J. Org. Chem. 1984,49, 343-347
343
Carbene Reactions with Cis Azo Functions. Formation of Ester Azines from A3-1,3,4-Oxadiazolines Diane Keus, Maciej Kaminski, and John Warkentin* Department of Chemistry, McMaster University, Hamilton, Ontario, Canada L8S 4 M Z
Received June 13, 1983 Thermolysis of a 2-alkoxy-2,5,5-trialkyl-A3-1,3,4-oxadiazoline (l),either neat or in a solvent such as benzene, leads to a carbonyl ylide intermediate which fragments to carbonyl compounds and carbenes. The latter attack the parent oxadiazoline at the azo function, presumably to form azomethine imine ylides. The latter ylides then fragment to form carbonyl compounds and azines such as R1(R20)C=NN=C(OR2)R1,R1(R20)C=NN=C(R3)2, and (R3)&=NN=C(R3)* The mechanism proposed is supported by results of studies of the dependence of the azine and propene yields on the initial oxadiazoline concentration. More propene and less (R3)2C=NN=C(R3), are obtained at low oxadiazoline concentrations, as would be expected if both arise from dimethyl carbene.
Reactions of carbenes or carbenoids with heteroatom centers of organic molecules are well-known.’ For example, ethers,2 t h i o e t h e r ~ ,amines? ~?~ and halides2s5act as nucleophiles toward carbenes6 to form the appropriate ylide intermediates (eq 1). Compounds containing hetY: + R’2C: Y+--CR’ 2 (1) Y: = R20:, R2S:, R3N:, RX:
Scheme I
-+
eroatoms in the sp2 or in the sp state of hybridization interact similarly with carbenes. Examples of such compounds include imines: thiocarbonyl compounds,!’ carbonyl compounds,lOJ1and nitriles.12 Although ylide intermediates (eq 2) are not necessarily involved in all cases, there is some spectroscopic evidence for the formation of carbonyl ylides (Y = 0, eq 2) by that route” and for the R2C=Y R’2C: R2C--+Y=CR’2 c* R2C=Y+--CR’2 (2) Y = NR”, S, 0
+
-+
(1)The subject of ylide formation from carbenes has been reviewed recently: Nicolaev, V. A.; Korobitsyna, I. K. Zh.Vses. Khim. Oua. 1979, 24,496. Only selected references from that review are cited here. (2)Ando, W.; Kondo, S.; Nakayama, K.; Ichibori, K.; Kohoda, H.; Yamato, H.; Imai, I.; Nakaido, S.; Migita, T. J. Am. Chem. SOC.1972,94,
1
t R’GOR‘
t 1
1 -
lk$R3
3
3870. (3)(a) Diekmann, J. J. Org. Chem. 1965, 30, 2272. (b) Ando, W.; Higushi, H.; Migita, T. Ibid. 1977,42,3365. (4)Lloyd, D.; Singer, M. I. C. J. Chem. SOC.C 1971,2939. (5)(a) Kirmse, W-’Carbene Chemistry”; Academic Press: New York 1971;pp 442-447. (b) Baron, W.J. Decamp, M. R.; Hendrick, M. E.;
Jones, M., Jr.; Levin, H. R.; Sohn,M. B. In ‘Carbenes”; Jones, M.; Jr., Moss, R. A., Eds.; Wiley: New York, 1973;Vol. 1, p 18. (c) Ando, W.; Yagihara, T.; Kondo, S.; Nakayama, K.; Yamato, H.; Nakaido, S.; Migita, T. J. Org. Chem. 1971,36,1732. (6)Nucleophilicattack on singlet carbenes is easily visualized. It does not follow, however, that triplet carbenes cannot lead to ylides except through prior intersystem crossing, because it may be possible for intersystem crossing to be part of the activation process. For an example involving capture of a carbene by methanol, see ref 7. (7)Griller, D.;Nazran, A. S.; Scaiano, J. C. J. Am. Chem. SOC.,in press. (8) Seyferth, D.; Tronich, W.; Shih, H. J. Org. Chem. 1974,39,158and references cited therein. (9)Seyferth, D.; Tronich, W.; Marmor, R. S.; Smith, W. E. J. Org.
