MIMI HM ‘ I WU l I l 1 01—3 05¢. ]| #4:- A STUDY OF THE REACTION BETWEEN CHLORACET‘ONE AND GRIGNARD'S REAGENT Thesis for the Degree of M. S. MICHIGAN STATE COLLEGE Boyd Harding Carr Jr. 1942 —. mu 9» w. «wuss-“v- . t 1 v ‘ ‘ " I". .. AIM-iliziq.‘ .: . ‘ iv:\.'“~;' th'lL, ) .I‘ W.“ H’wvdl -. v n'JLnH-In’. . alarm ’17 «- ‘4A—H- A KIUJY Q3 T;L 4,-- -’ I- r 'f-‘f-vj I \I—? .‘T .-~‘.. _‘_ .. -r A v ’_ .. I“ ,A 15-11-»! L u“. .L)‘ ‘O'l. .-._g_,- ”3: U1 .LJ‘I-..‘ V . a V?" J. u. .33.; -_. I1’>.- .‘w c." v.0 q p. Y .~..1 '9' 1x4...) \Iitl~lx.l Id'k) J»."J‘\I‘.’.L 3 by Boyd Farding Carr Jr. A THESIS Submitted to the Graduate School of Kichigen State College of Agriculture and Applied Science in partial fulfilment of the reguirementa for the degree of m.— (‘r-"- .Q .-\ n '— ”Iva“ .k L')....J~i\ U45 ”crl'b-L'J Degcrtment of Chemistry 1942 / ,f} (/31; / l 1. Introduction “o Lietorical C 1.0 .1. C. Y" 4.1. u. Eheereticnl :nd Liecuseion e. Lx,erimentc1 gateriala'ueed Preg:r:tion of Lee-otente Reactions prayer Proof of structure 5. Conclueiqne 6. Bibliograghy 331616 _.- “1 r c . a. 1 v H v ‘ 11 U a. ~J M. 41.1"} .. ~ .1. The rather wishes to exgreue sincere eyyrecirtion for the hel) tendered by St. L. 3. luaton, iithout which the aork of this theeia would have been imp- oeeible. IKTRODUCT IUN The grollem of this thesis is en investigation of the reasons why a secondary instead of a tertiary alcohol re- sulted from the reaction between chloroscetyl chloride and Grignerd‘s reagent. Huch of the work of this laboratory has dealt with the condensation of various alcohols with phenols. bezene and other aromatic hydrocarbons. Esny methods of synthesis have been used, and tried, to preosre the many alcohols needed. One of the methods that was used in attemyting to pre- psre tertiary alcohols was the reaction between halogen acid halides and Grignsrd's reagent. Euston and Spero1 utilized this method of synthesis in attemyting to preosre di methyl ethyl carbinol. hey reached chloroscetyl chloride and excess methyl Gri;nsrd. It was expected th=t the reaction would groceed as follows: l.methyl group would re)lsce both halogens end a third methyl Grignerd would add at the csrbonyl group. This re- action would be exoected to yield di methyl ethyl cerbinol on the hydrolysis of the groduct. Towever, the groduct 0f the reaction was a secondrry alcohol, methyl iso QrOpyl cerbinol. the purgose of this thesis is an sttemgt to trace the route of the reaction and to investigate the mechanism of the re-srrangement. In the shove reaction, the fir:t intermediate product that was formed was considered to be chlorscetone. The work of this thesis continued the grohlem from that point. H IST OR ICAL Though the indegendent class reactions of either hal- ogen comgounds or ketones are many. there has been Very little work done on the reaction between alpha halogen alkyl ketones and Grignard's reagent. The literature did. yield the following useful reactions. The secondary alcohol. methyl lSO'prOgyl carbinol, was pregsred in 1877 by Einogredow2 by reacting brom- acetyl bromide and excess zinc methyl. And in 1981 Bogo- molt—2y:5 carried out the some