an ionized product. No
provement in reaction rates and yields was observed. Thus, with second acylation was evident, although excesses of the basic and
the ground polymers, benzoylation of acetophenone was completed acylating polymers were still present. This was further checked
in less than 15 minutes, whereas only 72% of the product were with two of the products. They were reacted in a separate ex-
obtained in that time with the polymers Ia and IIa prepared from periment with 1 equiv of base and then with an excess of the
nonground polystyrene beads. All the “wolf and lamb” reactions soluble acylation reagent. No further acylation was detected.
described in this work were therefore carried out with ground Polymers Carrying para-Substituted Trityl Groups. Polymer
polymers. I was obtained with loadings of trityl groups as high as 2.3
Control reactions with analogous soluble reagents were per- mmol/g. If the only modification occurring in its preparation is
formed in solution. An equivalent of trityllithium was first reacted at the phenyl rings of the polystyrene, this would mean that, on
with 1 equiv of the carbon acid, followed by addition of an excess the average, one out of every 5.9 phenyl rings is substituted.
of the acylating reagent. Without exception, the resulting reaction However, after examining molecular models, it seemed doubtful
mixtures had to be separated by chromatography. The work-up that such a high loading of the bulky trityl groups could be
of the two-polymer reaction was much simpler: after the reaction achieved solely by modification of the phenyl rings of polystyrene.
mixture was neutralized, the polymers were filtered and washed It seems much more likely that benzhydryl substitution also occurs
several times. The inorganic salts were washed with water and on the trityl groups generated in the initial reaction, the ultimate
the organic phase dried and evaporated to give the product in high result being grafting of the polystyrene (Scheme IX).
yield. This bushlike structure explains the low rate of hydrogen ab-
straction (see Figure 1) even when using the relatively unhindered,
(26) Kalir, R.; Fridkin, M.; Patchornik, A. Eur. J. Eiochem. 1974, 42, highly reactive methyllithium reagent. It is therefore assumed
151-156. that under the reaction conditions used routinely which lead to
7624 J. Am. Chem. SOC..Vol. 103, No. 25, 1981 Cohen, Kraus, and Patchornik
Table I1
09’ yield of
acylation % mction in
starting material reagent product yield solution
C,H,CH,CN C,H,CH(CN)COC,H, 94 45

C,H,CH,CN C,H,CH(CN)CO,Et 91 37
JNo2

CH,CN C,H,COCH,CN 90 27
d O C O C 6 H 5

C,H,COCH, C,H,COCH,COC,H, 96 48

C,H,COCH, C,H,COCH,CO,Et 92 40
(9-@-0c02E,
CH,CON(CH,), C,H,COCH,CON(CH,), 92 42
d O C O C 6 H 5

ca. 1.5 mmol/g of trityllithium groups, only the less sterically Scheme X I
hindered sites undergo ionization.
Since grafting of this type is likely to occur only at the para
position of the phenyl rings, blocking these positions should prevent
do /Ol
substitution. In order to test this point we prepared polymers I11
and IV carrying para-substituted trityl groups (Scheme X).
Loadings of only 1.1 mmol/g for polymer I11 and 1.O mmol/g
for polymer IV were obtained. These figures were determined
both by increase of weight, and by conversion of the trityl polymers
to their respective anions, IIIa and IVa, followed by titration, as
previously described for polymer Ia.
These loadings correspond to an average modification of one
out of every 7.5 phenyl rings of the parent polystyrene for polymer Scheme XI1
I11 and one out of every 7.4 rings for polymer IV. While these
values are almost identical, they differ from the value of 1/5.9
which was calculated for polymer I, assuming no grafting. The
differences in molecular sizes of the various polymer-bound trityl
groups cannot alone account for these loading values so that
grafting probably occurs in the case of polymer I.
The polymeric anions IIIa and IVa are expected to be stronger
bases than the polymer Ia.*’ No nucleophilic character of the
para positions in these anions is to be expected, as observed for
trityllithium.28 Because of these features, polymers I11 and IV
may find specific uses in the future.
Reactions under Kinetic Control. “Wolf and Lamb’ Reactions start in excess, can immediately react with enolate molecules
with Esters. Ester enolates can undergo self-condensation, a formed a t the basic polymer, without reaction between the two
reaction which competes with the desired acylation. When acy- polymers. Thus, the concentration of enolate molecules can be
lating an ester in solution using a strong base (such as trityllithium) kept low, and side products are not detected (Scheme XII).
and an acylation reagent, quantitative enolate formation must be The results of several “wolf and lamb” acylations of esters and
attained (as evidenced by the disappearance of the red color of yields of the control reactions in solution are shown in Table 111.
the base) before the acylation reagent can be introduced, otherwise The solution reactions produced various side products attributed
it will react with the remaining base. During this waiting period, to self-condensation. These impurities were avoided with the
some self-condensation may occur, depending on the reactivity polymeric approach. In addition to the kinetic advantages, the
of the enolate, its concentration, etc. For example, when y-bu- “wolf and lamb” reactions also proved to be superior by providing
tyrolactone is benzoylated, two products, a-benzoyl-y-butyro- high yields of acylation, a result of overcoming the proton-exchange
lactone and a-( 1-benzoyloxy-1-tetrahydrofury1)-y-butyrolactone, phenomenon in the particular esters being reacted, which had a t
are produced, the latter resulting from self-condensation (Scheme least two a-hydrogens.
x1).29 The rate of enolization and the lifetime of the enolate have an
When the same reaction is carried out as a “wolf and lamb” important role in determining the outcome of these reactions. It
reaction, using polymeric reagents, no waiting for complete enolate was already mentioned that no satisfactory alkylations of esters
formation is necessary. The acylating polymer, present from the were possible by using polymeric trityllithium and soluble al-
kylating reagents. The relatively long time (up to a few minutes)
needed for complete enolization of the ester when using the
(27) Streitwieser, A. Prepr., Diu. Pet. Chem., Am. Chem. SOC.1967, 12, polymeric base enabled self-condensation to occur. The compa-
C-21, C-22 (Chem. Absrr. 1967,67, 57703~). rable reaction with a soluble base is much more rapid and yet may
(28) Tomboulian, P.; Stehower, K. J . Org. Chem. 1968, 33, 1509-1512.
(29) Spencer, E. Y.;Wright, G. F. J . Am. Chem. SOC. 1941, 63, give rise to side products. In a “wolf and lamb” reaction, on the
1281-1285. other hand, the electrophilic polymer is present from the start and
Equilibrium in Multipolymer Systems J . Am. Chem. SOC.,Vol. 103, No. 25, 1981 1625
Table 111
~~