(R3),C: t 1
Chem. 1972,37, 1537. (10)(a) Martin.C. W.: Gill. H. S.: Landmebe. J. A. J.Om. Chem. 1983. 48,.l898;-(b)H u b , Z.;Landbebe, J. A.; Petekon, K. Tetrahedron Lett: 1983,24,2829. (c) Gill, H. S.; Landgrebe, J. A. J. Org. Chem. 1983,48, 1051. (d) Gill, H. S.; Landgrebe, J. A. Tetrahedron Lett. 1982,23,5099. (e) Martin, C. W.; Lund, P. R.; Rapp, E.; Landgrebe, J. A. J. Og. Chem. 1978,43, 1071. (0Landgrebe, J. A.; Martin, C. W.; Rapp, E. Angew. Chem. 1972,84,307.(8) Martin, C. W.; Landgrebe, J. A.; Rapp, E. Chem. Commun. 1971,1438. (h) Martin, C. W.; Landgrebe, J. A. Ibid. 1971,15. (i) Seyferth, D.; Tronich, W.; Smith, W. E.; Hopper, S. P. J.Organomet. Chem. 1974,67,341. (11)Wong, P. C.; Griller, D.; Scaiano, J. C. J. Am. Chem. SOC.1982, 104, 6106. (12)Griller, D.; Montgomery,C. R.; Scaiano,J. C.; Platz,M. S.; Hadel, L. J. Am. Chem. SOC.1982,104,6813.
formation of nitrile ylides by an analogous route.I2 Recently it was shown that carbonyl ylide formation from an alkoxy alkyl carbene and acetone is re~ersib1e.l~ The azo function too has been used as a carbene t r a ~ . ~ , ’ ~ For example, decomposition of PhHgCC12Brin the pres-
t
I
(13)BBkhazi, M.; Warkentin, J. J. Am. Chem. SOC.1983,105,1289. (14)Seyferth, D.; Shih, H. J. Am. Chem. SOC.1972,94,2508.
0022-3263/84/1949-0343$01.50/00 1984 American Chemical Society
344
J. Org. Chem., Vol. 49, No. 2, 1984
Keus, Kaminski, and Warkentin
ence of azoarenes leads to tetrachloroaziridines8(eq 3), and
?(;,
CI ArN=NAr
EtO,CN=NCO,Et
-
t PhHqCCl2Br
+ PhHgCC1,Br
ArN
-
(3)
c1
(EtOzC)2NN=CCl, (4) the analogous procedure with diethyl azodicarboxylate affords hydrazonodihal~methanes'~ (eq 4). While studying the thermolysis chemistry of a number of 2-alkoxy-A3-1,3,4-oxadiazolines (1) we discovered not only that they can generate carbonyl ylides by extruding nitrogen and carbenes by subsequent fragmentation of those ylide~,'~J"'~but also that there are nitrogenous products. The latter are formed in minor amounts in the case of thermolyses run in dilute solution, but their yields increase with initial concentration of the oxadiazoline substrates. We now report that those products are azines formed by attack of carbene intermediates at the azo function of the parent oxadiazoline (Scheme I). The presumed mechanism involves azomethine imine intermediates which fragment to azines and carbonyl compounds (Scheme I). Although the initial result of attack of a carbene on oxadiazoline 1 is formally an ammethine imine, analogous to those thought to be involved in the chemistry of eq 3 and 4,the result is new and different. Several new alkoxy-substituted azines, prepared by the novel routes of Scheme I, are reported.