reactions. In 1107 Henry4 synthesized the secondary alcohol. methyl iso prooyl carbinol from both chloracetyl chloride and chloracetone using three and two mole of bethyl Grig- nerd respectively. He also greosred the secondary alcohol from the reaction of isobutylene oxide and isobutyreldeh- yde with methyl Grignard. In 1921 HcKenzie and Boyle5 reacted phenyl elghe hal- ogen acid halides with Grignar"s resgent and.obtsined an unsaturrted alcohol. is- I; '-= phenyl 2: Cl :1\ /OI.I;gZ:2r >c< -+ s 1.3:; g7“.r > ,c=c\ L 0001 R h' - + (the intermediate product (H) HOH was thought to be a ketene) h h \‘C=C=O IL L' it ,7 6 In 1901 IVY oregrred some tertiery alcohols of the folloiin; nature, (1) Ad c(on)-c:o and (4) n4 C(oK)-CTClz by reacting Gri;n:rl's reegent and ethyl dichloroacctste. In lads hohler and Tisnler rezcted ghenylflalth hal- ogen.ketones with methyl Grignard. The reactions assesred to go in the same general way. is- 9 (05:15 ) fCH-C(C(SII5)-Er-C-CCSIE5 4- 31%;-..32‘1 “-3, 0:73;]: vn= H- -" P (cant),3 c 9(06H5*é c6 5 DU‘LEMI a (CAB); rummaging—54515 In all of these reactions KOhler and Tishler found only a single reglacement of a halogen by a hydrogen. Thee carbonyl group entered the reaction as an intermediate enol addition product. " 1- vr-m .8 In 1963 hawk and Lchlvsin carried out some Griznerd reactions with ethyl benzoyl bromo acetate. ie- v 9 Q ' 9 9 0.1!.--5-CHBr-o-o-c I?" + Clings: ——> c Med-CELC-O-CWH E) D 2, 3 c) 6 0 do 4': 5 From the products of the reaction they concluded that a halogen atom proximzte to an oxygen may appear in th‘hypo- bromite strte or the proximity'nay cause an enol-keto re- arrangement. 731‘ o p e ‘/ C IT;c-—c::-Ez-o-C.JL c6135c3-cnsr-b-o-cg-15 /_7\ 5 0 ° , “ i O \" c_.132g=03r-6-o-c.,,z3 t) b at b The reactivity of the resulting molecule must be due to the unsaturstion. In 1340 Ziegler and Connor9 stated thrt the reactivity of a halogen proximate to a carbonyl qroug may be due prrtly to the effect at the oxygen indirectly on the carbon-hel- ogen lin¥(loosening it) and also to the polarity of the orygen. The result might be an unszturated molecule due to a halogen shift, as stated by Hash End lchlvain. In 1940 Huston and Spero reacted chloracetyl chloride and chloracetone with excess methyl Grignard and lerys obtained the secondery alcohol, methyl iso grOyyl carbinol as the main product. This represents practically all of the work analazous to that of this thesis found. DI [‘11 fun“ 1," "w I‘ A373) V f» n? 7" f.“ I MJUU\’~) "J“ LL '-'Q‘" l t O U 1 "‘ i V. . 0 V As_stnted oeiore, the synthesis of a tertitry alcohol dimebhyl e byl carbinol was attemgted in this laboratory in the following way. 0137-3301 + 073195;?41' 31373000: 4— on, zygter I" 9 z. .5 .5 93 \\3\ qxgrr 07‘3“ -c-oz«:, 6—— CTILfl-r 43193:: "-03.