% yield of
polymeric % reaction in
starting material acylating agent product yield solution
CH,CO,Et C,H,COCH,CO,Et 92 38

CH,CO,Et 88 35

C,H,CH,CO,Et CBH~CHCOZEI
98 47
I
COCgHg

C,H,CH,CO,Et C,H,CH(CO,Et), 92 35

C,H,CH,CH,CO,Et 92 40

0 95 31

b C6H5C0f7
Scheme XI11 Scheme XIV
J N 0 2

C6H5\ yC’
/c=c
C6H5 ‘COCeH,

reacts with enolate molecules as soon as they are formed.

“Wolf and Lamb” Reactions with Short-Lived Species. Poly-
meric Lithium Diisopropylamide. High- yield “wolf and lamb”
acylations of esters can be carried out a t room temperature,
showing that ester enolates are relatively long-lived in the two-
polymer system. Because their side reactions are basically sec-
ond-order reactions, they can be controlled by reducing the ef-
fective enolate concentration with an excess of electrophilic
polymer. However, anions can also undergo first-order intra-
molecular changes, which are a function of temperature, but not
of concentration. As described above, a two-polymer system may
be used for reactions under kinetic control, whereby a short-lived
species generated at one polymer is reacted with a second polymer
before its decomposition can occur. We chose to study the acy-
lation of l , l -diphenyl-2-chloroethylene.The carbanion derived
from this olefin is stable in solution at -70 OC, and may be acylated
a t that temperature (Scheme XIII). At higher temperatures it
Va VIa
rearranges to d i p h e n y l a ~ e t y l e n e . ~ ~
W e attempted to acylate this anion a t higher temperatures,
using a two-polymer reaction. Trityllithium was found to be
insufficiently basic to abstract the ethylenic proton from 1,l-
diphenyl-2-chloroethylene.Therefore, a stronger polymeric base,
polymeric lithium diisopropylamide Va, was prepared according
to Scheme XIV.
8-Phenyldiisopropylamine was prepared by modification of a
general synthetic route for secondary hindered amines.” increase of weight) of 1.7 mmol of diisopropylamine groups/g of
Chloromethylation was carried out by using more than 1 equiv polymer. It was ionized with n-butyllithium in T H F to give the
of stannic chloride in order to complex the free amine and prevent polymeric anion Va, a dark brown polymer. Titration of the
it from being alkylated by chloromethyl methyl ether. The anionic polymer as described for polymeric trityllithium gave a
Friedel-Crafts attachment to the polymer was accomplished by loading value of 1.6 mmollg.
using the hydrochloride of the chloromethylation product. Polymer That polymer Va is a stronger base than polymer Ia was visually
V was obtained as white beads, with a loading (determined by verified by reacting the former with triphenylmethane. The
blood-red color of trityllithium gradually developed, the reaction
being slow because of the bulkiness of the two components.
(30) Kobrich, G. Angew. Chem., Int. Ed. Engl. 1972,II, 473-485. For the second component of the “wolf and lamb” experiment,
(31) Stowell, J. C.; Padegimas, S.J. Synthesis 1974, 127-128. the benzoyl derivative of polymeric N- 1-hydroxybenzotriazole
1626 J. Am. Chem. SOC.,Vol. 103, No. 25, 1981 Cohen, Kraus, and Patchornik

