THE «ACYU‘LTLOE‘L OF {I‘L’CiAJL “PR GPA? E3 Thesis fear the Segree afP L.) D LL‘LLCLLLTAN S'LISTE .LLL‘L NE? 3% TY MEL-LAKE LL. SCHLGSSE RG 1§67 [HESLS ' ““ ——‘( LIBRARY 0 blicl'utm. ~JBC é Universi. ' r4? This is to certify that the thesis entitled THE ACYLATION OF CYCLOPROPANES ptesented by Richard H. Schlosberg has been accepted towards fulfillment of the requirements for Ph . D . degree in Chemistry ~43,qu LL ‘LL-ar Major professor Date August 16, 1967 0—169. ABSTRACT THE ACYLATION OF CYCLOPROPANES by Richard H. Schlosberg The Friedel-Crafts acylation of cyclopropane was pre- viously (1) found to proceed smoothly at 0° to give a 60 to 80% yield of a mixture of two isomeric chloroketones. These products were shown to be the anticipated y—chloro- ketones, and the unexpected, rearranged B—chloroketones, with the latter product predominating. R-fi-Cl + A1c13 + CH2 2 R-C-CHz-CHz-CHz-Cl ° HZc——CH2 O + R-C-CH(CH3)-CH2-Cl 0 Since the earlier work was carried out before the era of vapor phase chromatography and nuclear magnetic reso- nance spectroscopy, it was the purpose of this work to re- examine the scope and generality of this reaction with the aid of these techniques. It was also hoped that with these modern methods some light would be shed on the mechanism by which the unanticipated B-chloroketones were produced. Treatment of cyc10propane with a 1:1 acetilchloride- aluminum chloride complex in chloroform at 5° gave after work—up: 4-chloro-3-methyl—2-butanone, 3-methyl-3-butene- 2-one, 5-chloro-2-pentanone, and 3-chloro-2-pentanone in the ratio of 42:31:23:4. The overall yield of acylation Richard H. Schlosberg product was 96%. The proposed intermediacy of edge-pro- tonated cyc10propane Species readily accounts for these pro- ducts, and variations in product ratios with reaction condi- tions support the mechanism. Several substituted cyclopropanes were investigated. The reaction of 1,1-dimethylcyclopr0pane with acetyl chlor- ide afforded 4-chloro-3,4-dimethyl-2-pentanone in 78% yield and 3,4-dimethyl-3-pentene-2—one in 22% yield. 1,1,2-Tri- methylcyclopropane smoothly reacted in the acylating medium to produce 4-chloro—3,3,4-trimethy1-2-pentanone in 80% yield. The identical chloroketone-was also prepared from 2,3-di- methyl-Z-butene and acetyl chloride. CH‘CH3 CH CH3-c-c1 + A1c13 + 3\‘c’/| -—> CH3-C-C(CH3)2-C(CH3)2C1 0 CH3 H3 CH3-C-C1 + A1c13 + :::c = c//£ __§ CH3-C-C(CH3)2-C(CH3)2C1 5 ~CH3 \\CH3 6 2-Ethyl-1,l-dimethylcyclopropane and 2,3-dimethyl-2- pentene were acylated under identical conditions using stan- nic chloride as the Lewis acid catalyst. The reaction mix- tures from the two acylations were found to be quite compli- cated, but were virtually identical. Thus, it appears that a dialkyl-substituted cyc10pr0pane opens to a tertiary carbonium ion which may isomerize to the most stable olefin prior to acylation. Richard H. Schlosberg MethylcyclOprOpane was acylated to three major products: 4-chloro-2-hexanone (65%), 4-chloro-3—methyl-2-pentanone (18%), and 3-methyl-3-pentene—2-one (12%). A rationalization for the mode of formation of these reaction products, yi§_ protonated cyclopropanes, is presented. Phenylcyclopropane was readily acetylated to Eycyclo- propylacetophenone in 75% yield and 1-(4—acety1phenyl)-2- chloropropane in 15% yield. Thus the benzene ring is attacked more readily than the cyclopropane ring. pfcyclOpropylaceto- phenone furnished the same substituted chloropropane when treated with the acetylating reagent. Both products can be envisioned as arising from initial attack of an acyl cationic species at the para-position of the benzene ring. This leads to an ion which can deprotonate to pfcyclopropyl- acetophenone or suffer nucleophilic attack to furnish 1-(4- acetylphenyl)-2-chloropropane. However, the substituted chloropropane may arise in another manner; $32,, as an acylation product of pfcyclopropylacetoPhenone. (1) H. Hart and 0. E. Curtis, Jr., J. Am. chem. Soc., Lg, 112 (1956). THE ACYLATION OF CYCLOPROPANES BY \ Richard Hiquhlosberg A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1967 G .4..th a? ') I .- [.0 0 _ a .- _) - L. ACKNOWLEDGMENT The author wishes to express his sincere appreciation to Professor Harold Hart for his encouragement, counsel, and enthusiasm during the course of this investigation. Appreciation is extended to Michigan State University for a Teaching Assistantship from September, 1963 to June, 1964 and from September, 1964 to June, 1965. Appreciation is also extended to the National Science Foundation for providing financial assistance from June, 1964 through September, 1964 and to the National Institutes of Health for providing financial assistance from June, 1965 through August, 1967. ii To Pamela TABLE OF CONTENTS Page INTRODUCTION . . . . . . . . . . . . . . . . . . . . 1 EXPERIMENTAL . . . . . . . . . . . . . . . . . . . . . 23 I. General Procedures . . . . . . . . . . . . 23 II. The Acylation of Cyclopropane . . . . . . . 23 A. The Friedel-Crafts Acylation of .Cyclo- propane . . . . . . . . . . . 23 1. Product Identification . . . . . . 25 a. 5— —Chloro-2-pentanone . . . 25 b. 4-Chloro-3-methyl- -2-butanone . 25 c. 3-Methyl- -3-butene-2-one . . . . 26 d. 3-Chloro-2-pentanone . . . . . 27 (1) Physical prOperties . . . . 27 (2) Independent Synthesis of 3- chloro-Z—pentanone . . . . 27 B. The Acylation of Cyclopropane in Various Solvents . . . . . . . . . . 28 C. The Inverse Addition Acylation of Cyclo- propane . . . . . . . . . . . . . . 28 D. The Acylation of Cyclopropane with added 5-Chloro-2-pentanone, 4-Chloro-3-methyl- 2-butanone, or 3-Chloro-2-pentanone . 30 E. The Acylation of Cyclopropane with Added Relatively Non-nucleophilic bases 30 1. The Acylation of Cyclopropane with Added Tetrahydrofuran . . . . . 30 2. The Acylation of Cyclopropane with Added 2, 6-Lutidine . . . . 31 3. The Acylation of Cyclopropane with AddedN N-Diisopropylethylamine . . 31 F. The reaction of Cyclopropane with Acetyl Perchlorate . . . . . . . . . . . . . 31 G. Nmr Study of a Homogeneous Solution of Acetyl Chloride—Aluminum Chloride Complex and Cyclopropane in Carbon Tetrachloride 32 TV‘_ TABLE OF CONTENTS (Cont.) Page III. Experiments with Acetylcyclopropane . . . . 33 A. The Reaction of AceQflcyclopropane with Hydrogen Chloride and Aluminum Chloride 33 B. The Acylation of Cyclopropane with Added Acetylcyclopropane . . . . . . . . . . . 34 C. The Acylation of AcetylcyClOprOpane . . . 35 1. The Acylation of Acetylcyclopropane under Normal Conditions . . . 35 2. The Acylation of Acetylcyclopropane under Forcing Conditions . . . . 35 IV. The Acylation of Phenylcyclopropane . . . . . 37 A. The Normal Acylation of Phenylcyclo- propane . . . . . . . . . . . ... . . 37 B. The Acylation of pryc10propylaceto— phenone. . . . . . . . . . . 38 C. The Reaction of pryclopropylacetophenone with sulfuric acid. . . . . . . 39 V. The Acylation of 1,1-Dimethylcyclopropane . . 40 VI. The Acylation of 1,1,2-Trimethylcyclopropane. 41 VII. The l-Ethyl-l,1-dimethylcyclopropane System . 42 A. The Preparation of 2-Ethyl-1,1—dimethyl— cyclopropane. . . . . . . . . . . . . 42 B. The Acylation of 2-Ethyl-1,1-dimethyl- cyclopropane . . . . . . . . . . . . . 44 C. The Acylation of 2,3-Dimethyl-2-pentene . 44 VIII. The Acylation of Methylcyclopropane . . . . . 44 RESULTS AND DISCUSSION . . . . . . . . . . . . . . . . 47 SUMMARY . . . . . . . . . . . . . . . . . . . . . . . 68 REFERENCES CITED . . . . . . . . . . ... . . . . . . . 70 APPENDIX . . . . . . . . . . . . . . . . . . . . . . . 74 TABLE II. III. IV. LIST OF TABLES Page The acylation of cyclopropane in various solvents . . . . . . . . . . . . . . . . . 51 Cyclopropane acylation with added chloro— ketones or acetylcyclopropane . . . . . . . 53 Comparison of the normal and inverse addi— tion acylations of cyclopropane . . . . . . 55 The retarding effect of electron-withdrawing substituents on the rate of cyclOpropane acylation . . . . . . . . . . . . . . . . . 56 FIGURE 1. LIST OF FIGURES Proton magnetic resonance spectrum of 5-chloro-2-pentanone . . . . . Proton magnetic resonance spectrum of 4-chloro-3-methy1-2-butanone . . . . Infrared spectrum of 4—chloro-3-methyl- 2-butanone . . . . . . . . . . . . Proton magnetic resonance spectrum of 3-chloro—2-pentanone . . . Infrared spectrum of 3-chloro-2-pentanone . Proton magnetic resonance spectrum of 4-chloro-3,4-dimethyl-2-pentanone Infrared spectrum of 4-chloro-3,4-dimethy1- 2-pentanone . . . . . . . . . . . . . . . Proton magnetic resonance spectrum of 1-(4-acetylphenyl)-2-chloropropane . Infrared spectrum of 1-(4-acety1phenyl)- 2-chloropropane . . . . . . . . . . . vii Page 75 76 77 78 79 80 81 82 83 INTRODUCTION PART A PROTONATED CYCLOPROPANES FROM THE ngROPYL SYSTEM Reports of the intimate association of a proton with a three-membered ring (protonated cyclopropane) occur repeat- edly. The importance of such ions, generated from ring closure of the nfpropyl system will be discussed in this section of the thesis. Protonated cyclopropanes have been postulated to have three different structures, 1:3 . Since this carbonium ion has not yet been observed as a stable species, but only [CH3 CH2 CH2\ ” +\‘\ />(H* /\\ I'L'H H2C-_-_:_-_;.CH2 H2C-———-CH2 132c——=CH2 Methyl bridged '"Face-protonated" "Edge-protonated" "Ethylenonium ion" Cyclopropane Cyclopropane 1 2‘ 3 postulated as a reaction intermediate, it is not known which structure (or structures) is correct; see however, Part C of this introduction. The two most potent weapons used to secure evidence for the existence of a protonated cyclopropane have been isotopic labelling and trapping of the carbonium ion with a nucleophile. Five groups of workers have reported on the nitrous acid deamination of n-propylamine. Roberts and Halmann (1) 1 2 noted that the n—propyl alcohol obtained from the reaction of 