Methods, Results, and Discussion The oxadiazolines 1 used in this work were prepared by oxidation of the appropriate acylhydrazones with lead tetraacetate in the appropriate alcohol (eq 5).15J8 Oxa3
R2C=NNHCOR
1
Pb(0AC)r R'OH
R'
OR2
N
(5) A3
nothing else that is noteworthy about their 'H NMR spectra, and the mass spectra too were normal, showing highest mjz values corresponding to M+ - 28 when run in the E1 mode. Chemical ionization spectra, which included the peak due to the parent ion of an analogous oxadiazoline,13 were not obtained in this work. Thermolysis of oxadiazolines 1 and 5 in solution took the normal course outlined in the first line of Scheme I. An ylide intermediate was inferred for la and for 5 by running the decompositions in CD30D. In that solvent, ylide capture is so rapid15J7that fragmentation to carbenea did not compete, as shown by the absence of ketone and ester signals from the NMR spectrum when all starting material had been consumed. Additional evidence for carbonyl ylide intermediates came from the finding of enol ether acetals among the products, as illustrated for starting material la with eq 7. Similar products are known to be CH3 N
OCH2CH3
XO
\+CH3 CH3
la
CH3
-
Y
OCHzCH3
O
CH3 'ACH
3
-
CH3
H
OCHzCHj
X O
CHZ A C H ~
(7)
derived from other carbonyl ylides,13J5J7and they were readily recognized in the present work from their distinctive 'H NMR spectra. In an unreactive solvent like benzene, the ylide fragmentation processes in the first line of Scheme I could be inferred from the final products, which included ketone and ester in all cases except for 5, which gave ketone but not ester (y-butyrola~tone).'~Particularly diagnostic of the carbene intermediates of Scheme I (line 1) was the formation of propene, from rearrangement of (CH,),C: in benzene. I t is very likely, therefore, that the azines also found among the products originate from reactions of one or more of the known intermediates with the oxadiazoline substrate. In the following paragraphs arguments and evidence are presented which lead to the conclusion that the species reacting with the oxadiazolines are the carbenes and not the carbonyl ylides. 1,3-Dipolar cycloaddition of a carbonyl ylide intermediate to the oxadiazoline precursor (eq 8) is a conceivable
l a , R' = R3 = CH,; R2 = C2H, b, R 1= C,H,; R' = R3= CH, c, R' = R3 = CH,; R' = CH2CC1, d, R' = R3 = CH,; R' = CH,CF, e , R' = (CH,),CH; R' = C,H,; R3 = CH,
diazoline 5 was obtained by oxidation of the 4-hydroxybutanoyl hydrazone of acetone with lead tetraacetate in dichloromethane (eq 6) The 'H N M R spectra of the new
.
n
5
oxadiazolines are listed in Table I. Some of those spectra are relatively complex because of diastereotopism. Oxadiazoline 5, for example, has three pairs of diastereotopic methylene protons in the tetrahydrofuran ring. There is (15) Bbkhazi, M.; Warkentin, J. J.Am. Chem. SOC.1981,103, 2473. (16) BCkhazi, M.; Warkentin, J. J. Org. Chem. 1982, 47, 4870. (17) BCkhazi, M.; Warkentin, J. Can. J . Chem. 1982, 61. 619. (18) For reviews concerning oxidation of derivatives of carbonyl compounds see: (a) Butler, R. N. Chem. Znd. (London) 1968. 437. (b) Warkentin, J. Synthesis 1970, 279.
first step of a mechanism leading to the three azines of Scheme I. Although the two possible regiochemistries of cycloaddition shown in eq 8 would provide the connectivity needed for forming all three azines by subsequent fragmentations, that route is incompatible with known properties of the carbonyl ylides. Even the best dipolarophiles such as dimethyl acetylenedicarboxylate(6) present at the highest possible concentration (neat, ca.8 M) intercepted (19) Although 5 was first prepared in the expectation that it might lead to only one of the two potential carbenes, the reason for this result is still being sought.