A
VIa32 was used. This polymer is the fastest known polymeric
acylating agent. An improved preparation of this polymer is
described in the Experimental Section.
The “wolf and lamb” experiments in this system, however, were
not successful. No acylation product was found when the reactions
were carried out a t temperatures down to -15 OC. Only the
rearranged product, diphenylacetylene, could be isolated (Scheme
XV) .
Apparently, the need to migrate between the polymers limits
these reactions to species with relatively longer lifetimes. Although
a carbanion molecule has to travel less than 0.1 mm to make this
trip (when a thick slurry of finely ground polymers is stirred),
the solid beads are surrounded by unstirred layers through which
the species must diffuse. Apparently, the diffusion is slow relative
to the lifetimes of the species we studied.
While these experiments were being carried out, a paper by
Rebek and co-workers was published.22 In that work, singlet
oxygen was generated under various conditions a t one polymeric
reagent and trapped by an olefin supported on another polymer
in the same system. The result of Rebek‘s experiments was that
singlet oxygen, with a half-lifetime of about 0.1 s, has little chance
of being trapped a t the second polymer before decomposition.
Single oxygen is a small and mobile molecule and Rebek’s reaction
was carried out in the gaseous state. Changing to organic reactive
species in organic solvents will make such reactions even less likely,
as our work verifies. Thus, enolates were found to be suitable
for “wolf and lamb” experiments whereas very short-lived species
are not. Figure 2. Apparatus for “wolf and lamb” reactions: a, main reaction
‘‘Wolf and Lamb Reactiom with Sodium Hydride as the Strong chamber; b, bath; c, sintered glass disk; d, side arm; e, solvent reservoir;
f, injection inlet.
Base. So far, only polymeric reagents consisting of soluble reagents
attached to insoluble polymers have been described. The general
considerations indicating that two noninteracting solid phases and to its basicity. Consequently, samples of this polymer were
a surrounding liquid phase may bring about distinct synthetic routinely reused for the “wolf and lamb” reactions. Other
advantages in two-stage reactions are not necessarily limited to polymeric bases described in this work which undergo ioniza-
tion-protonation cycles are also assumed to be recyclable, although
polymeric solids. Any insoluble, well-dispersed material capable
of carrying out chemical transformations should be suitable. this has not been checked.
Polymers, however, are unique in that any soluble reagent, in At the end of a “wolf and lamb” reaction, the mixture of
principle, may be attached to them, imparting a general appli- polymeric reagents may be separated by selective flotation, utilizing
cability. In addition, porous polymeric beads provide a large differences in their densities. Benzene (d = 0.88) and chloroform
surface area enabling easy access to solute components. Solid ( d = 1.5) can be mixed in such proportions as to cause flotation
chemicals are usually reactive only a t their surfaces and may be of one polymeric reagent and precipitation of the other. Each
less efficient. may then be collected and purified.
W e substituted sodium hydride for polymeric trityllithium Ia Experimental Section
in two “wolf and lamb” reactions. Otherwise, these reactions were General. The polystyrene used throughout this work was XE-305
run under the same conditions as the two-polymer reactions. As (Rohm & Haas). The polymer beads were ground for use in “wolf and
an example for an equilibrium-type reaction, the benzoylation of lamb” reactions as follows: the beads were suspended in the minimum
acetophenone was carried out with solid sodium hydride and amount of chloroform necessary for complete swelling. The slurry was
polymeric mitrophenyl benzoate IIa. The reaction was completed transferred to a blender operated at maximum speed for a few minutes
within 1.5 h due to the slower rate of reaction of the hydride, as (the blender blades must be very sharp to prevent the formation of fine
compared with the polymeric base Ia. The yield was however, dust). The polymer was dried and the 100-150 mesh fraction was col-
quantitative. lected.
When trying to benzoylate y-butyrolactone with sodium hydride Apparatus for “wolf and lamb” reactions: Figure 2 describes the
and the polymeric ester IIa, a mixture of products resulted. system used. It enables the preparation and washing of the polymeric
base under inert atmosphere in the main reaction chamber a, while the
Apparently, slow deprotonation with sodium hydride is incom- second polymer is stored in the side arm d. By turning it 180°, the second
patible with the lifetimes of ester enolates, and side reactions polymer is introduced into chamber a. Thus, all operations can be con-
become more pronounced. This implies that the success of the ducted conveniently in the same apparatus.
“wolf and lamb” two-polymer reaction is also due to the rapid Tetrahydrofuran and 1,2-dimethoxyethanewere directly distilled into
reaction between polymeric trityllithium and the soluble ester. the solvent reservoir e from trityllithium as follows: after a preliminary
Recycling of the Polymeric Reagents. The recycling of poly- drying and peroxide removal, half a liter of the solvent was treated with
meric reagents is an important goal, as their preparation is usually LiAIH4 until no hydrogen evolution was visible. Then 2-4 g of benzo-
longer and more costly than that of their soluble analogs. The pinacolone was added. The solvent was distilled from the deep red
ease of separation of the polymeric reagents simplifies their re- solution under an inert atmosphere. It should be noted that the polymeric
strong bases described in this work are washed several times with the