1-aminopropane-1-14C with nitrous acid contained 8.5% of isotope-position rearranged product (label at C-2). Scheme I gives Roberts' postulated mechanism for the rear- SCHEME I + CH3CH2C*H2NH2 CH§CHC*H3 -————o CH3CHOHC*H3 LHONO t + + CH3CH2C*H2N2 > CH3CH2C*H2 '—————> CH3CH2C*H20H 7 1 L / IE§3 ——"’ CH3C*H2CH20H , \ \ sz;=—C*H2 rangement. Oxidation of the 1—propanol with acid perman- ganate followed by hydrazoic acid treatment gave ethylamine containing 8.5% of the label. On the basis of his reaction mechanism Roberts argued that this 8.5% of the label was entirely on C-2. Reutov and Shatkina (2), who repeated this experiment, determined that the activity was in fact on the methyl group of the ethylamine. Reutov suggested two possible modes of rearrangement: (a) a 1,3-hydride shift, or (b) two succes- sive 1,2-hydride shifts. Use of a tritium label on C-2 of + > C//'\\ < > CHZCH2C*H3 H2 /C*H2 (a) CH3CH2C*H2+ < +CH2CH2C*H3 CH3CHC*H3 < (b) CH3CH2C*H2+ < 3 the propylamine excluded the second pathway (3). Here it is evident that under the experimental conditions the isopropyl cation does not rearrange to the n—propyl cation. Support > CH3CHTCH20H CH3CHTCH2NH2'HC104 HONO > CH3CTOHCH3 > CH3CHOHCH2T for Reutov's proposed mechanism appeared in 1962. An nmr study using 1,1,2,2-tetradeuteriopropylamine (4) indicated that a mixture of alcohols containing only deuterium at and other C-2 was produced. On the basis of his/data, Karabatsos suggested that the 1—propyl cation irreversibly rearranges to the 2—propyl cation, that the l—prOpyl cation undergoes a 1,3-hydride shift, but that protonated cyclopropanes are not formed and methyl migration does not occur. Repudiation of the 1,3-hydride shift mechanism appeared in 1964. Deamination of 3,3,3-d3-1-aminopropane (5) was the crucial experiment. Rather than look at the 1-propanol formed, Baird and Aboderin studied the cyc10propane frac- tion and found 43 i 1% cyclopropane-d2 and 57 i 1% cyclo- propane-g3. Invoking formation of a protonated cyclopropane followed by extensive H and D mixing (Scheme II) they sta- tistically calculated 4/7 cyclopropane-g3 and 3/7 cyclo- propane-dz‘as the product distribution, in very good agreement with the observed results. 4 SCHEME II )— — + D D D ‘c’. ( D H‘ .D //r\ .3 c’ + — . CD3CH2CH2 ——'> H2C\: 'E'D CV? H c/:‘\\ é], H2 : —";> H2 ' +D ... ‘ \é \ 'I” 11 D I'- L . — d a 9 . H D pro uc H LL l _ + F- D .D D D g2 QC: ‘c’. product I \ H2C/| -—> H c/: \+H -— £3 <__ 2 . > product I l I l / C,‘—-H \ ,’ .D i... H _ _j H D A paper by Karabatsos, Orzech and Meyerson (6) endorsed Baird's scheme. Equations (1) and (2) display the isotopic distribution of the 1-propanols, as calculated from mass spectrometric fragmentation patterns. At 40° approximately (1) CH3CH2CD2NH2 —-> CH3CH2CD20H + C2H4DCHDOH + C2H3D2CH2 OH 95.7% 1.0% 3.3% 1.2% 0.9% 97.9% (2 ) CH3CD2CH2NH2 —> 5 5% of the 1-propanol was felt to arise via protonated cyclo- propanes. A final word on this controversy concerns two papers (7,8) which lend further credence to the involvement of protonated cyCIOpropanes. When 1-propy1amine-1—3H was deaminated (7), the l-propanol contained 1.7 i 0.1% tritium at C-2 and 1.2 i 0.1% tritium at C-3. 1-Propylamine-1-14C deamination again resulted in 4-6% isotopically scrambled 1-propanol (8). These data led Lee to suggest that the three carbon atoms became equivalent or approached equi- valence via protonated cyclopropanes (2 or 32, 32, 32). CH2 + H2C~ ‘ ~ , ’1’CH2 CH2 / k H / \\ +H H?’ I, \ / \ l ‘ , Hzc——CH2 Hzc——-‘ci{2 H‘gc5——CH2 H2C\ ----- I CH2 \ I Z, 3,.9 £2 ‘33" 319 Other reactions involving the n—propyl system have been examined. For example, whereas acetolysis of 1-pr0pyl tosylate-1-14C resulted in no isotopic rearrangement, form- olysis of the tosylate afforded 1-2% of rearranged substi- tution product (9), Lee suggested that the C—2 and.C—3 labelled formates arose from "edge—protonated" cyclopropane precursors*. *The question of "edge-protonated" gs. "face—protonated" cyclopropanes will be discussed in Part C. 6 Treatment of alcohols with bromoform and strong base provides products which appear to be typical of carbonium ions (Equations (3) and (4)) (10). anropyl alcohol "deox-» (3) R0_ + :CBrz ——> Br‘ + ROCBr -——> R+ + co + Br- or (4) 120' + :CBr2 —> 2Br- + Roc+ ——> R+ + co ideates" to cyc10propane. The cyclopropanes from the "de- oxideation" of 1,1—d2-1—propanol (11) were C3H4D2 (94 i 2%) and C3H4D (6 i 2%). Although Skell discounted a protonated cyclopropane intermediate, his results are probably best accounted for by a carbonium ion sequence such as outlined in Scheme II. If the electron-deficient site generated by "deoxideation" is more reactive than that arising from de- amination, incomplete scrambling would be expected: the ion would collapse to stable product in a very fast step. Hence the 57:43 ratio observed in the deamination of 3,3,3-d3—1— propylamine (5) could not be approached. One obtains more cyclopropanes from "deoxideation" than from diazotization reactions (12). Thus, the ions generated from alcohols in the former cases appear less selective (higher in energy) than those derived from amines. It is therefore reasonable to assume that k1 > k2 and as a result g2 product predom- inates in this case. A study of the cyclopropanes formed from the "deoxideation" of 3,3,3-gs-1-propanol and from the deaminations of 1,1—g3- and 2,2-d2-1-propylamine might shed further light on this question. CH3CH2CD20H _ > CHacfichz —> H2C :+H k prSEuct R0 1 ro lenes p py kzLLk_2 _ £1) < product k3 > H2C----ECD2H 2 | ‘ CH2 d 1 <_:‘2:_ HZC/iéié\ /’ \\ The reactions of nfpropyl chloride with hydrogen chlor- ide and zinc chloride (13) and of nfpropyl bromide with aluminum bromide (14,15) have been investigated recently. Treatment of 1-propyl chloride-1-14C for 100 hours at 500 with a twofold excess of zinc chloride and hydrochloric acid (13) led to 7% 1-propyl chloride-3-14C, designated as a 1,3-hydride shift product. However, since the eXperimental method for determining the isotope position employed in this case was the same as that used in Reutov's deamination work, this experiment might profitably be repeated. Douwes and Kooyman (14) treated 1—propyl bromide—2,2-g2 with aluminum bromide in carbon disulfide at -200 and recovered only iso- topically unrearranged starting material. Treatment of CH3CH2CD2Br with approximately 0.2 molar ratio aluminum bromide for five to six minutes furnished (15) a product with 15-20% isotope position rearrangement. Similar treat- ment of CH3CD2CH2Br yielded 5-8% rearranged deuterium. 1— Propyl bromide-1-13C led to about 7% label at C—2 and about 13% at C-3. These data require that the bulk of rearranged 8. 1-propyl bromide arise gig protonated cyclopropane inter- mediates. 1 Whereas the route to protonated cyclopropanes is quite rigorously demonstrated in the nfpropyl system, the neo- pentyl system does not appear to close to a protonated cyclopropane. Hydrobromination of neopentyl alcohol-1-13C with hydrogen bromide (16) provided only 2-bromo-2-methyl- butane-3-13C (Wagner-Meerwein rearrangement product), and none of the 2—bromo-2-methylbutane-4-13C expected if a bridged ion were involved. Neopentyl alcohol-a,a-g2 with bromoform and strong base (17) "deoxideated" to 2-methyl-1- butene-3,3-d2 and 2-methyl-2-butene-3-d_as the only olefins. Failure to find deuterium on C-4 corroborates the 13C evi- dence (16) which excludes a protonated cyclopropane (Scheme III). SCHEME III cH3 CHBr3 cH3 + cH3 cH3 CHs-C-CDZO Ro- > CH3-C—CD2 9 EEOC—"7:132 <%> ’(:H3'-C-\-—-CD2+ I I \ +I CH3 CH3 ‘C'H3 CH2 H ‘- A X H CH3 + CH3 CH3 I _ n I CH2=C-CD2CH3< H CH3-C-CD2CH3 < CH3- -—1pnz + [45:1 CH3 / (£12 ' CH3C=CDCH3 1 CH3 no products derived from this ion I CHé-E-CHz-CDZH 9 Solvolyses of neopentyl-1-13C tosylate and iodide and deamination of neOpentyl-1-13C amine produced Egrtfamyl aLmflrfl.with the label confined to the C-3 position (18). These results eliminate the involvement of protonated cyclo- pr0panes in these reactions: hydrogen—bridged species, if formed, would lead to product labelled at C-4 as well as at C-3 (Scheme IV). SCHEME IV CH3 9H3 #9. 9H3 CH3-C-C*H2X > ens-c - C*H2-CH3 I > CH3-cL—¥b*H2---x' CH3 CH3 ’,/”’: \\\\\\-A CH3 l + _ CH3-c-C*H2 x I CH3 V' . . CH3 CH3 c -+——-H > CH3-C-C*H2-CH3 + CH3-C-CH2-C*H3 Cfis/ \C*H2 + + Intermediate cases, the nfbutyl and isobutyl systems, display less propensity for a protonated cyc10propane path- way than the gfpropyl system and more than the neopentyl system (19,20,21,22). In conclusion, compelling evidence has accumulated supporting the intervention of protonated cyclopropanes to a small but significant degree in carbonium ion rearrange- ments of species generated from aliphatic precursors. These hydrogen-bridged ions are most important in the n-propyl 10 system, become far less prevalent when the alternative clas- sical carbonium ion is secondary, and apparently are not involved when a tertiary carbonium ion may be preferentially formed. PART B PROTONATED CYCLOPROPANES FROM CYCLOPROPANE It has been generally accepted that cyclopropane under~ goes simple Markownikov acid cleavage and reacts as an ole- fin would, albeit somewhat less readily*. The reactions of cyclopropane with sulfuric acid (23), hydrobromic acid (24, 25), and hydrofluoric acid (26), for example, give only £- propyl products. Although some speculation on a protonated cyc10pr0pane intermediate was advanced (25), the first ex- perimental evidence supporting the existence of such bridged ions in electrophilic attack on cyclopropane appeared in 1963. This short note revealed (27) the remarkable observa- tion that when D+ was added to cyclopropane extensive mix- ing of the deuteron and the ring protons occurred. In the subsequent full paper (28), Baird and Aboderin disclosed that the average deuterium distribution in the 1-, 2-, and *- For example, 1,1,2-trimethylcyclopropane upon treatment with hydrobromic acid yielded only 2,3-dimethyl-2-bromo- butane (N. Kizhner and G. Khanin, J. Russ. Phys. Chem. Soc., 52. 