This dissertation has been 64-2653 microfilmed exactly as received LEVAND, Oscar, 1927- PART I. SOME CHEMICAL CONSTITUENTS OF MORINDA CITRIFOLIA L. (NONI). PART IT. THE STRUCTURE OF THE NITRO- CAMPHOR ANHYDRIDES. University of Hawaii, Ph.D., 1963 Chemistry, organic University Microfilms, Inc., Ann Arbor, Michigan
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PART I. SOME CHEMICAL CONSTITUENTS OF MORINDA CITRIFOLIA L. (NONI ... · part i. so~llichemical constitu~ntsof morinda citrifolia l. (noni) part ii. the structure of the nitro camphor
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This dissertation has been 64-2653microfilmed exactly as received
LEVAND, Oscar, 1927-PART I. SOME CHEMICAL CONSTITUENTSOF MORINDA CITRIFOLIA L. (NONI).PART IT. THE STRUCTURE OF THE NITROCAMPHOR ANHYDRIDES.
University of Hawaii, Ph.D., 1963Chemistry, organic
University Microfilms, Inc., Ann Arbor, Michigan
PART I. SO~lli CHEMICAL CONSTITu~NTS OF
MORINDA CITRIFOLIA L. (NONI)
PART II. THE STRUCTURE OF THE
NITRO CAMPHOR ANHYDRIDES
A THESIS SUBMITTED fro THE GRADUATE SCHOOL OF TI-IE
UNIVERSITY OF HAWAII IN PARTIAL FULFILLMENT
OF THE REQUIREr.'iENTS FOR 'rHE DEGREE OF
DOCTOR OF PHILOSOPHY
IN CHEMISTRY
JANUARY 1963
By
Oscar Levand
Thesis Committee:
Harold O. Larson, ChairmanDavid E. ContoisMichael M. FrodymaRichard G. InskeepPaul J. Scheuer
PART 1.
TABLE OF CONTENTS
SOME CHEMICAL CONSTITUENTS OF fl10RINDA CITRIFOLIA
L. (NONI)
LIST OF FIGURES •••••••••• 0 •••••••• l) ••••••••••••• v
::~G:~!';c~k' m-s~]WJ;~;U'H"fE ~i~rt;~j~~t1~~'- hi~.- ··~1=j j, roJ .. .5 6 7 B ';) 10 if 12 13 14 I) '--'6 0
Fig. 2. - The infrared spectra of ~-D-glucopyranose pentaacetate isolated from •noni fruit (upper), prepared by the method of Wolfrom and Juliann (lower).
21.
r-D-Glucopyranose pentaacetate was prepared accord
ing to the method of Wolfrom and Juliano (16). A mixture
of 4.1 g. (0.0228 mole) of D-glucose and 10 g. (0.122
mole) of sodium acetate in 70 mI. of acetic anhydride
was gently refluxed for 10 to 15 minutes. The reaction
mixture was slightly cooled, poured into 400 mI. of ice-
water, stirred for 3 hours at room temperature, and ex-
tracted with four 60 mI. portions of chloroform. The
combined chloroform layers were washed twice with water
and dried over anhydrous sodium sulfate. After removal
of chloroform, the residue was dissolved in anhydrous
ether, filtered and crystallized by the addition of
petroleum ether (b.p. 30-600 ) to incipient cloudiness.
The crystals were treated with Darco and crystallized
three times from ethyl acetate-hexane. White crystals
weighed 2.0 g. and melted at 132-1330 • Lit. m.p. 13305
1340 (16).
10. Characterization of Compound B (Asperuloside Tetra
acetate)
Compound B (3.3 g.) obtained from the chromatography
of the acety1ated material was crystallized four times
from ethyl acetate-hexane. White crystals melted at
152-1530 and weighed 0045 g. (yield: 2.5 x 10-3%based
on the fresh fruit). If] 28 -133.8 (£.5.0, chloroform).D
2.5 r
2.1
1,7
1.5
210 220 230 240
1V'A VE LENGTH (mp)
Fi~. ~. - The ultravinlet spectrum of
~-D-glucopyranose pertaacetate isolated from
-4the noni fruit. (c= 7.PS x 10 M in abs.
alcohol)
23.