cycling, provided that no irreversible changes occur during their solvent prior to reaction. Even the smallest amount of water or oxygen
reactions. will produce a color change on the surface of the polymer beads. Such
The recycling of the polymer I, which was extensively used a sensitivity to solvent impurities is impossible with the soluble bases.
throughout this work, was studied by subjecting a sample of it NMR spectra were recorded on a Bruker 90-MHz NMR spectrom-
to three repetitive ionizations and titrations, as previously described. eter. Melting points are uncorrected.
Loadings of 2.20, 2.15, and 2.25 mmol/g, respectively, were re- Loadings of the polymeric reagents were measured either by increase
corded, proving that no changes occur in the polymer with respect of weight or by titration of the relevant functional group.
Polymer I Carrying Triphenylmethane Groups. a. Reaction of Poly-
styrene with Benzhydrol. Benzhydrol(l8.4 g) was dissolved in 100 mL
(32) Kalir, R.; Warshawsky, A.; Fridkin, M.; Patchornik, A. Eur. J . of chloroform and impregnated into 10.4 g of polystyrene by evaporation.
Biochem. 1975, 59, 55-61. A solution of 16 g of AlC13 in 50 mL of dry nitrobenzene was added. The
Equilibrium in Multipolymer Systems J . Am. Chem. SOC.,Vol. 103, No. 25, 1981 1621
resulting dark mixture was heated at 60 “C for 24 h. Workup was by “Wolf and L a m b Reactions. These reactions were carried out in the
a mixture of 50 mL of concentrated HCI, 50 mL of DMF, and 100 g of apparatus described in Figure 2. Dry THF was distilled directly into the
ice. After the beads became light-colored they were washed with warm solvent reservoir before each reaction. The acylating polymer was in-
(60 OC) DMF until the washings were colorless and then with six portions troduced into the side arm. The system was sealed and flushed several
of methylene chloride-methanol (2: 1). After being dried, the white times with pure nitrogen while the walls were heated to remove traces
polymer weighed 11.8 g (loading 0.7 mmol/g). of moisture. The bath was filled with an ice-water mixture, and the
b. Reaction of Polystyrene with Benzhydryl Chloride. Distilled ben- polymeric base Ia was prepared and washed as described above. The
zhydryl chloride (20.2 g) was absorbed into 10.4 g of polystyrene. A bath was then filled with water at room temperature, and the acylating
solution of 2 g of AICIJ in 50 mL of dry nitrobenzene was added. HC1 polymer was introduced by rotating the side arm. No reaction was
immediately evolved. After being stirred for 24 h at room temperature, apparent between the two polymers. The solvent level was adjusted so
the reaction mixture was decomposed as in a. Washing and drying of as to just cover the polymer mixture. The stirrer was rotated at moderate
the polymer afforded 16.9 g of white beads (loading 2.3 mmol/g). to high speed, and the substrate to be acylated was injected after being
Polymeric Trityllithium Ia. Although polymer I is indefinitely stable, dissolved in a small amount of dry THF. The colors of the polymers
the polymeric anion Ia is very sensitive to moisture, oxygen, and COZ. changed immediately. The reaction mixture was neutralized with hy-
It was therefore prepared individually for each experiment. Polymer I drochloric acid, and the polymers were washed 6-8 times with methylene
(2 g) was introduced into the reaction chamber a (Figure 2). Dry THF chloride-methanol (2: 1) solution. The solvents were evaporated, and the
was directly distilled into the solvent reservoir e. The system was closed, residue was taken up in ether, which after drying and evaporation af-
the walls were heated, and the apparatus was flushed with purified ni- forded the desired product. Sometimes, small polymer particles, either
trogen several times. Solvent (20 mL) was introduced and an ice-water formed by the abrasive action of the stirring or present due to imperfect
mixture was placed in bath b. An 8-mmol sample of a solution of n- sieving during the grinding of the polystyrene, were present. These fine
butyllithium in hexane or methyllithium in ether was injected slowly. particles could not be removed by using filter paper, and a short chro-
The polymer turned red, the color deepening with time. After the desired matography column was required.
period, the polymer was washed with 20” portions of solvent until the Thus, 120 mg of acetophenone were benzoylated by a mixture of ca.
washings were free of base. The appropriate reaction (titration, alkyla- 5 mmol of polymer Ia and 2 mmol of polymer IIa, to yield dibenzoyl-
tion, “wolf and lamb” reaction, etc.) was then performed. methane in 94% yield. Less than 15 min were required for completion
Titration of Polymer Ia. After preparation, polymer Ia was treated of the reaction. The results of other acylations are shown in Table 11,
with excess ethanol. The resulting ethoxide was washed into water with along with the results of control reactions in solution.
THF-ethanol (1:l) solution and then titrated with dilute hydrochloric Control Reactions in Solution. The reactions were carried out under
acid. The dependence of loadings on time is shown in Figure 1, where inert atmosphere. A 2-mmol sample of trityllithium in 30 mL of THF
methyllithium in 1,2-dimethoxyethane was used for ionization of I. Most was prepared from triphenylmethane and n-butyllithium. To the deep-
reactions, however, were done with polymer Ia prepared with a 100% red solution was injected 2 mmol of the same carbon acid used for the
excess of n-butyllithium in THF for 2 h at 0’ O C . Titration of the re- corresponding “wolf and lamb” experiment. The red color disappeared
sulting polymer showed ca. 1.5 mmol/g of trityllithium groups. within a few seconds, and the soluble acylation reagent was then intro-
Recycling of Polymer I. Samples of polymer Ia that participated in duced in 50% excess. The reaction mixture was neutralized and extracted