1775 (1911); Beil., g (I), (1911). H3 HBr \CH- Br CH3 ’ ’ .CHé/ H 3 CH3 Also see, R. T. Morrison and R. N. Boyd, "Organic Chemistry", Allyn and Bacon, Inc., Boston, 1967, p. 277. 11 12 3—positions of the 1-propanol formed from solvolysis of cyclopropane in 57% (8.43M) D2504 was 0.38, 0.17 and 0.46 deuterium atom respectively. This widespread isotope posi- tion rearrangement was interpreted according to Scheme V*. SCHEME v r- — + H‘ .H H‘ H CH ’//?; 9” 2 \ 11+ + / \ > H2C\ E jD < > HZC/: Hzc—-CH2 4c” Xé.‘ H H ..H — H/ .D - so CHzDCH2CH20H I if _ q + H H H H H 1 . \. 'HH ‘c .' /(':“ S??’ /'L HDC : +‘-H < > HDC : —> HZC ; H \| ’I \I \ l” C: Co (E. l . 4.; l '. II H ‘H III H H H D lSOH JSOH CH3CHDCH20H CH3CH2CHDOH + CHzDCHZCHon The possibility of deuterium scrambling subsequent to formation of the acid sulfate or alcoholic products was excluded. A control experiment demonstrated that l-prop- anol-1,1-g2 was not affected by conditions (8.43M D2SO4 at 50° for one week) considerably more severe than those used * Actually the equilibration of ions I, II, and III by the rotation of quasi—methyl groups is a variation suggested to Baird by Prof. K. Wiberg. Baird originally invoked methyl- bridged ions. 13 in ordinary solvolysis (8.43M D2804 at 25° for 10 hours). When solvolyzed in concentrated acid (96% D2804) cyclo- propane yielded 1-propanol containing equal amounts of deu- terium at carbons one and two (29). These data are consistent with those obtained by Baird in his studies (27,28). In 96% acid the bridged ion is relatively free from solvation by water and nucleophilic attack by solvent is quite slow in comparison with the rate of equilibration of protonated cyclopropanes. In the weaker acid system used by Baird and Aboderin there is approximately a 4:1 molar ratio of water to sulfuric acid and the ion formed here consequently under- goes more rapid solvent capture. Therefore scrambling would be expected to be less complete. Reaction of cyclopropane with benzene and aluminum chloride (30), cyclopropane with benzene and hydrofluoric acid (31) and the cationic oligomerization of isopropylcyclo- propane catalyzed by aluminum bromide (32) are but a few examples of the many allied reactions which may involve bridged ions. Much remains to be done before valid proof of protonated cyclopropane formation in these and other reactions* can be demonstrated. Along with sulfation . the standard electrophilic re- actions are Friedel—Crafts acylation, Friedel—Crafts alkylation, *- For example, D. J. Abraham and W. E. Truce, J. Org. Chem., 28, 2901 (1963) reported that treatment of cyclopropane with tosyl chloride and aluminum chloride in methylene chloride at room temperature for 48 hours led to a 32% yield of the 1, 3-addition product along with smaller yields of two other products which were not identified (perhaps the 1, 2- and 1, 1- addition products). 14 halogenation and nitration. The acylation of cyclopropane under Friedel-Crafts conditions has a long history. When cyclopropane was bubbled into a carbon disulfide solution of an acetyl bromide-aluminum bromide complex (33), a 15- 20% yield of a C5H30 ketone was reported. The remainder of the material presumably was "Friedel—Crafts tar". Krapivin could not characterize this ketone, although its probable structure was 3—methyl—3-butene-2—one (34). In a homogeneous solution of acetyl chloride and aluminum chloride in chloroform (34), cyclopropane was rapidly and exothermically absorbed at 0°. The reaction mixture was subjected to an acid-work-up and the crude product refluxed with 20% sodium bicarbonate. Under these conditions Hart and Curtis realized a 36% yield of 3-methyl-3-butene—2-one and a 30% yield of 5—chloro-2-pentanone. From the known chemistry of cyclopropane it was felt that acylation of cycloproPane to the 1,3-addition product followed by base catalyzed dehydrohalogenation would provide a facile syn- 'thesis of cyclopropyl ketones (Eq. 5). The formation of (5) /\ + RCOCl > RC0(CH2)3C1 Hzc——c, H2 lzB CH2 ' _ " _/_ E <——q-L—-— RcogHCHaszfcl RCO H2 H 3-methyl-3-butene-2-one as the major product was not expected and no plausible mechanism describing its formation was 15 advanced. Although 4—chloro—3-methyl-2-butanone was not found, its initial formation was inferred from the fact that B-chloroketones of structure 4,were identified as products when cyclopropane was acylated with propionyl chloride (R = C2H5) and isobutyryl chloride (R - (CH3)2CH). Yield of g,(%) R-C-CH(CH3)CH2C1 R O c2115 39 2. (CH3)ZCH 34 Furthermore, only 4—chloro—3,4-dimethyl-2-pentanone (5) (49% yield) (35) was isolated from the acylation of CH3COCH(CH3)C(CH3)2c1 é, 1,1-dimethylcyclopropane. None of the "normal" y-chloro- ketone, 5-chloro-5—methyl-2—hexanone was observed. In sharp contrast with the far-reaching rearrangements observed in the acylations of cyclopropane and 1,1-dimethylcyclopro- pane, nortricyclene afforded the expected 2-chloro-6-acetyl- norbornane (6) in 69% yield and no unexpected products (36). CH3C Q, Since the work on cyclopropane acylation (33,34) was carried out before the era of Vpc and nmr one purpose of 16 this investigation was to reexamine the reaction products with the aid of these techniques. Furthermore it was hoped that with the aid of vpc minor products, if present, could be detected, separated and identified. In addition it was hoped that some additional data could be obtained which might shed light on the mechanism of the unusual rearrange- ment discovered by Curtis (34). These reinvestigations comprise the major part of this thesis, but before the results are presented, the question of "edge" XE: "face"- protonated cyclopropanes will be considered. PART c "EDGE-" 1s_. "FACE-PROTONATED" CYCLOPROPANES The structure of protonated cyclopropanes has been dis- cussed in terms of a symmetrical methyl-bridged ion (1), a symmetrical, "face-protonated" Species (2), or a species in which the proton is associated with only two carbon atoms of the cyclopropane ring; 1,2,, "edge—protonated" cyclopropane (3). CH3 CH2 + cal. J \ H \ ‘ ’1, + \\ X \\ :EH H2C ----- CH2 H2C-—'CH2 H2C_—_'CH2 l. 2. 52. Two alternative molecular orbital representations of cyclopropane are the bent-bond model (7) (37) and the Walsh model (8) (38). The optimum configuration for the Z. bent-bond model leads to bonds which are "bent" by about 21°. Addition of a proton to either model of cyclopropane readily leads to either a "face-protonated" or an 17 18 "edge-protonated" species. Extended Hfickel molecular orbital calculations (39) suggest that the preferred avenue of approach for the addition of a proton to a cyclopropane ring is in the plane of the carbon atoms and in the direc- tion of the center of a carbon-carbon bond; $33,, the “edge-protonated" form § (40). This is a case in which theory preceded experimental evidence. Recently, the re- sults from the formolysis of l—propyl tosylate-1-14C (Eq. 6) (6) CH3CH214CH20TS HCOOH > CH3CH2CHZOC0H %14C in product - C-3 (0-68%): C‘Z (0°15%) C-1 (99.17%). led Lee to suggest (41) that edge-protonated cyclopropanes are the bridged ions which best accomodate the observed isotope-position rearrangement. The first formed methyl- bridged species (9) could lead to product via two pathways (Eq. 7). ’Cga k 1 * * ,’+\ > CH3CH2CH20COH H2C£--1%CH2 2. > + (7) CH3CH214CH2 kzlf 14CH //¥\3 'X‘ \ H2 MHZ > CH3 CH2 CH2 OCOH If k1 > k2 more label would be expected at C-2 than at C-3. If k1 < k2 the label would become equally distributed over all three carbons and the product would have equal amounts of 14C at carbons 2 and 3. Since the product was determined 19 to contain a greater amount of 14C at C-3 than at C-2 the methyl-bridged ion was discarded as a species which could lead to products. A face-protonated cyclopropane is sym- metrical and would lead to an equal amount of label on C-2 and C-3 in the product. It, too, was excluded on the basis of the experimental results. The first formed edge-pro- tonated cyclopropane, 12, however, would give product with more label at C-3 than at C—2. In order to give CH314CH2CH20COH lg'must equilibrate to ll'(Eq.{8). 1 .+ 14C52~ ' 14 H2 (8) CH3CH2 4CH2 > ‘// ‘\ fiH > \\ H2C-————cfi2 Hzc;---7cH2 10 ‘\i§1’ W ’19]; l 1 14CH3CH214CH20COH CH314CH2CH20COH Related studies on the norbornyl system have been conducted and reflect on the situation in the cyclopropyl ion. Ionization of apoisobornyl, gngcamphenilyl and 5- fenchoisocamphoryl brosylates (42) led to the observation of anchimeric acceleration xii the proposed bridged ions lz'and £2; A 6,1-hydride shift form (edge-protonated) was favored Over a 6,2-hydride shift species (face—protonated) in these systems. l 6————--l 1_H~ A. ----6 ' 1-H~ ..