The infrared spectrum (Fig. 4) showed prominent bands
at 5.66f (d.,(~-unsaturated t-lactone) (18); 5.74,8.08
and 8.22ft (combined acetyl groups) and 6001/U (enol
ether) (19, 20). The ultraviolet spectrum (Fig. 5)
exhibited a maximum at 232 mf (log E 3.89) in 95% alcohol.
On the basis of the chemical analysis and of the
mixture melting point with an authentic sample* kindly
provided by Dr. L. H. Briggs, and by comparison of their
infrared spectra (Fig. 4), Compound B was identified
as asperuloside tetraacetate. Lit. values (21): m.p.
154.5-155; the ultraviolet spectrum, 234.5 m~ (log E
acid (XVI), etc., (Lf5) it is reasonable to believe that
40.
oIol o1'l. 0 0
0/' h- ~ ~
XI XII 0
< }C~:CHO~OXIII
;~~o
C~JOHoXV
C.4II 10H
CH - c.--t--lr0 C.H 3
J OJit
XVI 0
asperuloside as it occurs in the fruit has some anti-
bacterial properties. According ~o Briggs and Cain (21),
extensive bacteriological testing of asperuloside has
revealed. no outs~anding antibacLerial properties.
4. Miscellaneous
Steam distillation of ripe yellow fruit yielded
caproic and caprylic acid. The acids are probably re-
sponsible for an unpleasant odor in the ripe fruit.
Caprylic acid was bac1eriologicallf inactive.
Hexane extraction of dried noni fruit pulp afforded
a liquid re sidue and a high me 1ting solid. rrhe crude
41.
liquid residue was active against Salmonella typhosa,
Shigella flexnerii, Bacillus subtilis and inactive against
Staphylococcus aureus; whereas the solid was bacterio
logically inactive and was not investigated further.
The liquid residue, l10wever, was separated into acidic
and neutral fraction with sodium bicarbonate, but no
attempGs were made to investigaGe these fractions.
42.
D. SUMMARY AND CONCLUSION
The methanol residue from the extraction of dried
noni fruit was investigated for antibacterial substances.
Preliminary experiments~o isolate chemical substances
directly from Ghe residue by column and ion exchange
chromatography were unsuccessful. Acetylation of the
methanol residue followed by chromatography over silica
gel G yielded three compounds: an unknown liquid, b.p.
183° at 0.6 mm., ~-D-glucopyranose pentaacetate, m.p.
132-1330 and asperuloside tetraacetate, m.p. 152-153°.
The unknown liquid was bacteriologically inactive and
it was not identified. Inconsisten0 elemental analyses
indicated that the liquid could not be purified by dis
tillation. On treatment with concentra~ed nitric acid
and with sodium hydroxide, phthalic acid was isolated,
but the liquid was resistanc to ozone.
The acetylated sugar, ~-D-glucopyranose penta
acetate, was also bacteriologically inactive and no
attempts were made to hydrolyze it. The third compound,
asperuloside te~raacetaGe, exhibited no activity either.
Asperuloside itself could not be tes~ed for antibacterial
activity because its structure is very labile to the
condition of hydrolysis of the acetyl groups in the sugar
moiety. In view of the fact that asperuloside is an
aucubin-type glucoside which is bacteriologically active,
and it contains an unsaturated lactone which is presentI
in many antibiotics, it is reasonable to believe that
asperuloside as il occurs in the frui~ migh0 have some
antibacterial properties.
42a.
E. BIBLIOGRAPHY
1. Josep F. Rock" "The Indigenous Trees of the HawaiianIslands,," Published Under Patronage" Honolulu"1913" p. 467.
2. Otto Degener, "Planes of Hawaii National Park,,"Honolulu Star-Bulletin, Ltd." Honolulu" Hawaii"1930 pp. 282-286.
3. The antibacGerial properties of some plants foundin Hawaii. O. A. Bushnell, Mitsuno Fukuda" andTakashi Makinodan. Pacific Sci. ~, 167-83 (1950)
4. Ueber den Farbstoff der Morinda citrifolia. Th.Anderson. Ann.·, 71, 216-24 (1849).
5. On morindin and morindon. T. E. Thorpe and T. H.Greenall. J. Chem. Soc., 21, 52-8 (1887).
6. On morindon. T. E. Thorpe and William J. Smith.ibid. 53, 171-5 (1888).
7. Morindone o John Lionel Simonsen. ibid." 113, 766-74(1918) •
8. Trihydroxy-methylanthraquinones. V. Synthesis ofmorindone. R. A. Jacobson with Roger Adams. J.Am. Chem. Soco, 47" 283-90 (1925).
