Higher Order Cycloaddition Reactions of ~ d a r n a n tlsobenzofulvene ~l and isobenzofuran A Microscale Synthesis Illustrating the Involvement of Highly Reactive Intermediates and a Simple FMO Treatment of Their Cycloaddition Periselectivities Richard A. Russell, Robert W. Longmore, and Ronald N. Warrener Department of Chemical Sciences, Deakin University, Geelong, Victoria, Australia 3217 Molecular orbital treatment of the Diels-Alder [4n + 2x1 cvcloaddition reaction is now covered in undermaduate textbooks, but little is available on higher order &oaddition reactions. I n new of the success of the frontier molecular orbital (FMO) theoryto treat a range of cycloaddition reactions (1. 2 ) using a n extremely s i m ~ l emathematical approach, we set oucto develop anundebgaduate laboratory experiment to illustrate this process. We were attracted to the use of a n isobenzofulvene 1 as a cycloaddition partner (Fig. 1) because i t is known to display a variety of cycloaddition modes including [Xn + 2nl w i t h simplr olefinst u furm ndducr 2 ,3, 4 , Inn ml wnh rroponc to form adduct3 ( 5 I Im + fin1 in its self-dirnerirationro form addurz 4 161 I n selecting1 the generation of adamantylisobenzofulvene 7 and isobenzofuran 6, we demonstrate two higher order llOn + 8x1- cvcloaddition reactions. One involves self" dimerization of the isobenzofulvene, and the other involves the mixed reaction of the isobenzofulvene with isobenzofuran. Each of these cycloaddition reactions displays incredibly high selectivity. There are well over 100 suprafacial cycloaddition combinations for these reagents, of which around 50 are symmetry-allowed and geometrically possible. Yet onlv a sinde cvcloadduct is ~roducedin eaeh c l a s i clearly this is not a chance result. Both the guiding forces behind t h i s selectivity and any theoretical treatment that can predict it successfully are important to the modem synthetic organic chemist. These ideas are incorporated into two groups of microscale experiments. The first group make the starting materials for the final, one-pot synthesis which yields the two [lox + an1 cycloadduds. In the ~ re. r e.~ a r a t i oofn the reagents quired for the generation of isobenzofuran 6 and adamantvlisobenzofulvene 7, we achieved several teaching objectives.
We used both regular and reverse eleetmn-demand DielsAlder [4n+ 2nl cycloaddition reactions. We illustrated the practical value of retro Diels-Alder reactions, often called the Alder-Riekert or retrodiene reaction. We showed how highly reactive intermediates, often too reactive to isolate, are still useful synthetic reagents. We touched on the topic of nonhenzenoid aromatic compounds. As a bonus, we were able to introduce the student to the ~~cloaddition potential of heterocyclic compounds via furan, isobenzofuran,and the s-tetrazine 19.
Formation of Cycloadducts Isobenzofuran 6 and adamantylisobenzofulvene 7 a r e each generated in situ using the cascade of cycloaddition/retmcycloaddition reactions shown in Figure 2. This multistep Drocess is initiated by the separate attack of dicnophiie 9 (Aldrich, and dicnodhile 10 i n the s-trtrazmc 19 in a reverse electron-demand Dtels-Alder reaction. rScc Figure 3 for the FMO treatment of Diels-Alder reactions.) Reverse electron-demand dienes, of which the s-tetrazine 19 is typical, have a low energy LUMO. Reaction is favored with the dienophiles having a high-energy HOMO, which are typically found in electron-rich dienophiles or in compounds with strained x bonds. (See Figure 3b.) Thus, reaction ofthe benzonorbornadiene derivatives 9,10 a t the
'~ithoughwe appreciate that working with reagents that are free of substituents helps to avoid steric or electronic complications, this was not practical because isobenzofulveneis extremely difficultto prepare (7, 8). The adamantyl derivative 6 used in this experiment involves stalting materials and products that are easily handled on the micro scale. The periseiectivily of the reactions is not effected by the substitution of the 8 position. Figure 1. Cycloaddition modes of isobenzofulvene.