¢_ < < _ 12 13 W w 20 In the solvolysis of exo-norbornyl brosylate the endo— hydrogen at C-6 will migrate to the two possible configura- tions at C—2 with about equal facility if ion 14 is formed. "Nortricyclonium7lon" Exclusively endo-migration will occur if the edge-proton— ated ion lé'is generated. The intramolecular transannular hydride shift of the 2-carboxy-3-methyl-5-norbornyl cation (lg) proved to be exclusively endo -—> endo (43), thus supporting the existence of ion l2; CH3 l HOOC ‘~ _ ..... X H + 16 Hydrolysis of the substituted norbornyl tosylate £1 afforded seven alcohols (44) as outlined in Scheme VI. 21 SCHEME VI 22 Species gg'and Qg'depict the only reasonable face-protonated and face-deuterated ions derivable from the hydrolysis of 11, Collins averred that it is inconceivable that gg'could yield products containing deuterium in the bridgehead posi- tions (249,, 25,27). He also suggested that 32'does not seem capable of yielding products other than those with deuteriums on adjacent carbons, thereby excluding g}, 21’ and 2Q, Mechanistic employment of edge-protonated forms (2433, Age) leads to the ready formation of all alcohols produced. Thus, both on the basis of theoretical considera- tions (39,40) and experimental evidence (41,42,43,44) edge— protonated structures appear to be the preferred geometries for protonated cyclopropanes. EXPERIMENTAL I. General Procedures All nmr spectra were measured with a Varian A—60 or Jeolco C-60H spectrometer. Chemical shifts are reported as T values measured from tetramethylsilane or methylene chloride as an internal standard. Analysis by vpc was carried out on columns of 5- or 10-foot lemming packed with SE-30, 20% on Chromosorb W, FFAP, 20% on Chromosorb W, or SF-96, 20% on Chromosorb P at approximately 130°. The infrared spectra were obtained on a Unicam Model SP—200 infrared spectrometer and all ir spectra were calibrated using a polystyrene film. All ultraviolet spectra were measured with a Unicam Model SP-800 or a Beckman Model DB spectrophotometer. The mass spectra of the chloroketones arising from the acylation of cyclopropane were obtained by S. Meyerson and E. Bednar, American Oil Company, Whiting, Indiana. Other mass spectra were obtained by Dr. H. Harris and Dr. J. Wettaw of this department with a Consolidated Electrodynamic Corporation 21-103C instrument operating at an ionizing potential of 70 v. II. The Acylation of Cyclopropane A. The Friedel-Crafts Acetylation of Cyclopropane The method of Hart and Curtis (34) was employed in this reaction. A 300-ml, three-necked flask equipped with a dry—ice 23 24 condenser, stirrer, gas-inlet tube, and pressure equalizing dropping funnel was cooled by means of an external salt-ice bath. Into a 250-ml, one-necked flask equipped with a mag- netic stirrer and dropping funnel, was introduced a mixture of anhydrous aluminum chloride (26.67 g, 0.200 mole) in 50 ml of methylene chloride. A solution of 16.49 g (0.210 mole) of acetyl chloride in 50 ml of methylene chloride was added over a one-hour period. After addition of the acetyl chlor- ide solution the mixture was stirred for an additional hour and then filtered through a scintered glass funnel into the three-necked flask. While the Clear, pale yellow sOlution was maintained ,‘below 10°, cyclopropane (11 ml, 7.9 g, 0.19 mole) was condensed in a trap cooled to -79° and bubbled into the acylating medium over a 45 min period. After the addition of the cyc10propane the reaction mixture was Stirred for one hour at 3-6°. During the time of addition and stirring the solution took on a deep orange-brown color. The reac— tion mixture was hydrolyzed by slowly pouring it with stir- ring onto a mixture of 100 ml of concentrated hydrochloric acid and 250 g of crushed ice. The aqueous layer was sepa- rated and washed successively with 50-ml portions of water, 10% sodium bicarbonate solution, and water and dried over anhydrous sodium sulfate. After removal of the solvent, the yield of acetylated product was 21.8 g. Vpc analysis on a 5-foot Se-30 column at 115° with a Helium flow rate of 40 ml/min indicated that the product consisted of 14% of C5H80 (ret. time 0.80 min) and 86% of C5H90Cl (ret. times 25 2.2, 4.8, 7.5 min) material. On this basis there was a 96% yield of monoacylated product. The reaction products were separated by preparative scale vapor phase chromatography. The product with the retention time of 2.2 min was present in 4%, the second chloroketone was formed in 42% and the third in 23% yield. 1. Product Identification a. 5-Chloro-2-pentanone. This compound had a retention time of 7.5 min and a boiling point of 75-770 at 23 mm, literature value (34), 77-78° at 22 mm. It was a clear, colorless liquid which quickly darkened and decom- posed upon standing at room temperature. Its ir spectrum (liquid film) showed principal bands at 1710 (v and c=o) 760 cm-1 (VC_C1). The mass spectrum indicated parent peaks at m/e 120, 122 and peaks at m/e 84 (parent - HCl), 58 (CH3C(OH)=CH2+), and 43 (CH3CO+). The nmr spectrum (neat) consisted of a sharp singlet at T 7.89 (3H), a triplet (J = 6.5 cps) at T 7.38 (2H), a complex multiplet centered at 1 7.89 (2H), and a triplet (J = 6.0 cps) at 1 6.42 (2H), assigned to the protons on C-1, C-3, C-4, and C-5 reSpec- tively. b. 4-Chloro—3-methyl-2-butanone. The retention time of this chloroketone was 4.8 min. It was a clear, colorless liquid which quickly darkened and decomposed overnight at room temperature. The principal ir bands (liquid film) 26 appeared at 1710 (VC=O) and 758 cm-1 (vC-Cl)' The mass spectrum indicated, in addition to the parent peaks at m/e 120, 122, intense peaks at m/e 85 (parent - Cl), 84 (par- ent - HCl), and 42 (CH2CO+), and no sign of the mass spec- trometrically induced rearrangement products characteristic of carbonyl compounds containing y-hydrogens (45). The nmr spectrum (neat) showed a sharp singlet at T 7.85 (3H; methyl ketone), complex multiplets centered at r 7.18 (1H: methine proton) and T 6.45 (2H; methylene protons), and a doublet (J = 7.0 cps) at T 8.80 (3H; methyl group on C-3)*. c. 3-Methyl-3-butene-2—one. The a,B-unsaturated ketone had a retention time of 0.80 min, and a boiling point of 44-45° at 98 mm, literature value (34), 45-46° at 98 mm. It was a clear, colorless liquid with AggfhtOH 218 mu 95%EtOH max 218 mu. Its (log 6 3.84), literature value (46), 1 ir spectrum (CC14 soln) displayed prominent bands at 1678 (vc=o) and 1635 cm-1 (v ). The nmr spectrum (CC14 soln) c=c consisted of a sharp singlet at T 7.71 (3H; methyl ketone), complex multiplets centered at T 4.10 (1H; H ) and trans T 4.25 (1H; H ), and a three line absorbance centered at cis r 8.15 (3H; allylic methyl) (47). C-3 is an asymmetric center thereby producing a magnetic nonequivalence of the methylene protons and of the protons of the C-3 methyl group. For a discussion of this phenom— enon see, G. M. Whitesides, D. Holtz, and J. D. Roberts, J. Am. Chem. Soc., 86, 2628 (1964). 27 d. 3-Chloro-21pentanone. (1) Physical properties. This was the compound with a retention time of 2.2 min. The principal ir bands (liquid film) appeared at 1718 (vc_0)* and 758 cm‘1 (Vc-c1)° The mass spectrum had prominent peaks at m/e 120, 122 (par- ent), 92, 94 (CH3c(OH)=CHc1+) and 43 (CH3CO+). The nmr spectrum (neat) showed a sharp singlet at T 7.75 (3H), two doublets (J = 7.4 cps) centered at T 5.96 (1H), a complex multiplet centered at T 8.12 (2H), and a triplet (J = 7.1 cps) at T 8.97 (3H)** (2) Independent synthesis of 3-chloro—2-pen- tanone. The method of Buchman and Richardson (48) was used in this synthesis. Into a 300—ml, three-necked flask equip- ped with a magnetic stirrer, thermometer, pressure equaliz- ing dropping funnel and drying tube was introduced a solu— tion of 17.2 g (0.200 mole) of 2-pentanone diluted with 20 ml of dry benzene. Sulfuryl chloride (27 g, 0.20 mole) was dropped into the stirred solution over a period of 20 min while the reaction temperature was maintained below 24° by means of external cooling with a water bath. The clear, colorless solution was stirred for an additional 50 min at Halogen substitution in the immediate vicinity of a carbonyl group results in a shift to higher frequency of the carbonyl absorption. For a leading reference see, L. J. Bellamy, "The Infra—red Spectra of Complex Molecules", J. Wiley and Sons, Inc., New York (1958) p. 139. * *- See footnote page 26. 28 22°, then quickly poured onto approximately 100 g of crushed ice. About 20 ml of methylene chloride was added and the combined organic layers were separated and dried over anhy- drous sodium sulfate. After removal of the solvent in. ‘yaggg, the organic material was vacuum distilled and 4.1 g (17%) of a product with a boiling point of 57-58° at 49 mm, (literature value (48), 62-66° at 56 mm) was collected. This clear, colorless liquid darkened and decomposed slowly upon standing at room temperature, but appeared to be stable indefinitely when kept in the dark at 0°. This product was found to be identical in all respects (ret. time, ir and nmr spectra) with the acylation product, 3-chloro-2-pentanone. B. The Acylation of Cyclopropane in Various Solvents The Friedel-Crafts acylation of cyclopropane was car- ried out in carbon tetrachloride, chloroform, methylene chloride, carbon disulfide and nitrobenzene, solvents widely used in aliphatic acylations (49). All four products were produced upon the addition of cyclopropane to an acetyl chloride-aluminum chloride complex in each of the solvents employed. The data from these reactions are summarized in Table I. C. The‘lnverse Addition Acylation of Cyclopropane In a 250—ml, one-necked flask equipped with a magnetic stirrer and pressure equalizing dropping funnel, a mixture of 6.66 g (0.050 mole) of aluminum chloride and 50 ml of 29 methylene chloride was stirred. Acetyl chloride (3.96 g, 0.050 mole) was slowly added to the reaction vessel and the mixture was stirred for 20 min. The pale green solu- tion was filtered through scintered glass and kept dry in a one-necked flask fitted with a drying tube. Into a 300- ml, three-necked flask equipped with a stirrer, gas-inlet tube, pressure equalizing dropping funnel, and dry-ice condenser and cooled by means of a salt-ice bath was placed 50 ml of methylene chloride. Cyclopropane (29 ml, 21 g, 0.50 mole) was condensed in a trap cooled to -79° in a dry- ice/acetone mixture and slowly bubbled over a one-hour period into the three-necked flask. Finally the solution of acetylating reagent was dropped into the flask over a one-hour period at a rate that maintained the reaction temperature below 10°, and the reaction mixture was stir— red for an additional hour at 4-7°. During the time of addition and stirring the solution took on a very deep