9. Synthesis of morindone. Ramkanta Bhattacharya andJ. L. Simonsen. J. Indian Inst o Sci." lOA, 6-9(1927) •
10. Chemistry of the Coprosma genus. Part I. The colouring mat~ers from Coprosma australis. Lindsay H.Briggs and Jack C. Dacre. J. Chem. Soc." 564-8(1948).
11. Colouring matters of Australian plants. IX. Anthraqunones from Morinda species. J. H. Bowie andR. G. Cooke. AustralIan J. Chem., 15" 332-5 (1962).
12. Further observations on penicillin. E. P. Abraham"E. Chain" Co M. Fletcher, A. D. Gardner, N. G.HBRtley~ M. A. Jennings. Lancet, 241" 177-88 (1941).
13.
14.
15.
17.
18.
19.
44.
Samuel M. McElvain, "The Characterization of OrganicCompounds," 2nd Ed., The MacMillan Co., New York,N. Y., 1953, p. 191.
The preparation and properties of aucubin, asperuloside and some related glycosides. A. R. Trimand R. Hill. Biochem. J., 2.Q., 310-6 (1952).
Melville L. Wolfrom, "Advances In CarbohydrateChemisi~ry," Vol. 12, Academic Press Inc., Publishers,New York, N. Y., 1957, p. 23.
Chondroitin sulfate modifications. I. Carboxylreduced chondroitin and chondrosine~ M. L. Wolfromand Bienvenido O. Juliano. J. Am. Chern. Soc., 82,1673-7 (1960). -
A comparison of the optical rotatory powers of thealpha and beta forms of certain acetylated derivatives of glucose. C. S. Hudson, J. K. Dale. ibid.,37, 1264-70 (1915). ----
L. J. Bellamy, "The Infra-red Spectra of ComplexMolecules," 2nd Ed., John Wiley and Sons, Inc.,New York, N. Y., 1959, p. 187.
Infra-red adsorptions of vinyl and isopropenyl groupsin polar compounds. W. H. T. Davison and (in part)G. R. Bates. J. Chern. Soc., 2607-11 (1953)0
20. The infrared adsorption of vinyl ethers. G. D.Meakins. ibid., 4170-2 (1953).
21.
22.
23.
.24.
Chemistry of the Coprosma genus. Part IX, Theconsti tU-Gion of asperuloside. Lindsay H. Briggsand B. R. Cain. ibid., 4182-93.
Chroma tographic separation of sugars OrJ Charcoa 1.Roy Lo Whistler and Donald F. Durso. J. Am. Chern.Soc., ~' 677-9 (1950).
K. Paech and M. V. 'rracey, "Modern Me thods of PlantAnalysis," Vol. III, Springer-Verlag, Berlin, Germany,1955, pp. 626-725 and references cited therein •
The chemical nature of uhe antibacterial substancepresent in Aucuba javonica Thunbg. J. E. Romboutsand J. Links •. Experientia, 12,78-80 (1956).
26.
28.
29.
30.
31.
32.
33.
34.
35.
36.
structure of asperuloside. J. Grimshaw. Chem.& Ind. (London), 403-4 (1961).
C. A. 19, 29702 (1925). Asperu1osid, a new glucoside extracted from Asperula odorata. H. Herissey.Compt. rend., 180, 1695-7 (1925).
C. A. 20, 16467 (1926). The chemical compositionof Asperula odorata. Extraction and proyertiesof a new glucoside, asperu1oside. H. Herissey.Bull. soc. chim. bioI., 7, 1010-6 (1925).
C. A. 20, 2182 5 (1926). Detection of asperu10sidein plants. Extraction of this glucoside from Caliuma arine L. H. Herissey. Compt. rend., 182, 865-7
192 • ---
C. A., 27, 51489 (1933). Extraction of asperulosidefrom Coprosma baueriana Hook. H. Herissey. J.pharm. chim., 17, 553-6 (1933).