J. Org. Chem., Vol. 49, No. 2, 1984
Carbene Reactions with Cis Azo Functions
345
Table I. 'HNMR Suectra of Oxadiazolines 1and 5
k' oxadiazoline l a , R' = R3 = CH,; R Z = C,H, lb, R ' = C,H,; R2 = R3 = CH,
le, R ' = R3 = CH,; R 2 = CH,CCl, I d , R 1 = R3 = CH,; R2 = CH,CF, l e , R ' = (CH,),CH; R' = C,H,; R3 = CH, 5, R1, R 2 = (CH,),; R3 = CH,
'H NMR,asb 6 1.17 (t, 3 H, J = 6.0 Hz), 1.40 (s, 3 H), 1.60 (s, 6 H), 3.20 (m, 2 H) 0.81 (t, 3 H , J = 7.5 Hz), 1.27 (s, 3 H), 1.38 (s, 3 H), 1.56 (m, 1 H), 1.78 (m, 1 H), 2.90 (s, 3 H) 1.50 (s, 3 H), 1.60 (s, 3 H), 1.73 (s, 3 H), 3.87 (dd, 2 H,J,, = 9 Hz) 1.56 (si 3 H), 1.69 (s, 3 H), 1.76 (s, 3 H), 3.64 (m, 2 H) 0.94-1.34 (m, 9 H), 1.55 (s, 3 H), 1.63 (s, 3 H), 2.10 (m, 1 H), 3.38 (m, 2 H) 1.17 (s, 3 H), 1.21 (s, 3 H), 2.01-2.41 (m, 3 H), 2.43-2.60 (m, 1 H), 4.06-4.20 (m, 2 H)c,d
a In CDC1, with internal Me@ or CHC1, (6 7.27) as a reference; 90 MHz instrument unless otherwise indicated. Many of the spectra are complex because o f the presence o f diastereotopic 'H atoms. 250-MHz instrument. 13CNMR (CDCl,, Me,Si) 6 24.5, 25.0, 25.4, 33.7, 69.9, 119.4, 137.5.
Table 11. Spectra of Azines azinea
'H NMR, 6
1.87 (s, 6 H), 1.94 (s, 6 H ) , b 1.85 (s, 6 H), 2.02 (s, 6 H)C [(CH,),C=N-Iz (CH,),C=NN=C(CH,)OC,H, 1.31 (t, 3 H, J = 7.0 Hz), 1.95 (s, 3 H), 2.01 (s, 3 H), 2.03 (s, 3 H), 4.18 (9, 2 H, J = 7.0 H Z ) ~ , ~ [C,H ,O( CH,)C=N-] 1.30 (t, 6 H, J = 7 . 0 Hz), 2.03 (s, 6 H), 4.16 (9, 4 H , J = 7.0 H ~ ) ~ , f , g (CH,),C=NN=C( C,H ,)OCH, 1.26 (t, 3 H , J = 7.7 Hz), 1.99 (s, 3 H), 2.02 (s, 3 H), 2.86 (9, 2 H , J = 7.7 Hz), 3.77 (s, 3 H ) b [C H 0( C H ,)C=N-] 1.29 (t, 6 H , J = 7.6 Hz), 2.80 (9, 4 H , J = 7.6 Hz), 3.76 (5, 6 H ) b 1.50 (s, 3 H), 1.61 (s, 3 H), 1.97 (s, 3 H), 4.24 (s, 2 H ) c (CH,),C=NN=C(CH,)OCH,ccI, [Cl,CCH,O(CH,)C=N-1, 1.98 (s, 6 H), 4.25 (s, 4 H)C 1.95 (s, 3 H), 2.03 (s, 3 H), 2.12 (s, 3 H), 4.55 (m, 2 H ) C (CH,),C=NN=C( CH ,)OCH ,CF, [F,CCH,O(CH,)C=N-1, 2.12 (s, 6 H), 4.50 (m, 4 H ) C (CH,),C=NN=C(OCZH,)CH(CH3), 1.07 (d, 6 H, J = 6.9 Hz), 1.29 (t, 3 H, J = 7.1 Hz), 1.94 (s, 3 H), 2.00 (s, 3 H), 3.39 (septet, 1 H, J = 6.9 Hz), 4.14 (9, 2 H , J = 7.1 H Z ) ~ ~ ~ ~ ~ , ~ z ~ ~ ~ ~ , 1.11 ~ (d, , 12 ~ H,~ J ~= 6.9 = Hz), ~ - 1.28 l (t, z 6 H, J = 7.1 Hz), 3.48 (septet, 2 H, J = 6.9 Hz), 4.12 (9, 4 H, J = 7.1 H Z ) ~
L
a Alkoxy-substituted azines are assumed t o have the E configuration since that geometry, from inspection of models, appears t o minimize repulsions among nonbonded electron pairs. In C6D6. In CDCl,. IR (CDCl,) 1813, 1794 ( O - C = N ) , 1640 cm-'(>=N). e Molecular weight from high-resolution mass spectrum, 142.11; calcd for C,H,,N,O, 142.11. An authentic sample" f Molecular weight from high resolution mass spectrum, 172.12; calcd for C,H,,N,O,, 172.12. prepared from ethylorthoacetate and hydrazine had the identical spectrum. The mass spectrum (electron impact) o f this material had 209, 211, and 213 as the highest values o f m l z , corresponding to M' - C1 (C,H,,N,OCl~). I The mass spectrum had signals at m / z 341, 343, 345, and 347, corresponding t o C,H,,N,O,Cl, or M' - C1.