cherry—red color. The reaction mixture was slowly poured onto a mixture of 40 ml of concentrated hydrochloric acid and 100 g of crushed ice, and the organic layer was washed successively with 50-ml portions of water, 10% sodium bi- carbonate solution, and water, and dried over anhydrous sodium sulfate. Product composition was determined by vpc analysis on a silicone column at 120° with the Helium pres— sure at 40 ml/min. It was found that the yield of 1,2- addition products was increased at the expense of the 1,1- and the "normal" 1,3-addition products. The results from 30 inverse addition in two solvents, methylene chloride and carbon tetrachloride, are summarized in Table III. D. The Acylation of Cyclopropane with Added 5—Chloro—2- pentanone, 4-Chloro-3-methyl—2-butanone or 3-Chloro—2— pentanone These reactions were carried out using normal acylating conditions except that known quantities of 5-chloro-2-pen- tanone, 4-chloro—3-methyl-2-butanone or 3-chloro—2-pentanone were added to the solvent prior to the addition of the acylating reagent. The results of these experiments are summarized in Table II. E. The Acylation of CyglOpropane with Added Relatively Non-nucleophilic Bases 1. The Acylation of Cycloprgpane with Added Tetra- hydrofuran Cyclopropane (251 g, 0.050 mole) was acetylated as previously described except that an equimolar amount of tetrahydrofuran was added to the methylene chloride solvent prior to the addition of acylating agent. After work-up, only the products formed in the normal acylation of cyclo- propane (5-chloro-2-pentanone (17%), 4—chloro-3-methyl-2— butanone (47%), 3-methyl-3-butene-2—one (34%) and 3-chloro- 2-pentanone (2%)) were detected by vpc analysis. There was no sign of acetylcyclopropane as checked by a comparison of the vpc retention time of an authentic sample of acetyl— cyclopropane. 31 2. The Acylation of Cyclopropane with Added 2,6-Lutidine The acetylation of cyclopropane (0.4 g, 0.01 mole) with an equimolar amount of 2,6-lutidine added to the methylene chloride solvent prior to addition of the acetylating agent produced, along with the usual acylation products, no acetyl- cyc10propane as indicated by vpc analysis. 5-Chloro-2- pentanone was formed in 24%,4-chloro-3—methyl—2-butanone was formed in 52%, 3—chloror2-pentanone in 4%,and 3—methyl— 3-butene-2-one in 20% yield. 3. The Acylation of Cyclopropane with Added N,N-Di- isopropylethylamine This experiment was identical to the inverse addition acylation of cyclopropane in methylene chloride except that an equimolar amount of N,N—diisopropylethylamine was added to a methylene chloride solution of cyclopropane (2.1 g, 0.050 mole) prior to the addition of the acylating solution. After work-up vpc analysis indicated that only the usual acylation products and no acetylcyclopropane had been pro- duced. The yields as indicated by vpc were: 5-chloro-2- pentanone (8%), 4—chloro—3—methyl—2-butanone (42%), 3— chloro-2-pentanone (3%) and 3-methyl-3-butene-2-one (47%). F. The Reaction of Cyclopropane With Acetyl Perchlorate Into a 250-ml, one-necked flask equipped with a magnetic stirrer and drying tube was introduced anhydrous silver per- chlorate (29 g, 0.14 mole) and acetyl chloride (11 g, 32 0.14 mole) in 200 ml of methylene chloride (50). The mix- ture was stirred for 20 min, the silver chloride filtered off, and the filtrate was placed in a 300-ml three-necked flask equipped with a magnetic stirrer, gas inlet tube, thermometer, and dry-ice condenser and externally cooled by means of an ice bath. Cyclopropane (7.2 ml, 5.0 g, 0.12 mole) was condensed in a trap cooled in a dry ice- acetone bath and was bubbled slowly (one hour) into the acetylating agent, and the resultant mixture was stirred for 1.5 hours at 3-7°. The clear, colorless solution was poured onto a mixture of 100 ml of concentrated hydrochloric acid and 250 g of crushed ice, and the organic layer was washed successively with water, 10% sodium carbonate solu- tion three times (until neutral to pH paper) and water and dried over anhydrous sodium sulfate. The methylene chloride was stripped off Eli distillation and when the organic residue was transferred to a clean dry flask a violent ex- plosion occurred (51). G. Nmr Study of a Homogeneous Solution of Acetyl Chloride— Aluminum Chloride Complex and Cyclopropane in Carbon Tetrachloride The procedure used was identical to that employed for the normal acylation of cyclopropane in carbon tetrachloride. A sample of the reaction mixture was placed in an nmr tube immediately after all of the cyclopropane was added to the acetylating reagent. The methyl doublet (J = 7.0 cps) of 33 CH3C0CH(EE£)CH2C1 appeared at T 8.62 before work-up and at T 8.80 after hydrolysis. The methylene a- to the chlorine in CH3COCH2CH22§£C1 appeared as a triplet (J = 6.0 cps) at T 6.30 in the complex and at T 6.42 in the isolated com— pound. Integration of the doublet of 4—chloro-3-methyl- 2-butanone and the triplet of 5—chloro-2-pentanone gave (after statistical correction) a ratio of B/y-chloroketone of 1.20:1; the vpc ratio after work-up was 1.17:1 (see Table I). Separate experiments showed that 4-chloro-3-methyl-2- butanone is stable under the vpc conditions employed in this study. When a sample of 4-chloro-3-methyl-2-butanone was injected onto a column at the conditions normally used (130° at a Helium flow rate of 40 ml/min) there was no sign of 3-methyl-3-butene-2-one. Thus the B-chloroketone does not thermally dehydrohalogenate on the gas chromatograph. III. Experiments with Acetylcyclopropane A. The Reaction of Acetylcyclopropane with Hydrogen Chlor- ide and Aluminum Chloride In a 300-ml, three-necked flask equipped with a gas- inlet tube, mechanical stirrer, pressure equalizing drop- ping funnel, and dry ice condenser filled with liquid nitro- gen, 6.66 g (0.050 mole) of anhydrous aluminum chloride and 38 ml of methylene chloride were stirred. Hydrogen chloride (1.5 ml, 1.8 g, 0.050 mole) was condensed in a trap cooled 34 with liquid nitrogen and was bubbled slowly into the reac— tion flask. Finally acetylcyclopropane (4.2 g, 0.050 mole) was slowly added to the solution which was cooled by means of an external ice bath. After the clear pale brown solu- tion was stirred for 45 min, it was slowly poured onto a mixture of 40 ml of concentrated hydrochloric acid and 100 g of crushed ice. The organic layer was successively washed with 50-ml portions of water, 10% sodium bicarbonate solu— tion, and water and dried over anhydrous sodium sulfate. Vpc analysis of the clear, pale yellow solution on a 5-foot SE-30 column at 120° with a Helium flow rate of 25 ml/min showed the presence of a single peak (ret. time = 3.2 min) which was shown to be identical (ret. time, ir and nmr spectra) with authenticametylcyclopropane. There were no other peaks. B. The Acylation of Cyclopropane with added Acetylcyclo- propane The procedure used was identical to that employed for the normal acylation of cyclopropane. An equimolar amount (compared to the acylating reagent and cyclopropane) of acetylcyclopropane was added to the acetyl chloride-aluminum chloride complex prior to the addition of the cyclopropane. After work—up, vpc analysis on a 5-foot FFAP column at 125° with a Helium flow rate of 45 ml/min_indicated that all of the added acetylcyclopropane remained unchanged throughout the course of the reaction (see Table II). 35 C. The Acylation of Acetylcyclopropane 1. The Acylation of Acetylcyclopropane under Normal Conditions The usual acylation procedure was used, except that the substrate, acetylcyclopropane, was added by means of a pressure equilibrating dropping funnel rather than gig the gas-inlet tube used in the acylation of cyclopropane. After the addition of the acetylcyclopropane the reaction mixture was stirred for an additional hour at 3-6° before work—up. The gas chromatogram showed two peaks; one which proved to be unreacted starting material (92%) and the other (8%) represented some acylation product(s). 2. The Acylation of Acetylcyclopropane under Forcing Conditions In a 250-ml, one—necked flask fitted with a magnetic stirrer and drying tube 13.33 g (0.100 mole) of anhydrous aluminum chloride was stirred in 20 ml of methylene chloride. A solution of acetyl chloride in 20 ml of methylene chloride was slowly drOpped into the reaction flask, and the solu- tion was stirred for 25 min. After stirring the acetylating reagent was filtered through scintered glass and was added as a clear, pale yellow solution into a 250-ml, three-necked flask equipped with a magnetic stirrer, thermometer, conden- ser, and pressure equalizing dropping funnel. A solution of acetylcyclopropane (8.4 g, 0.10 mole) in 40 ml of methylene chloride was added to the flask over a 25 min period while 36 the reaction temperature was maintained below 40°, and the reaction mixture was stirred for an additional 48 hours at room temperature. During the addition of acetylcyclopropane and subsequent stirring the solution slowly acquired a fairly intense cherry—red color. The reaction mixture was poured onto a mixture of 55 ml of concentrated hydrochloric acid and 100 g of crushed ice, and the organic layer was washed with water, twice with saturated sodium bicarbonate solution, and water and the resultant clear, pale yellow solution was dried over anhydrous sodium sulfate. After removal of the solvent in vacuo vpc analysis indicated that about 40% of the acetylcyclopropane remained unreacted. Of the reacted material more than 95% proved to be a mix- ture of three chloroketones. These compounds were collected by preparative scale Vpc and submitted tormms spectrometric analysis. Each of the compounds showed parent peaks at m/e = 162 and 164, corresponding to C7H1102Cl. The first compound had a retention time of 1.2 min on a five foot Lexan (polycarbonate