-. O (" "\— O C) ) T V “In; 0 II. VI) 3 3 The erGUCt was, however, the seconfizry ElCUhOI, methyl 13° progyl carbinal. This obvious re-zrrenrement has had several actual attempts at an e glenrtion and in addition there rre several somewhat ans egous reactions thrt we can draw from. Probably the first attempt at an exolanation was that by the Lussian. linogradow in 1877 in his analagous work , gregaring methyl iso progyl carbinol from chlorecctyl chloride and excess zinc methyl. KaschirskylO suggested to him that the reason for forming a secondary end not a tertiary alcohol might be as folloss. {‘7' "an '7' PT'" - '_ Cl"”~CV“l'+’ ”“(V‘a)s“‘*:>-ClCIQeO373-+— Zn(C?5) 1‘ A Q" T" ’0\ Fr" @ ., " "‘"U Orb-z-Cfl ort- ed by Kohler and Tishlrr the followinz would hegpen. f. dTV, Clot-figcoczzs—r- 01151133 — -- ., CT'5CQCFR Q) The product of this reaction was not acetone. Ziegler rnc Connor offer a theory for an algla halogen kctone re-trrengenent. They stzted tlrt the cxrbonyl group increased the rescuivity or resonznce of the halogen of the 11650218. 16‘ Clot-34:9 ":7- II c =Q-C“r ‘4 ‘r‘r' m? ._.) .v (a . LI '0 pt .1 The reectivity of the molecwle would then be due to the rer-ctivity of the Line: turrted point. 'OJC’VE-Z', witl'cut ‘\ \e 11 theorizing farther, Kohler states thzt Griznordereezents do not add at 1:3 double bonds. If file LoXenzie-Bbylo mechanism were to take place then the reactions of this thesis would be as follows. II‘ ’01 n‘ /C 1- 33 C £3.43? “a } [0:030 I + g x / CYY fic;*r I" OIEJg‘I'r ,C=C< 1' (313 There was no evifience uheteoever of a ketere being an intermedizte. Her was the final product unsaturated, since the final groduct wee methyl ieo grooyl carbinol. I do not think that file ghenyl algha halogen ketonee cen be generally Considered enelrgous to chlorecetone in Grijnerd reactions of this type. ry looking closely at the Kohler-Tiehler reactants and comgerin; them to chlorecetone the reason will apgear obvious. p 06 17;. II n O (1) cdn -c--g’;3-ccn5+ CI —->(cm3).c - (2-6-05v5 06115 cart.) 9 QI3 (a) on;- “-CII ,c1 + answer ——-7 on 6-8-0" .01 In (1) the halogen is tertiary and easily replaced, in (a) it is primary end not as reactive; the benzene nuclei in (I) are themselves unreecuive and quite large in comparis- on to the small reactive hydrogen atoms. For these few reseans alone I do not believe the two different molecules crn be exgected to give, zenerelly, Pnelezoue reections with ’}ri ;m 1' 'e res: ; out. From the work of this thesis and from earlier work, the evidence points to the following route of reaction. ClCIICJCl-i- C7311; gj'r ~701‘CI dCoCIIs -‘~ u “ IIEr ClCII COCII, + CH I.;,33';r-—7 013‘? (gm-CH:3 £3 6 C) ‘SPQT in . ‘5 on 'Iir roe rrz-n gee 1n Cl-GIIJ‘gJ-«CII:5 greoence of ht. IQ~ “CY find CVO as IIqC-C-CI'I3 3 Grignrrd to- “ bH o v ‘ 3 'Y ('(Q'w- n1: ht. ‘- TY: 1"! {‘7' ll. uni; LII. ‘0 -. ' . z- ‘7 IIIJ’U‘UJ' CI * on? 3 .‘i .2 9 I; QII I; IEC- "CIT +011, ,;r —> 0‘ 0-0-0713 a.) L; ‘2'}? '1? ‘ 5 I Chs The reasons for believing thrt the reaction takes the above are as follows.(£ha assumgtion one first made that the first product of the rezction between chlorecetyl chloride and methyl Grignerd is chlorncetone) (l) Chloracetone on reacting with Grignerd's reagent yields isobutylene chlorohyrdrin in a Cl” yield. 911‘. Ifficoczzdcu CITE I: 33“ r ~e cza- -g-cv‘ 01 B.."t 1-45 1 37' c (.1 A. 3.?t. in Leilstein 155-157°c II , C 13. CH, -$-CII C1 + 1:333}? ——§II._.C-g-CII 13. "It . 5.3 C ‘J {y ‘1; «J 13, ‘3 0...