only about 20% of the trimethyl methoxy ylide from 1 (R1 = R2 = R3= CH3)13because fragmentation of the ylide is so very rapid.13 Oxadiazolines such as 1 and 5 are bound to be very much poorer dipolarophiles than 6, if for no other reason than the steric hindrance that tetrasubstitution provides. Therefore, azines should be formed as trace products, at most, from thermolysis of neat oxadiazolines if they were derived from products of 1,3-dipolar cycloaddition. Evidence for attack of carbenea on oxadiazolines, to form azines ultimately (Table 11),comes from the finding that the yields of azines rise and the yield of propene falls with increasing oxadiazoline concentration. Table III illustrates this trend with yields obtained from total decomposition of the oxadiazoline sample. In such a "preparative" run, the substrate concentration changes greatly during the course of the reaction, and the observed concentration dependence of the yield of a product is averaged. Table IV which shows the yields of products from runs that were stopped at low conversion of substrate, illustrates more strikingly the decrease in the yield of propene (from 28% to 18%) and the corresponding increase in the total yield
of azines containing the kopropylidene function (from 16%
to 35%) resulting from a 5.4-fold increase in the substrate concentration. This feature is readily accounted for only in the framework of the carbene mechanism (Scheme I). Dialkyl carbenea such as dimethyl carbene are short-lived intermediates that rearrange rapidly to alkenes such as propene, and the fraction undergoing the intramolecular rearrangement to propene must clearly depend on the concentration of the reagent (oxadiazoline)that traps the same carbene in a competing bimolecular reaction. Enol ethers, which would result from an analogous 1,2 hydrogen shift in alkoxy carbenes, were either absent or barely detectable. Alkoxy carbenes must be formed, as indicated both by the formation of 2 (Tables I11 and IV and by the substantial yield of acetone from a run with low substrate concentration (Table IV).m A rationale for (20) Since acetone comes from ylide fragmentation (in the one sense) and from attack of carbenes on the oxadiazoline, it is necessary to make inferences about the fragmentation ratio for the ylide from results of experiments in which the second source of acetone made only a minor contribution.
346 J . Org. Chem., Vol. 49, No. 2, 1984
Keus, Kaminski, and Warkentin
Table 111. Product Distributions from Complete Thermolyses' products and yields, % (CH ,),C=NN=C( O R Z ) R ' [R'(OR*)C=N] 19 4.0 22 3.8 23 3.9 26 3.9 27 4.6 10 4 15 7 25 13
" X C h, j
!/I 1.57 2.09 2.61 3.14 3.70 0.32 0.92 7.2'
l a , R ' = CH,; R z = CHzCH,
lb, R '
=
CH2CH,;Rz= CH,
CH,CH=CH, 18 17 13 9 8 14
12 1
[(CH,),C=Nl z 10 11 11 12 14 0 2 7
'
a Yields are expressed as moles of product per mole of oxadiazoline decomposed times 100, in the usual way. With this definition the sum of the yields exceeds loo%, if all products of Scheme I are considered, because o f the fragmentations that are involved. Errors in the yields were estimated to lie within i 10% of reported values that are larger than 15% and Initial concentration of oxadiazoline in C,D,. Samples were within i 25% of reported values that are smaller than 10%. thermolyzed t o completion, and the product distribution is therefore not characteristic of any particular substrate concentration but is more indicative of results t o be expected from preparative conditions. Neat oxadiazoline. Concentration calculated from a measured density of 1.14.