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( 4 ) R ;H (endo and w o isomers) ( 5 ) R R = ~ d a r n a n t y l l e n d oisomerssnly)
V
t r e a t e d w i t h two eouivalents of stetrazine. Under these conditions the isobenzofuran and adamantylisobenzofulveue generated take part in two competing cycloadditions. One produces the (61 I71 mixed [lox + 8x1 cycloadduct 8. The other produces the self-dimerization [lOn + 8x1 cycloadduct 5. In each case t h e cycloaddition reactions are perispecific and stereospecific. These prod(491 ucts can be separated by chromatogra\ A N phy, and the structures can be assigned PY by 'H a n d I3C NMR spectroscopy. In (,s,x=o ~y (O)x=o (11)X;O (10) x= ~d ,121 X = ~d 1 1 4 ) ~ ;~d particular, the endo stereochemistry can be confirmed using the 3J coupling between protons H, and Hz, which is deAd=% finitive for this stereochemistry (6).4 The reaction of isobenzofuran and PI= p y r ~ n . 2 . y 1 isobenzofulvene (high HOMO energy) with electron-deficient dienophiles (low N 0 LUMO energy) produces [8x + 2x1 (6) X = 0 PY (15) cvcloadducts according to the normal 5 " - .A >. ," zectron-demand ~ i e l s k d e reaction. r Figure 2. The generation and dimerization reactions of 6-adamantylisobenzofulvene. (See Fimre 3a.l Maleic anhydride, various N-substituted maleimides, pbcnzoquinone, dimethyl fumarate, and trtracyanoA ~ "x bond (raised HOMO energy, for reasons similar to ethylene are commerci:~llvavailable (Aldrich, artiv:itt,d norbomadiene itself7 occurs rapidly with the s-tetrazine 19 dienophiles, which react quantitat~velywith 6 or 7. Some to form the dihydropyridazines 13,14 by instantanous loss rcactlons prodnce $1 mlxturc ofcndo and exo itrreolsumcrs; of dinitrogen from the firsbformed DielsAlder intermedithew can be rcadily a s s ~ p e d the basis ol 'H NMH couates 11,12. ohne constants (3. i ~ ~ - and- chrm~cal ~ ~ shill ~ data ~ ~ reac. -. 4 1 . ~T h ~ Fragmentation2 of the dihydropyridazines 13, 14 is also tion presents a n interesting set of selectivities because the facile because it has a strong driving force-the formation electron deficient dienouhile can be included in the orieiof aromatic heterocycle 15 and either isobenzofuran 6 or nal reaction mixture containing s-tetrazine and the benzoadamantylisobenzofulvene 7, each of which have aromatic norbornadienes 9 and 10. Preferential reaction occurs beclaims. Once formed, isobenzofuran is moderately stable tween the benzonort~on~adiene n bond and the s-lctannc: (91,but slowly undergoes polymerization. AdamantylisoThe clcctron defic~rntn-bonded com~oundsmust wall for benzofulvene is much more reactive. I n the absence of the generation of the isobenzofuran br isobenzofulvene to other opportunities, it will readily react with itself to profind a suitable partner. duce the [lox + 8x1 dimer 5 exclusively. Thus, it is important that the rate of formation of isobenzofuran be a t least comvarable with that of the isobenzofulvene3 if the mixed Discussion of Periselectivitv cycl~adductis to be observed. The orbital interactions which govern cycloaddition reacIn this experiment the two precursor benzonorbornaditions are svmmetrv-controlled. that is, the atomic orbitals enes are mixed together in equimolar proportions and a t the incipient bond-forming atoms of each reactant must have parity (plus with plus, negative with negative)! This Diene Dienophile Diene Dienophile parity is assessed by considering the'HOMO coefficients (eigenvectors) of one reactant and the LUMO coefficients LUMO (eigenvectors) of the other. See Table 1for a list of eigenvectors and FMO energies (10). When more one mode of interaction is allowed bv ----- - ~ than ~ symmetry, the preferred mode of interaction (perispecificity) can be evaluated in one of two ways. The first operates a t the 90% confidence level and uses a visual comparison method to evaluate the stabilization enerm -. of a varticular cycloaddition mode. The following assumptions are made in this treatment. o
..