-5 Co In; shove rrodnct (I) reacted in this way as stated by Henry. q - EH ’V "1’- _ ‘ 1r 3‘“ n Y 7" c. on. c-c: +—I:‘f Jo (dil. )—4» c "-Y-oI on “ CH5 ‘ 0 CH“ 4 L} O 1?. it. 130 C es in the litersture(¥enry) Ieobutglene chlorohyflrin 53051; rare: Hz.h urrd'e rezzent on rein: Leztei to yield in order. 1. Isobutylene oxide, 2. Ieobutyreldehyde, £3. gethyl ieo gregyl cerbinol. The above reaction was cerried out end the folloJing determined. A. Isobutyraldehyde was isolated as one of the graduate of the reaction and a derivztive was greyered. B. lethyl iso pregyl cerbinol was found to be the mein groduct and e derivative was grep- fired. Eeat must be Pp lied over a feirly long period RE- of time to make the erranzement texe place. $2.“. 1.. -v—, q—H «v-‘vy - J 1.1x-.- “51:5 5-7.1AJJ 4/ heteriele Used :Ither - 15.3.2. Dried om» ‘coaim. Lagneeium turninge- Lethyl Alcohol - pract.- Herck Chlorecetone - Stabilized - Commercial Solvents Co. Sodium Bromide - Tech. Squuric Acid - 0.9. - Gone. 3803 - Tech. Acetone - 6.“. - Ierck Sodium Calcium Chloride - Tech. Hazso4 d,4 Dinitro phenylhydrazine - Leegent - Beetmen 5,5 Dinitro benzoyl chloride ' " Emhyl Alcohol - 0.9. - Terck 384003 - Tech. Bromine KMnO4 Glaciel Acetic Acid - 0.9. H01 - 0.9. Pregaretion of Leectsnts 'I‘Iroz'Iz' cetone: K: F. '3 In a 5 liter, 5 neck fliok rre pltced e condenser glyCerine sealed stirrer, a thermometer, and a 500cc drogg- in; funnel. In the fleck is plzced lCJOcc HZO, 500cc acetone, and 3?ecc of glacial acetic acid. The stirrer is started, the flask placed in a water beth at 73-90 C and 3540c 3rd carefully added. Ihen the rerction mixture decolorizes in 1-3 hours, add 800cc of cold K30, cool to 10 C, and neut- ralize to Congo red with about 1000 gms YaQCOS. The oil which separates out is taken off, dried over 394304 and fractionated. The fraction bdilin; between 38 and 48 at 13mm pressure is saved and on refrectionetion that boiling between 40 and 43 C at 15 mm is used. Eromscetone is best stored cold and 5 little hydroguinone added to prevent ox- idation and polymerization. Yield between 430 end 48» gas. llethyl Grignerd: .RsF. 1+ The methyl Grignnrds were 511 pregared in the some way. A three mol run will be for exemple. All the oreccutions for enlenhydrous preparation are used. First, a methyl bromide generstor is set no. A 5 liter round bottom flask is plsced in a sand bath with a reflux condenser in it tnd a delivery tube leading from the condenser to 9 series of Hg: 4-?40 drying end washing bottlcs(e F3304, BKQOI end 3 safety bottles) To charge for s 45 mol run-plrce in the flask e doc of 3M0, zaOCgms sto4 Fnd 1760cc of methyl alc.(tcn;. kept below 79 C Then séOOgms 01 Telr are added, the Egyeratus is seslsd an! the bath is heated slightly. The g:e is evolved immediately CHM is passed into- In a 3 liter, 5 neck, round bottom flesh is plac- ed a glycerine sealed stirrer, & condenser, a thermometer and a glass entry tube for the gssClrrge sise to grevent glujjing) In the firsk is placed 7?;ns of L3 turninzs and P0000 of anhydrous ether. The flrsk is cooled in a srlt - ice bath to -5 C. The stirrer is strrted, a few crystrls 0f I;added {Ed the CTqEr is led into the mixture at such a rzte the ether refluxes gently in the condenser.