proton abstraction reactions (not in alkylations) were recycled as follows: with ether. The organic phase contained triphenylmethane, excess acy-
the polymer was washed with several portions of warm (60 “C) DMF, lation reagent, o-nitrophenol, the starting carbon acid, and the product,
then with methylene chloride-methanol (2: I ) , and dried thoroughly. A which was separated by column chromatography.
sample of the polymer was subjected to three cycles of ionization with A “Wolf and Lamb” Reaction with Nongound Polymers. Polymers
a 100% excess of methyllithium in 1,2-dimethoxyethane for 9 h at 0 O C , Ia and IIa were prepared from polystyrene beads of the original, com-
then titrated, washed, and recycled. The loadings of trityllithium groups mercial size (20-50 mesh). A “wolf and lamb” benzoylation of aceto-
were 2.20, 2.15, and 2.25, respectively. Thus, it was demonstrated that phenone was carried out in exactly the same way as described for the
polymer I is recyclable. Samples of the polymer were therefore used ground polymers. After 15 min, the reaction mixture still contained some
several times in the various experiments described here. acetophenone. After workup and chromatographic separation, di-
Alkylation Reactions Using Polymer Ia. The reactions were carried benzoylmethane was isolated in 72% yield.
out in the apparatus shown in Figure 2. Polymer I (2 g) was ionized by Examination for Possible Second Acylation. The acylation products
n-butyllithium in THF as previously described. To the resulting polymer are obtained at the end of the “wolf and lamb” reactions as their anions.
Ia (about 3 mmol) was injected 150 mg (1 mmol) of isobutyrophenone. No further acylation was detected. This was separately confirmed in
After stirring for a few minutes, 500 mg of benzyl bromide was injected. solution. The benzoylation product of acetophenone, dibenzoylmethane,
The reaction mixture was neutralized with hydrochloric acid, and the having two hydrogens, and the benzoylation product of phenylacetonitrile,
polymer was washed with 8 portions of 20 mL of methylene chloride. phenylbenzoylacetonitrile,having one a-hydrogen, were both reacted with
Pyridine was added to the combined washings to react with the excess 1 equivalent of trityllithium, followed by 1.5 equiv of o-nitrophenyl
of benzyl bromide. The salts and excess pyridine were washed with dilute benzoate at room temperature. After 15 min, the reaction mixtures were
HC1. The organic phase was dried and evaporated to yield 235 mg (98%) neutralized and worked up, showing no further acylation products.
of a,&-dimethyl-P-phenylpropiophenone. The results of other similarly Separation of the Polymeric Reagents by Flotation. At the end of the
performed alkylations are summarized in Table I. “wolf and lamb” reactions, polymeric triphenylmethane I and the poly-
Attempts to Alkylate an Ester with Polymer Ia. A ca. 3-mmol sample meric nitrophenol I1 (partially as its ester IIa or IIb) were mixed to-
of polymer Ia was prepared, as described above. Ethyl isobutyrate (1 17 gether. Their efficient separation for recycling purposes was accom-
mg) was injected, and the mixture was stirred for a few minutes. Benzyl plished by selective flotation in a mixture of 55% benzene and 45%
bromide (500 mg) was injected and the workup accomplished as de- chloroform (v:v). Polymer I floated, the other precipitated.
scribed for the other alkylation reactions. TLC analysis of the reaction Preparation of Polymer 11, Carrying Triphenylmethane Groups with
mixture revealed several spots, some of which became colored when Methyl Substituents at Para Position. 4,4’-Dimethylbenzhydryl chlo-
sprayed with 2,4-dinitrophenylhydrazinesolution. These spots, therefore, rideg5(34.5 g) was absorbed into 15.6 g of polystyrene beads. A solution
might be attributed to self-condensation products of the starting ester. of 3 g of A1C13 in 80 mL of dry nitrobenzene was added. The mixture
Preparation of the Polymeric o-Nitrophenyl Active Esters IIa and IIb. turned black and HCI evolved. After being stirred overnight at 60 “C,
Polymeric o-nitrophenol I1 was prepared from polystyrene and 4- the reaction was decomposed with a mixture of 100 mL of DMF, 50 mL
hydroxy-3-nitrobenzyl chloride in a FriedelCrafts reaction.26 A polymer of concentrated HCI, and 100 g of ice. The polymer beads became
loaded with 3.5 mmol/g of o-nitrophenyl groups was obtained. The light-colored and were then washed with warm (60 “C) DMF until the
polymeric active esters were prepared by reacting the polymer with a washings were colorless. The white polymer was further washed with 6-8
twofold excess of either benzoyl chloride and pyridine (to obtain IIa) or portions of methylene chloride-methanol (2:l) and dried. The yield was
ethyl chloroformate and pyridine (to obtain IIb) in dry chloroform at 0 19.8 g (loading of 1.1 mmol/g). A sample of the polymer was converted
OC for a few hours. The polymeric active ester was washed with dry to the anion IIIa by means of 100% excess of n-butyllithium in THF at
chloroform until no nonvolatile compounds were detected in the washings 0 O C for 2 h. Adding ethanol and titrating the ethoxide formed as
(about 6-8 washings) and then dried. The polymers IIa and IIb were described for polymer Ia showed a loading of 1.1 mmol/g.
obtained in loadings of 2.5 and 2.8 mmol/g, respectively, as evidenced Preparation of Polymer IV Carrying Triphenylmethane Groups with
by increase of weight or by titration with benzylamine. Methoxy Substituents at Para Positions. Polystyrene (10.4 g) was im-
For control reactions in solution, o-nitrophenyl benzoate and o-nitro- pregnated with 26.2 g of 4,4-dimethoxybenzhydryl chlorideJ6 by dis-
phenyl ethyl carbonate were prepared according to the l i t e r a t ~ r e . ~ ~ solving
~ ~ ~ the chloride in chloroform, adding to the polymer, and evapo-