&-6 ; &.p
/
mx+ 15 (7
--
L~
~
T
~
HOMO
~
~
~
2This is a [x4s + 02s + n2s + a2s] cycloreversion. Such 10n processes correspond to the Huckel (4n + 2) magic number and are thermally allowed 3The color change accompanying these initial steps acts as a senindicator and can be used to determine rough kinetics. The evolution of dinitrogen could be used in a similar role. 4 ~ I spectroscopy S can be helpful in wnfirming proton assigments (9)in the mixedadduct when the Eu(fod),coordinatesonto the bridge oxygen atom. 'H NMR spectra for the 8,8-dimethylisobenzofulvene analogues are included in the original literature (6). Note that only the endo dimer is produced from 7. 'Only suprafacial interactions need to be considered with planar reagents of the type studied here, due to steric constraints.
(a.
(a)Normal Diels-Alder reactions
(b)DielsAlderreactionswith
reverse electron demand
Figure 3. HOMGLUMO relationships for normal and reverse eketron-demand Diels-Alder reactions. Major interactions are shown with bold arrows.
Volume 69 Number 2 February 1992
165
Extended Huckel Eiaenvectors and Eigenvalues
for 8.8-~irneth~lisobenzofulvene, lsobenzofuran and Maleic Anhydryde 8.8-Dimethyisobenzofulvene
isobenzofuran
MaleicAnhydride
atom HOMO LUMO atom HOMO LUMO atom HOMO LUMO I
Eigenvectors
C1 4 . 5 3 0.37 C2 0 0.05 C3 0.53 0.37 C3a 0.20 -0.20 C4 4.30 -0.27 C5 -0.27 0.24 C6 0.27 -0.24 C7 0.30 -0.27
C1 -0.53 -0.48 02 0 0.28 C3 0.53 -0.48 C3a 0.21 0.11 C4 -0.30 0.46 C5 -0.27 -0.35 C6 0.27 -0.35 C7 0.30 0.46
C7a -0.20 -090
C7a -0.21
C8
0
0.11
-0.70 Eigenvalues E(eV)
1. The HOMOLUMO interaction with the smaller energy difbetween these frontier orbitals will dominate. This ference (AE*) interaction is enclosed in the solid box in Figure 4. 2. The coefficients with the largest value will mntral the specifieity.
Periselectivity can be evaluated using this method by constructing a n orbital coefficient map for each reagent and then overlapping these maps so that the participation of the larrrest coefficient is maximized. These coefficient maps are based on the eigenvectors: The size of the coefficient is directly proportional to the diameter of the circle, and the sign of the coefficient is positive if solid and negative if open. This type of assessment i s illustrated diagramatically in Figure 4 for the preferred mode of cycloaddition reactions involving isobenzofulvene and a selection of partners. For the second method. which is a n exact evaluation, the preferred mode of cycloaddition is determined using the second-order oerturbational enerm -. (AE).I t is calculated6 for each symmetry-allowed mode according to eq 1, and Involves both HOMOLUMO interactions.
This form of the equation has been truncated to include only those terms which involve HOMO's and LUMO's of both components. I n this way the stabilization energy for each transition state is evaluated a s a relative energy in units of S2/p, where 6 is the off-diagonal matrix element of the perturbational one-electron Hamiltonian, and !3 is the Hiickel resonance energy. The mode with the largest absolute number corresponds to the transition state that is stabilized the most, that is, has the lowest energy barrier. This perturbational molecular orbital (PMO) treatment correctly predicts the [lo% + 8nl product from the reaction of isobenzofuran with isobenzofulvene (10). Note that this PMO treatment predicts the preferred kinetic product. 166
Journal of Chemical Education
Fiaure 4. The coefficient maDs are shown for the frontier molecular o&is (FMOB)for three pais: isobenzofulvene and a simple olefin; isobenzofuran: and itself. The ...isoh~nznfolvene .and -.. .... . . . . . . isobenzofulvene ..... major interactions are designated with arrows. The dominant HOMCLLUMO interaction are encased in a solid box. Solid circles indicate the positive, open circles indicate the negative. The relative sizes are in accord with coefficients as determined by extended Huckel calculations, When the first-formed product undergoes change (e.g., isomerization (5)) or when the reaction is in equilibrium, the predictions are no longer valid. The reactions in the present theoretical treatment deal with the parent molecules. They are simplified due to their symmetry: Postions 1and 3 are the same in compounds 6 and 1. The introduction of substitutents onto the ring positions changes the coefficients a t these positions and a t other positions. Yet the predictivity is still valid. This has been tested with methyl-substituted isobenzofulvenes and isobenzofurans: with excellent results (11).