$he addition should take from c to 8 hours to comeletely use u) all of the L; in a 3 mol run. The Grignerd r88- umhes a dee) black color. Reactions Prooer Pregeretion of isobutylene chlorohydrin: Three mole of enhydrous chlorecetone dissolved in 7oOcc of anhydrous ether is slowly added to 3 mole of a stirred and cooled methyl Grigntrdithrouzh a-droy;in: funnelO (the cooling is done by means of e salt-ice beth‘Tflheiset-UP is the some for this rerction as for the pregerrtion of methyl Grignerd excegt that s 5300c droggin; funnel reglsces the gas delivery tube. The addition is kegt at such strata ,thzt the temgereture does not get shove 5 C. The eddition should be comglete in 5 to 6 honrs end the mixture should be ellosed to rise to room temoersture. It is then hydrolyu zed with acid and ice, extracted, collected and distilled 9t 17mm of pressure. th fraction boiling between as end 45 C should be kegt, dried over Ys¢fi04 and refrectionsted That boiling between 41 end 45 C at 17 mm is used. The yield should be about 1963.3 or 61“. It is best to add the chlorscetone to the Grignnrd to gravent excess chlorecctone from reecting «ith itself and any other products which mry be gree nt to form resinous wzssie. Since the folsosin: reactions ere mrinly ell elike I shell describe one and merely tell the veried conditions in the others. They are the reactions betseen isobutylene chlorohydrin end Cfiqufir. ?he condi ions were varied to ~. try to esteblisLb rt ihet temgerrture the re-rrrznzemont 5 takes glece iron chlorohydrin to isotatylune oxide, to iso- butyreldehyde and finrlly to methyl ieo pro:yl crrtinol. the reaction is crrried out in exce s Eethyl Grijnzrd. Lenction Of Isobutylene Chlorohydrin end Yethyl Grignerd at o to 5°C. In a 50000 round bottom, 5 nee? flask containing a condenser, glycerine sealed stirrer, and a thermometer was made one half of 9 mol 0 Cfifingr. To this mechanic- ally stirred and cooled Grignerd was added 50 3ms of chl- orohydrin in zSGcc of anhydrous ether. The addition was done so that the temp. did not rise ebove 5'0. The pIOdUCt was immediately hydrolyzed, extracted, dried and fraction- ated. The groduct was chlorahydrin, showing that no react- ion took plsce at this low temperature. Reaction of Isobutylene Chlorohydrin end Methyl Grignsrd at as to 53°C. The reaction was carried out es above, exce)t that .- fl.‘ the temgereture was Pest between 98 rnd b: o. Again there was no reaction. Yo cerbinol was formed. Leection of Isobdtylcne Chlorohydrin end lethyl Grignard _ r .q Pt 45 to do} b. The addition of chlorohydrin are crrrier‘1 out st room tem;er:ture rnfi'then the rerction mivture wee placed in e water bath, the ether discilled off end the viscous _ O broqn mess remaining are kept Pt 4; t) 53 3 f9. “ hours. The groduct wee difficult to isolrte because it polymerized in the greeenoe of hert 5nd Iydrolyzing acids. Fouever, 3 to 4 00's of isotutyrnldehyde were ieol: ed end 9 e,4 dinitro ghenylhydrezone derivative was oreozred. Leaction of Ieobutylene Chlorohydrin rnd Tethyl firiznsrd rt 55 to 65 C. The same technihue ewes followed as in the )rfiViOUB BXgeriment but the heating was crrried out for Stofi hours at 55 to 65 C. The groduot gas meinly methyl 180 pragyl carbinol, 7 or 8 cc's were isolateo. A 3.5 dinitro benz- oete ester was mzde of the crrbinol. Reaction of Ioobutylene Chlorohydrin end Lethyl Grignrrd nt.