resin) column at 130° with a Helium flow rate of 80 ml/min and was formed in 30% yield. This compound had a complex group of bands in the ir spectrum (liquid film) centered at 1715 cm—1. The compound was not further characterized. The second chloroketone, formed in 33% yield, had a retention time of 2.9 min and had a sharp carbonyl stretch at 1715 cm-1. The nmr spectrum (CCl4 soln) consisted of a one proton triplet (J = 6.1 cps) at T 6.40, a two proton 37 quartet (J = 6.1 cps) at T 7.48, a six proton singlet at T 7.88 and a complex two proton multiplet at T 7.95. On the basis of these data 3-chloroheptane-2,6-dione is tenta- tively assigned as the structure. The third chloroketone had a retention time of 3.8 min and was formed in 32% yield. The ir spectrum (CC14 soln) showed the carbonyl band at 1710 cm-1. The nmr spectrum (CCl4 soln) had a multiplet accounting for two protons centered at T6.42, a six proton singlet at T 7.83, and a two proton multiplet at T 7.80. A tentative structure of 3-chloromethylhexane—2,5-dione is assigned. The 12 line spectrum expected for the C—3 proton at about T 7.2 does not appear in the nmr Spectrum. IV. The Agylation of Phenylcyclopropanes A. The Normal Acylation of Phenylcyclopropane The procedure employed was identical to that used for the normal acylation of cyclopropane, except that the phenyl- cyclopropane was added by means of a pressure equalizing dropping funnel rather than gig the gas-inlet tube used in the acylation of cyclopropane. Vpc analysis indicated that two major products accounted for 95% of the completely re- acted phenylcyclopropane. The major product (78% yield) had Stretention time, ultraviolet and infrared spectra identical with those of authentic pfcyclopropylacetophenone, (31). The nmr spectrum (CC14 soln) of gl'consisted of an 38 aromatic Asz system centered at 1 2.10 (two lines) and at T 2.73 (two lines-, J = 8.5 cps) accounting for four pro- tons, a three proton singlet at T 7.42 for the methyl ketone, and a pair of multiplets at T 8.07 and T 8.93 for the cyclo- propyl hydrogens. The other major product (17% yield) was determined to be 1-(4-acetylphenyl-)-2-chloropropane, (32), on the basis of its spectral properties. Its ir Spectrum cnaco- CHz-CH(Cl)-CH3 22. (liquid film) showed principal bands at 1685 (vc=0), 1607 -1 (VC=C) and 752 cm (vC-Cl)' The nmr spectrum (CC14 soln) consisted of an aromatic A2B2 system (J ‘ 8.5 cps) at r 2.25 (two lines) and at T 2.87 (two lines) for four pro— tons, a Sharp three proton resonance at T 7.51 for the methyl ketone group, a complex multiplet centered at T 6.98 for the methylene protons, and a methyl doublet (J 3 7.2 cps) at T 8.52. The ultraviolet spectrum (95% EtOH) Showed xmax 250 mu (log 6 4.11); literature value for pfmethylacetophenone (52) xmax 252 mu (log 6 4.18). B. The Acylation of pryclopropylacetophenone Normal acylation of pfcyclopropylacetophenone (3.20 g, 0.0200 mole) at a reaction temperature of 30° led to 85% recovered starting material and 15% of a product identical 39 (ret. time and ir spectrum) with 1—(4-acetylphenyl)-2- chloropropane (32) after one hour. After 24 hours there was about 50% conversion of the starting material, as monitored by Vpc, and continued reaction led to the forma- tion of polymeric material. C. The Reaction of p7CycloprOpylacetophenone with Sulfuric Acid In a 100-ml, one-necked flask equipped with a dropping funnel and a magnetic stirrer, 1.0 g (0.0063 mole) of E: cyclopropylacetophenone and 10 ml of methylene chloride were stirred. Sulfuric acid (80%, 15 ml) was added over a 15 min period, and the ensuing dark brown solution was stir- red for an additional 15 min and then Slowly poured onto 100 g of crushed ice. The organic layer was extracted with 50 m1 of methylene chloride and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, 0.93 g (93% yield) of a pale yellow oil was obtained. This oil was pure according to Vpc analysis and was identified as 1-(4-acetylphenyl)-1-propene (33) on the basis of its Spec- tral properties. The principal‘ ir bands (liquid film) 1 appeared at 1680 ( 1650 (Vc=C)’ and 1603 cm- Vc=o)' (Vc=c)’ The nmr Spectrum (CCl4 soln) showed the presence of an aromatic A2B2 system centered at I 2.23 (two lines) and at T 2.77 (two lines) (J = 8.5 cps) for four protons, a multiplet for the allylic methyl centered at 1 8.18, a Sharp Singlet at T 7.57 for the methyl ketone protons, a 40 one proton multiplet centered at T 3.75 assigned to the a-styryl proton resonance, and a complex multiplet centered at T 4.82 for the B-styryl proton. The ultraviolet Spec- trum (95% EtOH) showed xmax 286 mu; literature value (53), A x 280 mu for pracetylstyrene. ma 0 CH3-C -CH=CH-CH3 33 V. The Acylation of 1,1-Dimethylcyclopropane The usual procedure for acylating a liquid substrate was followed. The reaction was carried out on a 0.10 molar scale (7.0 g of 1,1-dimethylcyclopropane) in methylene chloride for 45 min at 5°. After work-up, vpc analysis in- dicated the presence of two products; 4-chloro-3,4-dimethyl- 2 - pentanone (78% yield) and 3,4-dimethyl-3-pentene—2- one (22% yield). The structure of 4—chloro-3,4-dimethyl-2-pentanone was clear from its spectral properties. Its infrared Spectrum (liquid film) Showed principal bands at 1710 (VG 1370 =0)’ -1 and 1390 (V(CH3)2C)' and 760 cm (vC-Cl)° The nmr spectrum (CC14 soln) consisted of a quartet (J= 7.0 cps) at T 7.01 for the methine proton adjacent to the carbonyl function, a three proton resonance at T 7.79 for the methyl ketone 41 protons, a sharp six proton singlet at T 8.34 for the gem: dimethyl group, and a methyl doublet (J = 7.0 cps) at T 8.79. The identity of the a,5-unsaturated ketone was deter- mined from its ir and nmr spectra. The infrared spec- trum (CC14 soln) showed absorbances indicative of an a,6- 1 unsaturated ketone at 1680 (Vc=O) and 1625 cm— (v c=c)' The nmr spectrum (CCl4 soln) showed three singlets at T 7.95, 8.17, and 8.27 in the area ratio 1:2:1. The two high field resonances were slightly broadened due to long range coupling. A separate eXperiment Showed that treatment of 1.0 g (0.0066 mole) of 4-chloro-3,4-dimethyl-2—pentanone with a 20% solution of sodium carbonate (20 ml, 4 g, 0.04 mole) for 15 min at reflux in 15 ml of carbon tetrachloride led to a clean conversion to 0.67 g (0.0060, 91%) of 3,4—die methyl-3-pentene-2-one. VI. The Acylation of 1,1,2-Trimethylcyclopropane The procedure employed was identical to that used in the preceding experiment. After work-up, only one major product (80% yield) was observed upon Vpc analysis. The structure of the product, 4-chloro-3,3,4etrimethyl-2- pentanone was confirmed by ir and nmr spectroscopy. The infrared spectrum (CC14 soln) Showed a Sharp carbonyl band at 1700 cm-1. The nmr spectrum (CCl4 soln) consisted of three Sharp singlets at T 7.82, 8.42 and 8.75 in the 42 area ratio 1:2:2, assigned to the methyl ketone protons, the a—chloro dimethyl protons, and the 3,3-dimethyl pro- tons reSpectively. A separate experiment showed that treatment of 10 ml of a carbon tetrachloride solution of 60 mg (3.7 x 10-3 mole) of 4-chloro-3,3,4-trimethyl-2-pentanone with 10 ml of a 20% solution of sodium carbonate (2 g, 0.02 mole) for 15 min at reflux led only to the recovery of unchanged starting material. VII. The 2-Ethyl-1,1-dimethylcyclopropane System A. The Preparation of 2-Ethyl-1,1-dimethylcyclopropane The carbene used to prepare this compound was generated according to the method of LeGoff (54). To a hot (nearly refluxing) solution of 0.25 g of cupric acetate monohydrate in 25 ml of glacial acetic acid in a 250-ml, one-necked flask, 18 g (0.28 mole) of 30-mesh granular zinc was added. The mixture was Shaken for two min, keeping it hot during this period to prevent precipitation of zinc acetate. The acetic acid was decanted and the couple was washed with a 25-ml portion of glacial acetic acid. After decanting the acid and cooling the flask, the reagent was washed with two 50-ml portions of anhydrous ether. The flask containing the couple was then fitted with a reflux condenser, mag- netic stirrer and dropping funnel, and 50 ml of anhydrous ether was added. Next a few drops of methylene iodide 43 were added, and after brief warming a reaction began (bub- bles rose from the couple). While the mixture was kept at gentle reflux a solution of 16.8 g (0.20 mole) of 2-methyl- 2-pentene and the remainder of the methylene iodide (total of 75.2 g, 0.22 mole) was added dropwise over a period of 50 min. 'The reaction mixture was stirred at reflux for 36 hours. The dark, milky purple solution was slowly de— canted from the unchanged Zn-Cu couple into a one—liter separatory funnel containing 40 ml of 1N hydrochloric acid and 50 g of crushed ice. A slight evolution of gas ac- companied this step. The ethereal solution was separated, filtered and washed with two 75-ml portions of 1N hydro- chloric acid and crushed ice and with three 75-ml portions of water and the clear, colorless solution was dried over anhydrous potassium carbonate. Distillation on a stainless steel Spinning band column afforded 6.0 g (0.061 mole) of a clear, colorless compound boiling at 76-78°/740 mm. This compound proved to be (ir and nmr spectra) 2-ethyl-1,l-dimethylcyclopropane. The ir Spectrum (CCl4 soln) had bands indicative of the cyclopropyl ring at 3080 and 980 cm-1. The nmr Spectrum (neat) con- sisted of a 6 proton singlet at T 8.73 for the ggmfdimethyl group and the rest of the protons appeared in a complex : Spectrum from T 7.90 to T 9.90. 