Preparation of Starting Materials 3,6-Di(pyr;d;n-2'-yl)-s-tetrazine This microscale preparation (12) is based on a reaction discovered by Pinner (13) in the .late 19th century. I t involves the reaction of hydrazine (Fig. 51, a n active ambident nucleophile, with 2-cyanopyridine 16 (Aldrich) to pmduce aminoamidine 17, which r e a c t s f u r t h e r w i t h cyanopyridine and a second mole of hydrazine to produce the dihydrotetrazine 18 (14, 15). Nitric acid oxidation (14) of the orange dihydro compound 18yields the salmon pink salt of s-tetrazine, which turns purple following conversion to the free base 19. This method of oxidation is preferred to others that use sodium nitrite (15) or femc chloride (16). 6The equation applies to two reactants Aand B interacting through atoms k, K and I, f respectively. Gois the coefficient (eigenvector) of the atomic orbital of the thatom i n the HOMO of A . &", go,and are the energies of the HOMO's and LUM& of the interacying molecules. 'A list of 36 syrnmetry-allowed cycloaddition modes between isobenzofuran and dimethylisobenzofulveneis available from ref 11. The [I% + 8x1 cycloaddition heads the list (AE=0.48eV);the 1871+ 2n] mode with the n bond as the 2x component is the next most favored fAE=0.25 eV1. Note: Both interactions are included in these ca~cu~atibns. There are two contributionsto the energy term: HOMOA + LUMOBand LUMOA+ HOMOB.The combination with the lower HOMOILUMO orbital energy differencewill dominate. (See Fig. 3 and eq 1.)
aO,
au
for 3 h. Another aliquot of hydrazine hydrate (0.2 mL) is added, and the heating is continued for another 1h. The resulting mixture is diluted with ethanol (2 mL). The orange solid is collected by centrifugation and washed with cold ethanol (2 mL), then ether (2 mL). The crude solid (343 mg) is recrystallized from pyridine (1.4 mL). The resulting crystals are washed with ether (2 x 0.5 mL) to yield the product as bright-orange needles (309 mg, 60%), mp: 196197 'C.
The dihydrotetrazine 18 (300 mg, 1.26 mmol) is dissolved in glacial acetic acid (15 mL). The clear orange solution is stirred and treated dropwise with nitric acid (5 M, 1.5 mL). The reaction mixture is stirred for 1h. Then the resulting pink salt is collected by centrifugation and suspended in concentrated aqueous ammonia (7 mL). The resulting purple product, 3,6-(dipyridin-2'-y1)-s-tetrazine 19, is collected by centrifugation and washed with water (5 x 1mL). The dried product is sufficiently pure to use without recrystallization. However, when it is recrystallized from pyridine (about 1 mL), the pure product is obtained as red-violet plates, mp: 229-230 'C. The recovery from the recrystallization is approximately 50%.Thus, recrystallization is recommended only if an accurate melting point is required. Figure 5. The synthesis of starting materials. 1,4-Epoy-1,4-dihydronaphthalene and9-A amantyl1deny/-1,4-dihydro-1.4-methanonapthalene
The same type of reaction is used in each of these preparations. Benzyne 22, which is generated in situ by treatment of 2-aminobenzoicacid 20 (Aldrich)with isopentyl nit r i t e 21. is t h e first of the transient intermediates encountered in these experiments and is trapped by the amrouriate cvclic 1.3-diene. Formation of adduct 9. which is i,Lepoxy-i,4-dihydronaphthalene(17)(Aldrichj, demonstrates that furan (Aldrich), which is an aromatic compound in many of its reactions, can display its diene character. The adamantylfulvene 24 acts as a diene to yield exclusively the symmetrical [4n + 2x1 adduct 10, which is 9-adamantylidenyl-l,4-dihydro-1,4-methanonapthalene. This last reaction is another example of periselectivity. One cycloaddition prodnct, namely the [4n + 2nl product, is formed even though others are formally possible. For example, several [2n + 2x1 products and one [6n + 2nl product are also possible. The adamantylfulvene 24 is prepared from the reaction of adamantanone 23 (Aldrich) with the anion of cyclopentadiene. The generation of cyclopentadiene by the cracking of its dimer further demonstrates the retro Diels-Alder reaction. The stereoselectivity in the formation of the endo dimer from self-condensation of cyclopentadiene can also be discussed in orbital terms (secondary orbital overlap).I t can be contrasted with the mixture of isomers obtained in the [8n + 2x1 reactions of isobenzofuran and isobenzofulvenes (secondary orbital overlap plus competing dipoledipole interactions (3)). Experimental 3.6-Di(pyridn-2-y1)-1,4-dihydro-S-tetrazine