C. A. 27, 58909 (1933). Extraction~of asperulosidefrom Coprosma baueriana Hook. H. Herissey. Bull.soc. chim. bioI., 15, 793-5 (1933).
C. A. 21, 30694 (1927). Extraction of asperu10sideof GalIUm verum L. Probably presence of this glucoside in a number of species of Rubiaceae. H. Herissey.Compt. rend., 18L~, 1674-5 (1927).
C. A. 22, 11761 (1928). Extraction of asperulosideof Gallium vernum L. Probably presence of thisglucoside in many of the species of Rubiaceae. H.Herissey. Bull. soc. chim. bioI., 9, 953-6 (1927).
c. A. 21, 1148 (1927). Asperuloside in plants.Extraction of this glucoside from Galium aparine L.H. Herissey. ibid., 8, 489-96 (1926).
c. A. 3s, 70769 (1938). Extraction and localizationof asperuloside noted in Crucianella martima L. andC. angustifolia L. A. Jui1let, J. Susplugas andV. Massa. J. pharm. chim., 27, 56-62 (1938).
Chemistry of the Corposma genus. VIII. The occurrenceof asperuloside. Lindsay H. Briggs and G. A. Nicholls.J. Chem. Soc., 3940-3 (1954).
46.
37. 'rne accumula tion and utiliza tion of auperulosidein the Rubiaceae. A. R. Trim. Biochem. J., 50,319-26 (1952). --
38. Occurrence of asperuloside in Daphniphyllum macropodum(Euphorbiaceae) and a closely related ~lucoside inMonotropa~ Walt. (Pyrolaceae). A. R. Trim.Nature, 161, 4~5 (1951).
39. The preparation and properties of aucubin, asperuloside and some related glycosides. A. R. Trim andR. Hill. Biochem. J.,. 50, 310-9 (1952).
40. C. A. ~ 10985b (1956). The presence of asperuloside in Escallonia and of dulicitol in Brexia madagascariensis {Saxifrage). Victor Plouvier. Compt.rend., 242, 1643-5 (1956).
410 Structure of aucubin. J o Grimshaw and H. R. Juneja.Chem. & Ind. (London), 656=7 (1960).
42. Structure of aucubin. S. Fujise, H. Obara and Ho
Uda. ibid•. 289-90 (1960).
43. Aucubin. A. J. Birch, J. Grimshaw and H. R. JunejaoJ. Chem. Soc., 5194-8 (1961).
44. Die Struktur des Aucubins. W. Haegele, F. Kaplanand H. Schmid. Tetrahedron Letters, 110-8 (1961)0
45. Alfred Burger, "r~edicinal Chemistry, II 2nd Ed.,Interscience Publishers, Inc., New York, N. Y.,1960, pp. 951-952.
TABLE OF CONTENTS
PART II. 'l'HE STRUCTURE OF THE NITROCAr~PHOR ANHYDRIDES
LIST OF FIGURES •••••••••• 0.00 ••••••• 0•••••••••••••••• iii
11 :l! I' 1:';1' 111'1 I: I jl,I,q,111 ''', '. il.!,' I i! II "I'I iliil lj.i,""l' ,. 1"1"'" ' "I:::!'I I, ,
~ "I':r lill: I, !:O;": illi tl II'tr~I'I'I~II"';;;"'- "'t!~iftIT1;'I,riftrl'~'" I;-'j~::':';'