Table IV. Product Distribution from Partial Thermolysis of l a yield,' %
Ib
F b
~b
propene
acetone
ethyl acetate
2.93 0.99 0.54
2.60 0.87 0.48
2.76 0.93 0.51
18
22 28 33
63 55 48
-
a
See footnote a of Table 111.
Et0
OEt
[la], M
22
28
I = initial, F = final, A = average.
these results is that alkoxyalkylcarbenes are relatively long-lived with respect to intramolecular processes, at least in the singlet state, because of conjugative stabilization afforded b y nonbonding electrons at the oxygen atom.21 T h e y m a y live long enough that most of t h e m can react with oxadiazoline during their lifetime. The relatively low yield of 2, compared to that of 3 (Tables 111 and IV) may mean that alkoxyalkylcarbenes attack oxadiazolines preferentially at N-3. Although more work will be necessary before s u c h details can be understood, there does not seem to be a reasonable alternative to the carbene mechanism for explaining the gross features of the dependence of product distribution on substrate concentration.
The intermediacy of azomethine imine ylides, although likely, is the most speculative part of the overall mechanism. Experiments designed to observe and to intercept them are in progress. From the viewpoint of their potential for the preparation of azines, the reactions described in t h i s paper are clearly of greatest interest for t h e i r ability to generate azines 3, which are quite rare,n under conditions in which they are not equilibrated with azines 2 and 4. Azines of types 2 and 3 have been prepared from ortho esters and hydrazinez2 or from selenone esters.23 Azines 4 are common, of course, being readily available from carbonyl compounds and hydrazine or from decomposition of diazo compounds. The latter route, which probably involves a t t a c k of a carbene at sp2 nitrogen in some cases,24 is not of preparative value because of the less expensive and simpler direct route that is available. (21)Baird, N. C.;Taylor, K. F. J. Am. Chem. SOC. 1978,100, 1333. (22)Chihaoui, M.; Baccar, B. C. R. Hebd. Seances Acad. Sci., Ser. C 1978,287,69. (23)Cohen, V. I. J.Heterocycl. Chem. 1979,16,365. (24)Liu, M. T. H.; Ramakrishnan, K. Tetrahedron Lett. 1977,3139.
ICHtlzC=Nh=(
acetalC 27 32 36
[
CH,
25 19 12
)=.N--Iz
[(CH~I~C=N-IZ
CH3
3 2 2
10
7 4
CH,CH,OCH(CH,)OC(CH,)=CH,.
Experimental Section Synthesis of Oxadiazolines. The general procedure (eq 5) which has been described earlier15J8was used for the preparation of oxadiazolines la-e and 5. Oxidative cyclization of an acyl hydrazone with Pb(OAc)4 in the presence of an alcohol, either neat or in CHzClz, affords a mixture of the desired 2-alkoxyoxadiazoline and the corresponding 2-acetoxyoxadiazoline. The latter is saponified by adding strong base to the crude reaction mixture, and the remaining alkoxyoxadiazoline is extracted and purified by vacuum distillation.16~1s The synthesis of 5, which involves intramolecular rather than intermolecular capture of a reactive intermediate by the alcohol function, is described below, together with the preparation of the necessary precursors. (4-Hydroxybutanoy1)hydrazine. Hydrazine hydrate (11.0 g, 0.22 mol) was added very slowly to y-butyrolactone (17.2 g, 0.20 mol). When the addition was complete, the reaction mixture was heated on a steam bath for 5 h. The crude product, which solidified on cooling to room temperature, was recrystallized from ethanol to afford 18.6 g (79%)of the hydrazide, mp 91-92 OC (lit.% mp 88-90 "C). 1-(4-Hydroxybutanoyl)-2-(1-methylethylidene)hydrazine. The product described above (9.0 g, 0.076 mol) was dissolved in acetone (30 mL), and the solution was refluxed for 12 h. Removal of excess acetone and of water with a rotary evaporator left 12.0 g (100%) of the title hydrazone, mp 73-74 OC (lit.26mp 74 OC). Oxidative Cyclization t o 5. The hydrazone described just above (12.0 g, 0.076 mol) was added in small portions and with stirring to lead tetraacetate (42 g, 0.095 mol) in dichloromethane (95 mL) cooled with ice. After addition was complete, the reaction mixture was left in the ice bath for 3 h. Lead diacetate was removed by filtration through a bed of Celite. Most of the solvent was removed from the fitrate with a rotary evaporator, the residue was shaken with an aqueous solution of NaHCO, (5%), and the resulting mixture was extracted several times with CH2Cl2. The organic layer was dried over CaC12before the solvent was removed to leave 8.5 g of crude 5. This product was purified, first by (25)Huisgen, R.;Moebius, L.; Szeimies, G. Chem. Ber. 1965,98,1138. (26)Coirre, P. Belg. Pat. 613624,1962;Chem. Abstr. 1962,57,13629h.