Caution:Pyridine should be handled only in an efficient fumehood. Isopentyl nitrite is a powerful cardiac stimulant and exposure to its vapor must be avoided. 2-Cyanopyridine 16 (Aldrich) (500 mg, 3.74 mmol) and hydrazine hydrate (0.5 mL) are placed in a 5-mL vial, and the mixture is stirred a t 100 OC under a reflux condenser
Cracking of Dicyclopentadiene
Dicyclopentadiene (Aldrich) (4 mL) is placed in a 5-mL conical vial fitted with a Hickman still (12). The vial is slowly heated to about 160 'C in an oil bath whereupon cyclopentadiene collects in the still. The distillate can be removed with a syringe fitted with a suitably bent needle and stored at 0 'C until required for the next reaction.
A solution of potassium hydroxide in ethanol (2.5 M, 3.2 mL, 8.0 mmol) is dispensed into a 5-mL wnical vial and stirred at room temperature. Freshly distilled cyclopentadiene (495 wL,396 mg, 6.00 mmol) is added to the solution. This is immediately followed by the addition of 2-adamantanone 23 (600 mg, 4.00 mmol). The resulting solution is stirred for 2 h a t mom temperature. Then it is added to water (10 rnL) contained in a large vial and extracted with chloroform (3 x 5 mL). The combined organic extracts are washed with water (1x 5 mL) and dried with anhydrous MgS04. The dry extract is filtered through a Pasteur pipet plugged with cotton wool, and the solvent is removed in vacuo. The residual yellow oil, 6-adamantylfulvene 24, is crystallized in a Craig tube from ethanol (about 2 mL) to afford 6adamantylfulvene as yellow crystals (504 mg, 64%),mp: 86-89 ' C .
Two solutions are prepared for subsequent use in this experiment. Solution (a): isopentyl nitrite 21 (Aldrich)(550 pL, 4.14 mmol) in dimethoxyethane(1mL) Solution (b): 2-aminabenzoic acid 20 (Aldrich) (411 mg, 3.00 mrnal) in dimethoxyethane(1.5 mL) In a 5-mL conical vial a stirred solution of 6-adamantylfulvene (396 mg, 2.00 mmol) in dimethoxyethane (1mL) is heated a t reflux. Solutions a and b are added in alternating quarter portions. Solution a is added first, followed by the dropwise addition of the aliquot of solution b. The refluxing reaction mixture is stirred for 15 min between each pair of additions and for 1h after the final addition. Volume 69 Number 2
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The cooled reaction mixture is added to sodium hydroxide solution (lM, 20 mL) in a 100-mL separating funnel and extracted with light petroleum (3 x 20 mL). The combined extracts are washed with water (1 x 20 mL) and dried. The drying agent is fdtered off and the solvent is removed in vacuo to give a brown oil. This is purified by chromatography, using a column of silica (about 4 cm) contained in a Pasteur pipet a s follows. The oil is dissolved in light petroleum (1mL) and loaded onto the column, which is eluted with light petroleum (5 mL). The eluant is collected a s 0.5-mL fractions. The fractions are analyzed by thin layer chromatography (silica, light petroleum), and those containing the product are combined. Removing t h e solvent gives a light-yellow oil, 9adamantvlidenvl-(1.4-dihvdro-1.4-methanona~hthalene~ 10, whic6 soli&fiea to a colorless, crystalline mass. This solid is recrystallized from ethanol (about 2 mL) to which one drop of water has been added to afford the title compound a s colorless crystals (190 mg, 35%), mp: 89-91 'C. Cross Dimerization of 8-Adamantylisobenzofulvene and lsobenzofuran
A mixture of 3,6-di(pyndin-2'-yl)-s-ktrazine19 (236 mg, 1.00 mmol), the olefin 10 (137mg, 0.50 mmol), and the ether 9 (72 mg, 0.50 mmol) in chloroform (1 mL) is allowed to react a t room temperature until nitrogen evolution stops. The mixture is heated to 50-60 'C for 1h and then co~led.~ Then it is washed with hydrochloric acid (5%, 2 x 2 mL), followed bv water (1x 2 mL). The dried oraanic phase is freed of sGvent. Then the yellow residue isdissoived in a minimum volume of dichloromethane and is chromatographed on a column of silica gel. Elution of the column with dichloromethane in light petroleum (1:l) affords the dimer 5 as a colorless solid, which recrystallizes a s needles from ethyl acetak-ethanol(95 mg, 77%), mp: 2 7 5 2 7 6 'C. Further elution with the same solvent (1:l) yields the crossed dimer 8, also as a colorless solid, which can be recrystallized from light petroleum to afford colorless needles (16 mg, 9%), mp: 223-223.5 'C. 8The scale of this and preceeding reactions may be considerably reduced if the crossed dimer 8 is not required.