(33) Hubner, H. Justus Liebigs Ann. Chem. 1882, 210, 328-396. (35) Norris, J. F.; Banta, C. J . Am. Chem. SOC.1928, 50, 1804-1808.
(34) Bender, G. Ber. Deutsch. Chem. Ges. 1886, 19, 226552271, (36) Straus, F.; Dutzmann, A. J . Prakt. Chem. 1921, 103, 1-68.
7628 J . Am. Chem. SOC.,Vol. 103, No. 25, 1981 Cohen, Kraus, and Patchornik
rating to dryness. A solution of 2 g of AlCl, in 50 mL of dry nitro- by titration and found to be 1.6 mmol/g.
benzene was added, and the reaction was carried out and worked up as Improved Synthesis of Polymer VI Carrying N-l-Hydroxybenzo-
described for polymer 111. The polymer obtained weighed 13.5 g (loading triazole Groups. a. 4-Chloro-3-nitrobenzyl Alcohol. This substance was
of 1.0 mmol/g). The loading obtained by titration of the anion IVa was prepared by in situ diborane reduction of 4-chloro-3-nitrobenzoic acid.
1.O mmol/g. NaBH, (8.5 g) was dissolved in 250 mL of dry diglyme and cooled in
Benzoylation of y-Butyrolactone in Solution. y-Butyrolactone (0.17 an ice bath until the solution became very viscous. 4-Chloro-3-nitro-
g) was treated with 2 mmol of trityllithium and then with o-nitrophenyl benzoic acid (50 g) was then added in small portions. Cooling was
benzoate. Two benzoylation products were obtained and isolated by continued, and 40 mL of distilled boron trifluoride etherate was added
column chromatography. One (1 18 mg, 31%) was a-benzoyl-y-butyro- dropwise. Stirring was continued for 30 additional minutes. The mixture
la~tone.’~The other (90 mg), according to the ratio of aromatic to was poured over 500 g of ice. The solid was filtered and dissolved in ether
aliphatic protons in its NMR spectrum, was suspected to be a product and the unreacted acid washed with 10% aqueous NaOH. The ether
of self-condensation, followed by benzoylation, namely, a-(l-benzoyl- phase was dried and evaporated to give 40 g (yield 85%) of the alcohol.32
oxy- 1-tetrahydrofury1)-y-butyrolactone. Further evidence for this b. Binding to Polystyrene. The original preparation of polymer VI
structure was its hydrolysis and water elimination to give dibutyrolactone: calls for the binding of the alcohol to polystyrene.32 Here, however, the
200 mg of the substance was hydrolyzed overnight at room temperature 4-chloro-3-nitrobenzyl chloride, obtained from the alcohol by reaction
by a mixture of 1 mL of a solution of 40% benzyltrimethylammonium with thionyl chloride,j8 was used, the chloride affording a higher reaction
hydroxide (triton B) in water, 1 mL of water, and 2 mL of dioxane. The rate and requiring only catalytic amounts of aluminum chloride. Poly-
basic solution was extracted with ethyl acetate to remove unreacted styrene (20.8 mg) was impregnated with 17.3 g of the chloride, and a
starting material. The aqueous solution was acidified and extracted with solution of 4 g of A1C13 in 100 mL of dry nitrobenzene was added. The
ethyl acetate, in which the benzoic acid formed was also taken up. This mixture was stirred at 60 “C for 24 h. It was hydrolyzed with a mixture
was eliminated by aqueous sodium bicarbonate. The organic phase was of 100 mL of DMF, 100 mL of concentrated HC1, and 200 g of ice. The
evaporated to yield 105 mg of dibutyrolactone.28 polymer was washed with warm (60 “ C ) DMF until the washings were
Anal. Calcd for a-(1-benzoyloxy-1-tetrahydrofury1)-y-butyrolactone colorless and then with 6-8 portions of methylene chloride-methanol
(C16H1605): C, 65.21; H, 5.84. Found: C, 65.11; H, 6.01. NMR (2:l). The dried polymer weighed 32.1 g (loading of 2.1 mmol/g):
spectrum (CDC13): 6 1.96-3.40 (m,6 H), 3.61-3.79 (m,1 H), 4.27-4.41 nitrogen analysis, 2.97% (2.1 mmol/g); chlorine analysis, 7.46% (2.1
(m, 4 H),7.3C-7.55 (m,3 H), 7.95-8.06 (m,2 H). mmol/g).
“Wolf and L a m b Reactions with Esters. These reactions were carried c. Preparation of Polymer V. The polymer obtained above was re-
out under conditions identical with those described above for the reactions acted with hydrazine and then with hydrochloric acid according to the
at equilibrium. Workup procedures were the same as well. The reactions original p r e p a r a t i ~ n .The
~ ~ resulting polymer contained 1.7 mmol/g of
were carried out at room temperature with fast stirring. Control reac- OH groups.
tions in solution were carried out as described for the reactions in Preparation of the Polymeric Active Ester VIa. Polymer VI (10 g) was
equilibrium. The reaction mixtures of the control reactions were sepa- suspended in 60 mL of dry chloroform. Benzoyl chloride (5.8 mL) and
rated on TLC plates and showed triphenylmethane, o-nitrophenol, un- 4.0 mL of pyridine were added at 0 “C. After the solution was stirred
reacted nitrophenyl ester, starting material, and product, as well as for 30 min, the polymer was washed with dry chloroform under a ni-
variable amounts of other products. Some of these gave colored spots trogen atmosphere. Drying at high vacuum afforded 11.7 g of polymer
when sprayed with 2,4-dinitrophenylhydrazinesolution, revealing the VIa (loading of 1.4 mmol/g). Titration with benzylamine gave 1.3
existence of carbonyl groups. Acylation products were separated by mmol/g. The polymer is sensitive to moisture and was kept in a dessi-
column chromatography. Their yields are recorded in Table 111. cator.