€5 to 70 C. The eeme techniaun was used so before but the cond- itione were chtnged to a temgereture of 65 to 70 C for Ghoure. The product was mainly methyl 180 prouyl crrbinol. About 6 gme of cerbinol were isolsted and in addition about a cc’s of isobutyreldehyde were also isolated. I phenyl urethane derivative wee pregrred of the certinol and e e,4 dinitro ghenylhydrezone derivative was prepar- an of the aldehyde. proof Of fitructure Ieobutylene Chlorohydrin: 1 3 O L.pt--l~5 to 1e? 3 at 760 mm . 4a to 4e°c at 17 mm " on . " 49“" C 3--C--C'3§1+T%u)’-———=r0 --g--t”2 CH. on: s r.)+--53°c v 69““ . w ox . Ce -- -Chl-r-H,SO (d11)___=,CEq--C--CHrHE 3 If N "' 4 \J . y d Chm C11 .3 3 B.pt--170‘c These boiling yoints are 511 verified by Henry4 excegt that of 4a to 45.0 at 17 mm for the chloro- hydrin. This was determined during the work of this thesis. Ieobutyreldehyde: 0 4.9t---CS to F4 C( r, e _ 15 purine: and -ueon Derivative-e,4 dinitro phenylhydrezine - o A I.;.;)t-180 C (17)) Eethyl Ieogrooyl Cprbinol: f a?" L U. mvy fl .1 W'Y V'_"--J-- -’--:J--.~ t.) .011- -,'7_ Q 4..—.\. V B.pt--110 to 114': (39ero 1) I gregared two derivrtivee of the carbinol, the 3,5 diuitro benzoyl eeter(fi.qt 7000) end the ghenyl urethene(u.pt 72°C) 1 (Soero for the ester) Conclusions: (1) From the work of this thesis and previous work the indications are that the route of the rezction is as follows. Qfigir Cl 1: wear-W” :.~.:r —? Clc.i',:-o--CI-:3 " 0:1,, Qflf ,r It and eyceggs ClCK;--.--C"5__~ Q 6 0375:";11‘ ;C(-- 97:.-0 L- ‘3 CT. :5 3 H C--F--??7 7> CH -- o-CVO "' (321..L “’ czar-1.11 3 (57.2, I U 0 H o 14- H-o» H OH C}F1--C--CIO + 01%?ng r a CV --C--C--C}" U b123, dfl‘s ti 0 (3)Thet the best way to grepere ioobutylene chlorohyd- rin is to add the chlorecetone to methyl Grirnard. It eleminetel numerous side reactions and increreee the yield. (3) That elohn helojen glenyl Ictones and chlorrcetone are not anelexoue in t vir reactions with firiznerd'e reagent. \ ((),Ingpreoering isobutylene chlorohydrin it is heat to distill the groduct at reduced pressures to grevent golymerieztion. 1. Huoton and figure - “.8. Thesis 15¢J{ Jere) a. Iinogredow - Liebig'e Annalen der Chemie 131 p; lefi 1¢79 3- Boxomoley " " “ " 3 c : WI 70 x 4. Fenry - Congtee Eendue Vol.145(11) 1357 or 51 d) 5.16Kenzie and onle - Journ.Chem. Soc. 1341 V01 11% :31131 g, ivy - Soc. Chimi;ue Societe Ge Trence vol.49 1351 12 4% 7. Kohler and TiehlerlJ.£.C.fi. 54, 534 (133;) J 8.?awk and LJZIVIin-J.A.C.C. 55, 3334-33'3 i :3) k U.) ‘3- A O 9. Zieglo end Connor-J.A.C.S. 6;, “5‘5 (1 ,- o. zaechireky-Liebig'e Annalen der Chemie 1= L J H V H U) \2 C“ k L H i (:1 ll. Kohler-J.A.C.'. 41, 417 1393 1a. Beiletein - 9;. 393 land 1 13. Clarke-Grganic Lynth. vol 13 (1;) 14. Clarke “ ' ” vol 13 (31,76) 15. Chriner and Poeon - Identi . of Organic Comge.. 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