44 B. The Acylation of 2-Ethyl-1,l-dimethylcyclopropane The usual procedure for acylating a liquid substrate was employed. The reaction was carried out on a 0.0050 molar scale (0.49 g of 2-ethyl-1,1-dimethylcyclopropane) in 10 ml of methylene chloride for 45 min at 5°. Stannic chloride was used as the Lewis acid. The reaction was monitored by vpc and the reaction mixture was found to consist of at least seven products, a mixture that proved intractable to clean separation. C. The Acylation of 2,3-Dimethyl-21pentene The procedure used was identical to that employed in the preceding experiment. The reaction was monitored by vpc and a mixture of at least seven products was observed. A comparison of the vpc traces (10 foot SE-30 column at 155° with a Helium flow rate of 35 ml/min) from the acyla- tions of 2-ethyl-1,1-dimethylcyclopropane and 2,3-dimethyl- 2-pentene indicated that the reaction mixtures were virtu- ally identical. VIII. The Acylation of Methylgyclopropane _Since methylcyclopropane is a gas (bp 4°) this acyla- tion was run using the procedure outlined for the normal acylation of cyclopropane. Methylcyclopropane (Chemical Procurement Laboratories) was purified by slowly passing it through a trap containing saturated, neutral potassium 45 permanganate solution, then through a trap containing an- hydrous calcium sulfate (Drierite) and collecting the gas in a vessel cooled in a dry-ice/acetone bath. The resultant material was tested by vpc and found to be pure. A 0.10 molar scale reaction (5.5 g of mefludcyclopropane) in 50 ml of methylene chloride was carried out at 0° for one hour. The reaction was monitored by Vpc using a 5 foot QF-l column at 130° with a Helium flow rate of 70 ml/min. Three major components with retention times of 0.70, 3.0, and 4.0 min were observed. The compound with the retention time of 0.70 min was formed in 12% yield and was found to be a clear, colorless liquid. It was shown to be identical with the unsaturated ketone formed in the acylation of 2-butene; i;g,, 3-methyl- 3-pentene-2-one. The ir Spectrum (CCl4 soln) had princi- 1 pal bands at 1670 (VC=O) and 1640 cm- (vc=c). The nmr Spectrum (C6D6 soln) showed a quartet of quartets (J em = 7.0 cps, JVic = 1.4 cps) at T 3.68 for the vinyl proton, a singlet at T 8.00 for the methyl ketone protons, a three proton multiplet centered at T 8.25 (C—3 methyl group), and an eight line resonance at T 8.58 for the remaining methyl group. The second product had a retention time of 3.0 min and was formed in 18% yield. The structure was shown to be 4- chloro-3-methyl-2—pentanone on the basis of its ir and nmr spectra. The carbonyl band in the ir spectrum (CCl4 soln) appeared at 1710 cm . The nmr Spectrum (CC14 soln) 46 consisted of a one proton multiplet centered at T 5.80 (C-4 proton), a one proton multiplet at T 7.32 (C-3 proton), a singlet for the methyl ketone protons at T 7.82, a doub- let (J = 6.5 cps) at T 8.50 (C-4 methyl) and a doublet (J = 7.0 cps) at T 8.87 (C-3 methyl). The major product was formed in 65% yield, had a re- tention time of 4.0 min, and was shown to be 5-chloro-2- hexanone by its ir and nmr spectra. The ir spectrum (CC14 soln) had the carbonyl stretch at 1710 cm-1. The nmr Spectrum (CC14 soln) showed a one proton multiplet centered at T 6.02 (methine proton), a triplet (J = 7.0 cps) at T 7.38 for the two protons adjacent to the car— bonyl function, a Singlet at T 7.92 for the methyl ketone protons, a complex multiplet centered at T 8.08 for the C-4 methylene protons, and a doublet (J = 6.5 cps) at T 8.48 for the C-6 methyl protons. RESULTS AND DISCUSSION Cyclopropane Addition of cyclopropane at 0° to a homogeneous 1:1 acetyl chloride-aluminum chloride complex in chloroform resulted in the formation, after work—up. of four products (Eq. 9). These products were carefully separated and A1c13 (9) CH3C0C1 + H2C*——:;FH2 EEET;—> CH3COCH2CH2CH2C1(23i2%) CH2 Q2. + CH3COCH(CH3)CH2C1 (42:3%) + CH3c0c(CH3)=CH2 (31:3%) 3,2 52.2 + CH3COCH(C1)CH2CH3 (411%) 21 purified by preparative scale vapor phase chromatography. In the previous work (34), the reaction mixture decomposed upon distillation and consequently was dehydrohalogenated with a 20% solution of sodium carbonate at reflux prior to product isolation. Previously (34), 3-methyl—3-butene-2—one, (36), was identified and characterized as its 2,4-DNP deriva- tive, and the prior formation of 4-chloro-3-methyl-2-butan- one, (32), was inferred. Authentic 5-chloro-2-pentanone and the acylation product 34'gave identical derivatives (34). The minor product, 3-chloro-2-pentanone, (37), was not ob- served. In the present work, structure proof for all four products was based on their ir, nmr and mass spectra. In 47 48 addition, an unambiguous synthesis of 31 was carried out (see Experimental). The acylation of cyclopropane was shown to proceed readily in other Friedel-Crafts acylation solvents (carbon tetrachloride, methylene chloride, carbon disulfide, and nitrobenzene) and in all cases afforded the three rearrange- ment products, 35” 36” and §ZIalong with the expected 5- chloro—Z—pentanone. Subjection of the homogeneous acylation reaction mix- ture in carbon tetrachloride solvent to direct nmr examina- tion at room temperature led to the discovery that all four reaction products were present prior to work-up. The ratio of 4-chloro—3-methyl-2-butanone, (35), to 5—chloro-2- pentanone, (32), found by nmr was 1.20:1; the Vpc ratio after work-up was 1.17:1. This not only verified the reli- ability of the Vpc method, but also established that 3- methyl—3-butene-2-one, (32), is formed directly during the course of the acylation and not by dehydrohalogenation of the B-chloroketone during the work-up procedure. Separate experiments affirmed that indeed 32'was not dehydrohalogen- ated under the employed vpc conditions. Several experiments were performed to determine whether 4-chloro-3-methyl-2-butanone, (35), and/or 3-chloro-2- pentanone, (32), are formed directly in the acylation of cyclopropane, or whether they arise gig some indirect pathway. It is conceivable, for example, that formation of acetyl- cyclopropane followed by reaction with hydrogen chloride 49 (in the presence of the Lewis acid, aluminum chloride) might lead to the observed mixture of chloroketones. Although ring opening to the 6- and/or y-chloroketone does not seem likely (Eq. 10), acetylcyclOpropane was treated with alum- inum chloride and hydrogen chloride in methylene chloride H A1c13 , CH2, > CHsco-c”” HCl \AHZ A1C13 > (10) CH3COC1 + H2C-—--CH2 CH2 CH3C0CH2CH2CH2C1 + CH3COCH(CH3)CH2C1 + CH3COCH(C1)CH2CH3 14, 42. 9.4. at 5° for one hour. Vpc analysis showed a Single peak which proved to be identical (ret. time, ir and nmr spectra) with the starting material. Acetylcyclopropane was also found not to suffer ring opening in the acylating medium at 0° either in the presence or absence of cyclopropane. Indeed, the reaction of acetylcyclopropane with acetyl chloride and aluminum chloride at room temperature for 48 hours (approximately 60% reaction) led to three chloroketones whose parent peaks in the mass spectrometer each appeared at m/e = 162 and 164 (C7H1102Cl). Thus it is established that acetylcyclopropane cannot be a reaction intermediate in the acylation of cyc10propane. Another possibility is that the a- and B-chloroketones are formed by some rearrangement of the normal y-chloro- ketone, 5-chloro-2-pentanone, during the course of the acylation of cyclopropane (Eq. 11). Experimental results 50 A1c13 (11) CH3COCH2CH2CH2C1 :7———-—e CH3COCH(CH3)CH2C1 Y. ‘1 AlCl;\\\\\\\\\ //////1ilc13 A L CH3COCHCC1)CH2CH3 indicate that this postulate for the mode of formation of the abnormal products is also incorrect. Levitt (35) stir- red 5-chloro-2-pentanone in chloroform at 0-10° for one hour with a four-fold excess of a 1:1 acetyl chloride— aluminum chloride complex (thus reproducing all of the con- ditions of acylation except for the cyclopropane). The y—chloroketone was recovered unchanged in 80% yield and no evidence for the formation of any of the other acylation products was found. The acylation of cyclopropane was carried out in the presence of known quantities of initially added 3-chloro-2- pentanone, 4-chloro-3—methyl—2—butanone, or 5-chloro-2- pentanone. The data in Table II Show that the chloroketones are recovered unchanged in each case and hence are not interconverted during the reaction. Any mechanism which begins with the formation of a classical carbonium ion (e.g., (33), with or without stabili— O u + CH3-C-CH2-CH2-CH2 =22. zation by the carbonyl oxygen seems doomed to a series of irrational subsequent steps to account for the formation of 51 Table I. The acylation of cyc10propane in various solvents Yield (%) SOlvent 5-Chloro- 4-Chloro— 3-Methyl- 3-Chloro- 2-pentanone 3-methyl- 3-butene- 2-pentanone 2-butanone 2-one cc14 35 i 1a 40 i 1 21 i 1 4 i 1 C82 38 i 5 28 i 4 25 i 4 9 i 1 CHC13 23 i 2 42 i 3 31 i 3 4 i 1 CH2C12 25 i 1 53 i 2 17 i 3 5 i 1 C6H5N02 18 i 2 48 i 3 30 i 3 5 i 1 aYields are the average of at least two runs. Relative areas were obtained by multiplying the peak width at half height by the height and also by cutting out the peak traces and weighing them on a Mettler balance. 52 the abnormal products. The formation of a protonated cyclo- propane in a scheme similar to that proposed by Baird and Aboderin (28) leads to the ready formation of both the antici- pated 5-chloro-2-pentanone, and of the otherwise unexpected products, 4-chloro-3-methyl-2-butanone, 3-methyl-3-butene- 2—one, and 3-chloro-2—pentanone (Scheme VII). SCHEME VII 0 u H2 CH3-C-Cl + A1C13 + //£\\ > A1c14 + H2C——__CH2 _ _ + H H H 1 , V ..H 9 o ? /. \\ u /| HZC :-+fC-CH3 ( ,:_ H2C : 0 \: 1’ : " ‘ C (C .. CCH3 I: H H H H _ .4 39 H — — + .“H H H H H H (d. «C; 1C... 9~ /:‘\ 0‘ /| /'\\ , . 1'\ u ' : \ CHa-C+CH I. ;$H h H 22. 0 CH3 -c—- ‘ CH3 "C "' CH2 -CH(C1) -CH3 x;> p ...