Preparation of the Polymer V Carrying Diisopropylammonium Groups. Benzoylation of l,l-Diphenyl-2-chloroethylenein Solution. 1,l -Di-
a. B-Phenyldiisopropylamine. To a solution of 6.7 g of benzyl methyl phenyl-2-chl0roethylene~~ (430 mg) was dissolved in 20 mL of dry THF.
ketone, 12.8 mL of isopropylamine, and 100 mL of dry benzene at 0 “C The mixture was cooled to -70 “C, and 2 mmol of n-butyllithium was
was added dropwise a solution of 3.5 mL TIC4 in 15 mL of dry benzene. added dropwise, under a purified nitrogen atmosphere. After the solution
The mixture was stirred for 15 additional min and then hydrogenated at was stirred for 1 h at that temperature, 2 mmol of o-nitrophenyl benzoate
60 psi with 25 mg of platinum oxide (Edman catalyst). After hydro- was added. Stirring and cooling were continued for 15 additional min-
genation was completed (ca.30 min), 20 mL of 10% aqueous NaOH was utes, and the reaction was then neutralized with hydrochloric acid. The
added. Two phases formed, with solid titanium dioxide precipitating out. mixture was extracted with ether, dried, and evaporated. The residue
The organic phase was separated, dried, and evaporated. The amine was was chromatographed to give 402 mg (63% yield) of l,l-diphenyl-2-
distilled at 74 OC (ImmHg). Yield: 8.1 g (91%). chloro-2-benzoylethylene. It was identical with the target compound
Anal. Calcd for CI2HL9N:C, 81.30; H, 10.80; N, 7.90. Found: C, made according to the literature by a similar route.40
81.10, H, 10.88, N, 7.95. NMR spectrum (CDCl’): 6 0.93-1.08 (m,9 “Wolf and Lamb’Reaction with l,l-Diphenyl-2-chloroethyleneand the
H), 1.32 (s, 1 H), 2.4-3.4 (m, 4 H), 7.05-7.52 (m,5 H). Polymers Va and VIa. The reaction was carried out in the apparatus
b. B-( Chloromethy1phenyl)diisopropylammonium Hydrochloride. 0- described in Figure 2. Dry THF was distilled into the solvent reservoir
Phenyldiisopropylamine (10 g) was dissolved in 50 mL of dry methylene before the reaction. Polymer VIa (1.5 g, 2.1 mmol) was introduced into
chloride and cooled by an icesalt bath to 0 OC. SnCI, (10 mL) was the side arm. Polymer V (2 g, 2.6 mmol) was introduced into the main
added dropwise. Chloromethyl methyl ether (20 mL) was added drop- chamber and ionized as described above by a twofold excess of n-bu-
wise, maintaining the temperature at 0 “C or below. The solution was tyllithium. After excess n-butyllithium was washed from the polymer Va,
kept overnight at 5 “C and then poured over ice. Aqueous NaOH (20%) the bath was filled with water or a cooling mixture according to the
was added dropwise until the reaction mixture was basic, and the re- desired reaction conditions. Polymer VIa was then introduced. No
sulting oil was taken up with ether. The organic phase was separated and reaction was apparent between the two polymers. The amount of solvent
dried, and dry HCI was bubbled through it. The ether was decanted from was adjusted to just cover the polymers. With fast stirring 215 mg (1
the precipitating oil, which solidified upon scratching the vessel walls. mmol) of l,l-diphenyl-2-chloroethylene dissolved in a small amount of
The product was triturated with acetone to give a white powder (mp dry THF was injected. Polymer Va was immediately bleached. After
158-160 “C). a few minutes, the reaction mixture was neutralized, filtered, and worked
NMR spectrum (Me2SO-d6): 6 1.10-1.38 (m, 9 H), 2.53-3.60 (m, up. Only the rearranged product, diphenylacetylene, was found. Iden-
4 H), 4.75 (s, 2 H), 7.22-7.46 (g, 4 H), 9.24 (s, 2 H). tical results were obtained in reactions carried out at room temperature,
c. Binding to Polystyrene. Polystyrene (10.4 g) was mixed with 13.0 0 “C, and -15 “C.
g of 0-(chloromethy1phenyl)diisopropylammonium hydrochloride. A “Wolf and Lamb” Reactions with Sodium Hydride as the Strong Base.
solution of 2 g of AIClp in 50 mL of dry nitrobenzene was added, and These reactions were carried out exactly as were the “wolf and lamb”
the mixture was stirred at 60 “C for 24 h. The decomposition of the experiments with polymeric trityllithium Ia, except that ca. 250 mg of
mixture and washing of the polymer were carried out as for polymer I. NaH dispersed (5040%) in oil was substituted for the polymer Ia in the
Polymer V was obtained as white beads and weighed 17.3 g (loading of main reaction chamber. The oil was washed off the hydride with solvent,
1.7 mm/g): nitrogen analysis, 2.40% (loading of 1.7 mmol/g); chlorine prior to reaction. No reaction between the sodium hydride and polymer
analysis, 5.65% (loading of 1.6 mmol/g).
Preparation of Polymeric Lithium Diisopropylamide Va. This polymer
was prepared according to the procedure adopted for the other polymeric (38) Mckay, A. F.;Garmaise, D. L.; Gaudry, R.; Baker, H. A.; Paris, G.
bases described in this work, using a twofold excess of n-butyllithium in Y.;Kay, R. W.; Just, G. E.; Schwartz, R. J . Am. Chem. SOC.1959, 81,
THF. The loading of the resulting dark brown anion Va was determined 4328-4335.
(39) Korshak, V. V.; Samplavskaya, K. K.; Andreeva, M. A. Zh. Obshch.
Khim. 1949, 19, 690-695.
(37) Ebel, F.; Weissbarth, 0. German Patent 801 276, Dec 28, 1950 (40) Boehme, H.; Stammberger, W. Arch. Pharm. Ber. Deutsch. Pharm.
(Chem. Abstr. 1950, 45, 2972). Ges. 1912, 305, 392-395.
 J. Am. Chem. SOC.1981,103, 7629-1635 7629