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Journal of Chemical Education
Calculations The calculations and predictions based on FMO theory may be performed by the generalized steps shown below. Step 1. Calculate the eigenvectors (caeff~cientsand HOMO LUMO energies using, for example, an extended Hiickel oromam. Then construct an orbital man Step 2. As3ess H0510 1.1'410 inreracrmn, and select the rumbination having t h r I w e r energy dlflermce. Step 3. Alrkm w h t i l l j with thr rorrret panty, and as.ieus the symmetry-allowedreactions. Step 4. Using the orbital map, maximize the involvement of orbitals with large coefficient values. This should allow the prefemed mode of cycloaddition to be determined. Step 5. In critical cases, evaluate both energy contributions, and add these to determine the stabilization energy. Prepare a list of the top three predictions. Step 6. In the general case, if the top selection does not correspond ta the observed compound, it will be necessary to confm that the experimentally derived reaction product is really the primary kinetic isomer.
.
-
Acknowledgement We thank Transan Shiu, Wingkie Lai (Benowa State High School), and Stuart Love (Somerset College) who helped develop these experiments a s part of a work experience program sponsored by the Queensland Government. Literature Cited 1. Flemming, I. PmntlPr Mokculor Orbitals and Organic Chemiml R~octiona;Wiley: London, 1976. 2. Lehr, R. E.; Marehand. A. F! Orbitol Symmalry, A Pmblpm Soloing Appr-h; Aea. demie Press: London, 1972. 3. Watson, P L.; Warrener, R. N.Awtral. J C k m 1978,26,1725. 4. Tsnida, H.:Me, T,:lb% K Buli. Ckm. Sac Jpn. 1972.45, 1999. 5. Paddon-Row. M. N.;Warrener. R. N.Tefmkdron L e f t 1974,3797. 6. Warrener, R. N.: Paddon-Raw. M. N; Russell. R. A ; Watson. P LAvsfml. J Ch~m. 1981.34 397. 7. Warrener, R. N.: Russell, R. A; Collb, G. J. Tefmhedron Left. 1978.4447. 8. Gross, G.; Schdz, R.: Sehelg.A,: Wentmp. C. &em Chsm 1981,93,1078. 9. Warrener, R. N. J.Am. Cham Sa.1911.93,2346. 10. Paddon-Row, M. N.Aunm1. J Cham. 1974.27.299, 11. Warrener, R. N.: Evans, D. A. C.;Paddon-Row, M. N.;Russell, R. A. Ausfml. J. Chem. 1982,35,757. 12. Mayo, D. W.; Pike,M. R.; Butcher, S. S . Miemsmk OrgonlcLobomtory;Wlley: New
York,1986.
13. Pinner, A. Chcm. Ben 1884.17, 200% 1893.26.2126. 14. Dallacher, FMomfseh. Chem. 1960.91.294. 15. Geldard, J. F;Lions, F J O w Chem 1986,30,318. 16. Sandstmm, J.Adn. Cham. Smnd 1961.15.1575. 17. Fieser, L. F:Hadd8din.M. J.Con. J. Chem 1966.43.1599.