—... O CHs-C + ~ —CH"CH2 “CH2 H [I 1,2-H~ / 0 ll H-CH-CH3 H + A1C14‘ \/ O CH34C ><::> =CH-CH(C1)-CH3 H 61 0 0 CH3-C-CH(CH3)-C(CH3)2-Cl CHa-CFC(CH3)=C(CH3)2 2:1 32. The ir spectrum of gg'had bands at 1680 and 1625 cm-1 for the a. B-unsaturated ketone grOup. Its nmr spectrum con- sisted of three singlets at,1 7495, 8.17 and.8.27 in the area ratio 1:2:1. Separate experiments showed that refluxing 28 with 20% sodium carbonate solution for 15 min led to a facile dehydrohalogenation to 22; No sign of the expected 1,3-addition product, 5-chloro-5-methyl-2-hexanone, (35), was observed, nor was the 1,1-addition product, 3-chloro- 4,4-dimethyl-2-pentanone, (26), found. The reaction of 0 0 CH3-C-CH2-CH2-C(CH3)2-Cl CH3-C-CH(Cl)-C(CH3)3 22. $2 2-methyl-2-butene with acetyl chloride-aluminum chloride complex was reported to yield the same B-chloroketone,(g§), obtained in this study. It is known that cyclopropane does not isomerize to propylene prior to acylation; propylene when acylated yielded 4-chloro-2-pentanone, (21), and 3-pentene-2-one, (g8), (59), products not observed in the acylation of CH3COCH2CH(C1)CH3 CH3COCH=CHCH3 21. 22. cyclopropane. However, the results with 1,1-dimethylcyclo- propane and 2-methyl-2-butene suggest an alternative method 62 by which gg'and gé'might be formed; that is, the 1,1—di- methylcyclopropane might isomerize to 2—methyl-2-butene prior to acylation (Scheme IX). SCHEME IX £3 9 CH3 AlCl3 several. / ‘\ CH3 CH3-C-Cl + > steps --- K 7 ‘CH3 CH3 C=0 CH3 (A1C14_ H . 3 A1C13,H‘+CH3 ’,CH3 9 CH3 22,r_: H,/C‘C\\CH3 9§§é%§§lo CHs-EKCH(CH3)C(CH3)2C1 1,1,2—Trimethylcyclopropane A similar argument can be brought to bear upon the cases of 1,1,2-trimethylcyclopropane and of 2,3-dimethyl- 2-butene. Acylation of either compound furnished the same chloroketone, (22), in over 80% yield. This product did not dehydrohalogenate when refluxed in 20% sodium carbonate solution and was identified as 4-chloro-3,3,4—trimethyl-2- pentanone by ir and nmr analysis. The nmr spectrum of 22' 0 CH3—C-C(CH3)2-C(CH3)2-Cl :82. consisted of three sharp singlets at T 7.82, 8.42 and 8.75 in the area ratio 1:2:2. These were assigned to the methyl 63 ketone protons, the a,chloro dimethyl protons, and the 3,3- dimethyl protons respectively. An increase in the refrac- tive index of 1,1,2-trimethylcyclopropane over aluminum chloride has been attributed to both isomerization and polymerization (60). Other workers (61) report the very rapid and complete polymerization of 1,1-dimethylcyclopro- pane in the presence of aluminim bromide even at -50°, the reaction being complete within a few minutes. 2—Ethyl-1,1-dimethylcyclopropane In an attempt to determine which alternative mechanism is applicable in the acylation of polyalkyl-substituted cyclopropanes, 2-ethyl-1,1-dimethylcyclopropane was investi— gated. Scheme X indicates that if 2-ethyl-1,1-dimethyl—. cyclopropane is acetylated gig a bridged ionic intermediate (52), only 4-chloro-3-ethyl-3,3,4-trimethyl-2-pentanone, (5;), would be expected as a major product. If, however, the cyclopropane isomerized to 2,3-dimethyl-2-pentene prior to the acylation reaction, both Ql'and 4-chloro-3,3,4- trimethyl-Z—hexanone, (52), would be expected to be furnished in approximately equal amounts. Acylation of 2-ethyl-1,1- dimethylcyclopropane or 2,3-dimethyl-2-pentene using either aluminum chloride or stannic chloride as the Lewis acid led to a very complicated reaction mixture, with the formation of a large number of products. No single product was formed in over 20% yield according to Vpc analysis, and the entire reaction mixture from either substrate quickly poly- merized and decomposed upon standing. Identical acylations 64 SCHEME X 0 CH3 ‘3 A1C13 ' \ CH “ several ’ 3 CHa-C-Cl + CH3 > steps > CH 3 9H2 H CH3 2. O I HSC CH3 E2, 1A1C14‘ 0 CH3 CH3 II I I CH3-C-C-—C-—Cl H3C-CH2 \CH3 51 H3 0 - c=C,/CH3 CHa-C-Cl 9 9H3 $H3 an” \\CH2 _XIET;——> 51 + CH3-C-9 _—9 -Cl 9H2 éHa CH3 CHz-CH3 CH3 CH3 .A1C13 CH3\\ > < 52’ of 2-ethyl-1,1-dimethylcyclopropane and 2,3—dimethyl-2- pentene in methylene chloride using stannic chloride as the Lewis acid (thereby obtaining the cleanest reaction mixture after work-up) led to the formation of seven products. The reactions were monitored by vpc and the gas chromatograms from the two reaction mixtures (i;g,, the cyclopropane and the olefin) were virtually identical. From these data it can be concluded that polyalkyl-substituted cyclopropanes appear to isomerize to the corresponding stablest olefins prior to acylation. In systems where the classical carbonium ion structure would be primary (n-propyl or cyclopropane precursor) or would be otherwise destabilized, Baird (28) suggested that 65 hydrogen—bridged intermediates (edge-protonated cyclopro- panes) would be most important. On the other hand, in substituted systems, Wagner-Meerwein rearrangment, classical carbonium ions, or carbon-bridged structures should be favored over hydrogen-bridged species. Karabatsos (22) averred that protonated cyclopropanes are involved to ap- proximately 5% in the nitrous acid deamination of l-propyl- amine, to less than 1% in the deaminations of l-butylamine and isobutylamine, and were not observed in the case of neopentylamine. He suggested that these results were brought about because of the greater stability of the clas- sical carbonium ions (relative to the bridged ionic inter- mediate) in the substituted systems, and steric repulsions which would arise upon formation of an intermediate such as 22. A similar trend is seen in the acylation of cyclopro- pane. Cyclopropane acylates entirely yi§_protonated cyclo- propanes. In sharp contrast, 1,1-dimethylcyclopropane, 1,1,2-trimethylcyclopr0pane, and 2-ethyl-1,1-dimethyl- cyclopropane apparently isomerize to the corresponding olefins prior to acylation. 66 It seemed worthwhile to investigate a monoalkylcyclo- propane, to determine which of the two possible reaction paths would be followed. Methylcyclopropane The acylation of methylcyclopropane led to the forma- tion of 5-chloro-2—hexanone (65% yield), 4-chloro-3-methyl- 2—pentanone (12% yield) and 3-methyl—3-pentene-2—one (14%). The nmr spectrum of the major product, 5-chloro-2-hexanone, consisted of a one proton multiplet at T 6.02 (methine proton), a triplet (J = 7.0 cps) at T 7.38 for the methyl- ene protons d- to the carbonyl group, a, singlet at 1 7.92 for the methyl ketone protons, a multiplet at T 8.08 for the C-4 methylene protons and a doublet (J = 6.5 cps) at T 8.48 for the C-6 methyl protons. The nmr Spectrum of 4— chloro-3—methyl-2-pentanone had a multiplet at T 5.80 (C-4 proton), a multiplet at 1 7.32 (C-3 proton), a singlet at T 7.82 (methyl ketone protons), a doublet (J = 6.5 cps) at T 8.50 (C-4 methyl) and a doublet for the C-3 methyl protons at T 8.87 (J = 7.0 cps). The nmr spectrum of the a, fi-unsaturated ketone showed a quartet of quartets (J = 7.0 cps, J ' 1.4 cps) at T 3.68 (vinyl proton), gem vic a singlet at T 8.00 (methyLketone protons), a multiplet for the C-3 methyl group at T 8.25 and an eight line reso— nance for the remaining methyl group at T 8.58. Whereas the 1,2-addition products may arise either from a bridged intermediate or from prior isomerization of 67 the methylcyclopropane to 2—butene, the 1,3-addition pro— duct cannot reasonably arise from 2-butene. The formation of bridged intermediate §§ would lead to 5-chloro-2-hex- anone and subsequent equilibration to ion ég would lead to the formation of the other two products. Ion §§ is more stable than the corresponding ion from the acylation of cyclopropane, 22, and hence a greater percentage of the total product Should be derived from §§,than from 22; this was in fact observed (~70% vs ~80-40%). o 9 A1c13 ~ 5,cH3 AlCl4 [:>»CH3 + CHa-C-Cl -————» , M. -——————> fa ' \ H c ' + 2 \:/1H /CHCCH:””,,/,,»27' éh I / 23v CH3 0 +:::CH H H’ CH3-c-CH2-CH2-CH(C1)-CH3 CH3 + o CH3-c-CH(C1)-CH2-CH2-CH3 AlCl4 (not observed) CH3“C"C( CH3) =CHCH3 CHs-C-CH (CH3)-CH(CH3)-Cl SUMMARY 1. The acylation products of cyclopropane with acetyl chloride-aluminum chloride complex in chloroform at 0° were 4-chloro-3-methyl-2-butanone (42%), 3-methyl-3-butene-2- one (31%), 5-chloro-2-pentanone (23%) and 3-chloro-2—pen— tanone (4%). The overall yield of acylated product was 96%. 2. 1,1-dimethylcyclopropane with acetyl chloride at 0° furnished 4-chloro-3,4-dimethyl—2-pentanone, identical with the product from 2-methyl-2-butene and acetyl chloride, in 78% yield and 3,4-dimethyl-3-pentene in 22% yield. 3. 1,1,2-Trimethylcyclopropane with acetyl chloride at 0° produced only 4—chloro-3,3,4-trimethyl-2-pentanone (80%), identical with the product from 2,3—dimethyl-2- butene. 4. The product mixtures from the reaction of acetyl chloride with Z-ethyl-l,1-dimethylcyclopropane and 2,3-di- methyl-Z-pentene were virtually identical according to Vpc analysis. 5. Treatment of methylcyc10propane in the acylating medium led to the formation of 5-chloro-2-hexanone (65%), 4-chloro-3—methyl-2-pentanone (18%), and 3-methyl—3Qpen- tene-2-one (12%). 6. Phenylcyclopropane was smoothly acylated at 0° to pfcyclopropylacetOphenone (72% yield) and 1-(4-acety1phenyl)— 2-chloropropane (15%). 68 69 7. Acetylcyclopropane did not suffer ring opening under normal acylation conditions, nor did it react with hydrogen chloride and aluminum chloride in methylene chlor- ide at 5°. 8. The mechanism of the acylation of cyclopropane and substituted cyclopropanes has been discussed in the light of these results. Cyclopropane acylates entirely gig pro- tonated cyclopropanes, as apparently does methylcyc10proe pane. The most likely structure for these ions is the "edge-protonated" form (see Introduction, Part C). 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APPENDIX 74 75 .Acaom «Gov mcocmucmmlmtouoHfiCIm mo Esnuowmm mucmcommn Ufiuwcmmfi couomm .H 0.2.5:.— «3 ( .0 -, . , a . + . . ... w .. p .. _ E q , _ _ “-1..." .Mfl. - °“‘-':"_.‘(.EP.'."'. - 2159. m Wwo Eduuommm mosmc0m0u owumcmmamcououm .N ouaufim 3 6 ._ w a m l w p .Acaom «H03 mcocmusnlNlahfimEIMIOHOHnulfi b 4 "(a "‘ ) “7.. '- ecupusa‘. w'r.‘., 76 77 m .FBSIB v