J. Org. C h e m . 1 9 8 4 , 4 9 , 347-353 bulb-to-bulb distillation at 0.5 torr (30 "C) and then by column chromatography of the distillate on basic alumina. The first fraction eluted with ethyl acetate (10%) in hexane was 5 (7.2 g, 60%), with spectral data as in Table I. Thermolysis of Oxadiazolines. For a small-scale run in solution, an oxadiazoline (ca. 25 mg) in C6D6containing C6H6as an internal standard was sealed into a medium-walled NMR tube after three cycles of freeze-pump-thaw degassing, and the 'H NMR spectrum was recorded. The tube was then immersed in an oil bath a t 80.0 0.2 "C for 240 h (or more) with periodic monitoring for remaining substrate by 'H NMR spectroscopy. When starting material could no longer be detected, the 'H N M R spectrum (90 or 250 MHz) was measured again, for ultimate estimates of relative and absolute yields. The tube was then opened, volatile materials and solvent were distilled (bulb-to-bulb) on the vacuum line, and the residue was analyzed by GC/MS. Between 70% and 80% of the total 'H NMR signal could be assigned to products of known structure. Larger scale thermolyses carried out in solution or with neat oxadiazoline involved about 500 mg of oxadiazoline and heavywalled Pyrex tubing instead of an NMR tube. The contents of such tubes were analyzed immediately after freezing, opening, and addition of solvent (neat samples) to minimize losses of the more volatile products. After distillation of the volatile materials, which except for propene were identified from their GC retention times and from the spectra of collected materials, the residual
347
azines were separated by GC on an OV-17 column for the purpose of measuring their NMR spectra, mass spectra, and infrared spectra. Propene was identified by comparison of the 'H NMR spectra of solutions of authentic propene in and in cell with the spectra of total reaction mixtures.
Acknowledgment. T h i s work was financed from a grant provided by t h e N a t u r a l Sciences a n d Engineering Research Council of Canada. W e t h a n k Dr. M. BGkhazi, whose initial work with t h e oxadiazoline system indicated t h a t neat samples led to a greater variety of products t h a n d i d dilute samples. Registry No. la, 87937-99-3; lb, 87938-00-9;IC, 87938-01-0; Id, 87938-02-1; le, 87938-03-2; 2a, 87938-04-3; 2b, 87938-05-4; 2c, 87938-06-5; 2d, 87938-07-6; 2e, 87938-08-7; 2f, 87938-09-8; 3a, 87938-10-1; 3b, 87938-11-2; 3c, 87938-12-3; 3d, 87938-13-4; 3e, 87938-14-5;5,87938-15-6; [(CH,),C=N-],, 627-70-3; (CH3)2C= NNHCOCH,, 3742-63-0; (CH3)2C=NNHCOC2Hs, 3884-67-1; C2H50H, 64-17-5; CH,OH, 67-56-1; Cl,CCH,OH, 115-20-8;F3CCH,OH, 75-89-8; CH&H20CH(CH3)0C(CH+CH2,87938-17-8; CH3CH=CH2, 115-07-1; ethyl acetate, 141-78-6; hydrazine, (4-hydroxybutanoyl)hydrazine, 302-01-2;y-butyrolactone, 96-48-0; 3879-08-1; l-(4-hydroxybutanoyl)-2-(l-methylethylidene)hydrazine, 87938-16-7; acetone, 67-64-1.