IIa used in these reactions was evident. When y-butyrolactone was introduced into the mixture of the hydride
When 1 mmol of acetophenone was introduced into the mixture of and polymer IIa, TLC analysis of a sample of the reaction mixture
sodium hydride and polymer IIa, the reaction was slower than with revealed several spots. No attempt was made to isolate them.
polymeric trityllithium Ia. After 1.5 h, excess hydride was carefully
destroyed with water, and after workup 212 mg (yield 95%) of di- Acknowledgment. W e wish to thank the Camille and Henry
benzoylmethane was obtained. Dreyfuss Foundation for partial support for this research.

The Structure of CC-1065, a Potent Antitumor Agent, and

Its Binding to DNA
C. C. Chidester,* W. C. Krueger, S. A. Mizsak, D. J. Duchamp, and D. C. Martin
Contribution from The Upjohn Company, Kalamazoo, Michigan 49001, Received May I I , 1981.
Revised Manuscript Received July 20, 1981

Abstract: The crystal and molecular structure of a potent antitumor agent, CC- 1065 (C37H33N708), has been determined,
and circular dichroism studies have demonstrated a strong interaction between CC-1065 and DNA. The triclinic unit cell,
space group P1, of dimensions a = 11.063 (3) A, b = 13.311 (2) A, c = 13.405 (2) A, a = 85.18 (1)O, @ = 99.52 (l)', and
y = 103.36 (2)O, contains two CC-1065 molecules and disordered solvent molecules (two methanols and three waters). Intensity
data for 6284 reflections were collected at -155 (2) OC; the final R value was 0.08 for 241 1 significant high-angle reflections.
N M R spectroscopy was very important in assigning kinds of atoms. The CC-1065 molecule consists of three substituted
benzodipyrrole moieties linked by amide bonds. One terminal moiety has a cyclopropyl ring; the only asymmetric carbons
in the molecule are at the cyclopropyl ring junctures. The two symmetry-independent molecules have the same configuration,
but the absolute configuration is not known. The CC-1065 molecules are curved and somewhat twisted with the outer periphery
hydrophilic and the inner surface lipophilic. The interaction between CC-1065 and a number of DNA polymers was studied
by circular dichroism. The CD effect requires double-stranded DNA and is strongest with poly(dA-dT):poly(dA-dT).

A number of antitumor agents are known to bind to deoxy- Table I. "C NMR Shifts
ribonucleic acid by nonintercalative means.'-s Netropsin is an chemical multi- tentative chemical multi- tentative
oligopeptide that binds preferentially to poly(dA):poly(dT) and shiftu plicityb assignmentlS shift plicity assignment
is thought to interact through hydrogen bonds in the minor groove
of DNA.'s2 Anthramycin is a pyrrolo[ 1,4] benzodiazepine that 9.5 9 C3M 121.3 s C23
20.9 d c11 123.5 d c2
binds covalently to guanine in the minor g r o ~ v e . Braithwaite
~,~ 21.6 t c10 127.2 s C16
and Baguley have investigated netropsin, distamycin, and several 26.6 t C24 127.5 s C 29
bisamidine and bisquaternary ammonium heterocyclic drugs by 21.6 t c 37 128.9 s c22
viscometric, spectrophotometric, and fluorometric methods, and 31.5 S c9 129.1 s c35
propose that they all bind in the minor groove of the D N A double 49.4 t c12 129.5 s C4
helix.5 53.3 t C25 130.4 s C19
A new antitumor agent, CC-1065, also binds to D N A without 54.8 t C38 130.7 s C3 2
intercalation.6 CC-1065 is produced by a soil culture, strepto- 60.0 q C20M 132.4 s c21
, ~ was isolated in pure form8 and found to be
myces ~ e l e n s i sand 60.3 q C33M 133.1 s c34
significantly more cytotoxic in vitro than actinomycin, vinblastine, 105.9 d C17 138.0 s c20
106.3 d C30 138.4 s c33
or maytansine? In vivo, CC-1065 is highly active against a variety 110.6 d c7 157.5 s C40
of mouse tumors,* and, as a result, has been selected by the 113.0 S c3 157.5 s cs
117.3 S C18 160.2 s C27
117.7 S C31 160.7 s C8
(1) (1) Berman, H. M.; Neidle, S.; Zimmer, C.; Thrum, H. Biochim. 118.2 S C36 161.2 s C14
Biophys. Acta 1979, 561, 124-131. 176.4 s C6
(2) Wartell, R. M.; Larson, J. E.; and Wells, R. D. J . Bio!. Chem. 1974,
(I Chemical shifts in ppm relative to internal Me,Si. s=
249, 6719-6731.
(3) Hurley, L. H.; Gairola, C.; Zmijewski, M. Biochim. Biophys. Acta singlet, d = doublet, t = triplet, q = quartet.
1977. 475, 521-535.
(4) Kohn, K. W.; Glaubiger, D.; Spears, C. L. Biochim. Biophys. Acta National Cancer Institute (as NSC298223) for preclinical tox-
1974, 361, 288-302. icology studies.
( 5 ) Braithwaite, A. W.; Baguley, B. C. Biochemistry 1980,19, 1101-1 106.
(6) Swenson, D. H.; Krueger, W. C.; Lin, A. H.; Schpok, S. L.; Li, L. H. The structure of a fragment of CC-1065, the base degradation
Proc. Am. Assoc. Cancer Res. 1981, 22, 857. product, was reported previously.'0 A preliminary report of the
(7) Hanka, L. J.; Dietz, A,; Gerpheide, S. A,; Kuentzel, S. L.; Martin, D. structure of CC-1065 has also been published." W e report here
G. J . Anribiot. 1978, 31, 1211-1217.
(8) Martin, D. G.;Biles, C.; Gerpheide, S. A.; Hanka, L. J.; Krueger, W.
C.; McGovern, J. P.; Mizsak, S . A,; Neil, G. L.; Stewart, J. C.; Visser, J. J . (10) Chidester, C. G.; Duchamp, D. J.; Martin, D. G.Abslr. Am. Cryst.
Antibiot. 1981, 34, 1119-1125. Assoc., Winter Meeting 1979, 6 (Series 2, No. 2), 67.
(9) Martin, D. G.;Hanka, L. J.; Neil, G. L. Proc. Am. Assoc. Cancer Res. (1 l! Martin, D. G.;Chidester, C. G.;Duchamp, D. J.; and Mizsak, S. A.
1978, 19, 99. J . Antt610f.1980, 33, 902-903.

0002-7863 ,/8 1,/ 1503-7629SO1.25 /O I

0 1981 American Chemical Societv
-