Host-Guest Complex Chemistry. Structures of 18-Crown-6and Diaza-18-crown-6with Neutral Molecules William
H.Watson,*
J e a n Galloy, a n d David A. Grossie
FASTBIOS Laboratory, Department of Chemistry, Texas Christian University, Fort Worth, Texas 76129
F. Vogtle and W. M. Muller Institut fur Organische Chemie und Biochemie der Universitat Bonn, Gerhard-Domagk-Str. 1, 0-5300 Bonn, West Germany Received June 20. 1983
Single-crystal X-ray analyses of six stoichiometric complexes of neutral organic guest molecules (formamide, N-methylthiourea, dithiooxamide, 3-nitrophenol.2H20, 4-nitrobenzaldehyde oxime dihydrate, 2-guanidinobenzimidazole) with 18-crown-6and diaza-18-crown-6 are described and discussed with respect to characteristic features of host/guest and receptor/substrate interactions and binding. In mcwt cases the guest molecules approach from both sides of the plane of the crown ring, sterically fitting with XH3, XH2,and XH.-H20- functional groups (X = C, N, 0) and binding by multiple NH2-O- and OH-0- hydrogen bonds. If the guest contains only one hydrogen suitable for hydrogen bonding, one water molecule per guest molecule is bound by the crown receptor. N-Methylthiourea as the guest is able to bind in a chain-type manner by using its amino as well as its CH3 groups as links between neighboring crown ligands. T h e s t u d y of well-defined complexes formed between uncharged molecules represents a relatively unexplored area although complexation of t h i s t y p e plays a fundam e n t a l role in m a n y biochemical processes. T h e import a n c e of such interactions in normal chemical reactions may also be an area which is not fully appreciated. Though much d a t a o n interactions involving hydrogen bonds has been gathered, i t is still difficult t o suggest specific hosts (receptors) for t h e complexation of neutral (uncharged) guest molecules. The importance of "acidic" methyl a n d methylene groups in stabilizing complexes between neutral molecules such as 18-crown-6 with dimethyl acetylenedicarboxylate,' dimethyl sulfone,2 and m a l ~ n o d i n i t r i l eh~a s (1)Goldberg, I. Acta Crystullogr., Sect. B 1975, B31, 754. (2)
Bandy, J. A.; Truter, M.; Vogtle, F. Acta Crystallogr., Sect. B 1981,
B37 1568.
( 3 ) Kaufman, R.; Knochel, A.; Kopf, J.; Oehler, J., Rudolf, G. Chem.
Ber. 1977, 110, 2249.
0022-3263/84/1949-0347$01.50/0
not generally been a p p r e ~ i a t e d .Although ~~ the magnitudes of these hydrogen-oxygen interactions are probably n o t much greater t h a n normal van der Waals forces, they are sufficient t o lead to well-ordered crystalline solids. Such weak interactions m a y be of importance in orienting or directing substrate molecules at active sites. It is n o t known t o what extent spatial fitting of CH, groups in t h e cavity of crown compounds helps host a n d guest t o orient in t h e specific way observed. T h i s question holds for t h e crystalline state as well as for h o s t / g u e s t interactions in solution. Stable complexes formed between crown ethers and many highly volatile toxic chemicals suggests this may be a convenient m e t h o d of handling toxic reagent^.^ Substrates like t h e nitrophenylhydrazines, which exhibit low solubility i n organic solvents, have been transferred into lipophilic phases by using this type of c ~ m p l e x a t i o n . ~ (4)Vogtle, F.; Muller, W. M. Nuturwissenschaften 1980,67, 255.
0 1984 American Chemical Society