'I I fill' 11'1 Iill '!'/"I!' 1111 'ill 'I'll" IIlli 1:l>1", I I 1111: 1,1. 'III "II,II"T",II" d' 1'1 ,"i~ , ,,,",, 1'1 "'1'',II'·, 11'1" j' 1:'1" I ,.,. "":'ii' " .. " "Ii ':,. '.1. ! II i I'd 11'1, ·1·fl'.'II' JI" il ,.:: 1.1' .,il'i" ".: '.'1"1"'; ;1;1.11;1 1.'I[:i':·,:; ~' -11:'1'1"1 1, . ,I" 'I:' "I ··I! .. .1".1';11,1 1"" '. I:' .. II ' '1 1 '-I . 1'/' I 01 II I- I PI' . I ..' ,," 'j . ,I: I.j I. i , ' ,I,I I ·11 I. !I "'1 !.I.: ill! ',., ,.' '.:".1'1 I d"I':!' 111"/'. ';:1[1:1..• iiJ... ·i' ..... ',· f' 'I i II i r i "I' (I' !++: ht, /~! fIj: if1 :~I;! 'I'ii ~r ':;'j;;:: :;.;I i'l I Ii 11.1' 1'11':1'1" 11111 Iii' I. i4-l;;;i~' I,ll, Ii i" .1
1'. I." 'i
~ i' 1,li ;1. ii!,':;': I" ii:' lil l /li ! ';1' 'II: ,." ,.,ip!:! ':1:.;:. '"I 1,'1 11111'111'111'1 "I,'l' I' '~'I~";:i;"" :1"'I:!j:',1 '·'id:·':. ::· II I' I il'il
li 11 1HII" ; ! r.-:-: ill 1111'11; il dll 'II:!!", dill!' '1
.. ' ! .," i,ll I' 'W': [ltil I I" I Ii,! iI: I '\'11: I'" i~' I': 'II' ,. ":'1':'".I!, ,., , 'lill! r :I:dl:Ji,II:0~ U: li,·;L.•. L.:.:."."1'1' 1\11:'\ !'1 111ii.iil!I!'1 JI'ij'lililll qi iiitl ;", ,;' :':, d: !;-.~:L...,:, 'J.I I III! "lllpll .. !ll!" ]:Ill- . '1-""-' "I·, I
o :1' I III I I: , L j. t::::: , , 'I 1,1 Ill' II • ,I;! I I"o I It' 1 II , , II, "~ '" 'I I'! 11"1~ It! :". I, jll I, II, "I 'I 1 I '. I "ill~' I' t I I,
::U" :h' 0- ~rllLllihi :: i -;:; i ;-I;~: , e~ ..... ,., ;'i~l:il' :"1"': "Ic;II dl
'1111 '" " II ,I' I ,:.j:;::-, .,,: 'I II" , I: :, II'" ,g ::lil I I' II' 111'1 l'lt, III _ I I I! Illlld, , " ,
"" 1:1,. '1' 1"1 11':'111" H ':1'1'"~. I. 'I, Ill. 'I" 'I 11'1:1'1 III ilil '1' , I" " I;l 1-;' :...., ,: :11 I, J1::P ,I , " ' I ~.;l,.JL::.L .., " ..;.; I ' I" I I ! ill I " , 'II" 1:'1 I 'Iii : II I ,
'1 " 'II I" I'll " I, 'il 'I' I,., 'j I~ .:... ,.! ': ·~I:; ''':'I~,i '.; Ij.: ::.~::~: ~..:: i:!]:'~.:J[.J";!! II. !
I • I ,I, !' , I 'I l/ 1 I I 'I 1 ,I.' 101 I
II ' ~ 'I': I I" "I':' I": '1'1 ! '. I'" '.I' I ", ': l~tll',' Iithll" 1'1' ,', 1,1, ,I +J '
~!~. I-';...·~JI "I .,' .,' ::i', I : 'I ,.: 't'::-~'-~"" I" '''r-','~, I I ~ ''''I I .' II I :,'~ ! :1\ ,'I I. "11,\ " '... !" ,., " 1'1 I ".::: I, II 'I' 1 I II '::: "I' .. ..·":",:r"··, , .:. ." . '::'I~: d<l.I.: .."::'
~ U:~·Jl1ri....'i '::"JIl:'"'iil:: ::'I11i::: :.. il'''m·:':·l':Ell':'".'! iffi:/'~:I/, j::l, I I ", .. I I' I L' I I', ,H"" !? "p' '.. 'II. .' ,., ':::' , 'N_
resistance of the nitroso group to the oxida~ion by potas
sium permangana~e may be due to the protection provided
by bulky neighboring groups. The alkaline degradation of
the ni trocamphor anhydride described by wwry (3) seemed
too extensive to provide decisive information about the
structure of the anhydride, itself.
The molecular weight deGermination and the spectral
studies indicate that the nitrocamphor anhydride exists
as the monomer which is unusual for C-nitroso compounds
(13). Primary and secondary nitroso co~pounds easily
~automerize to the corresponding oximes and ~erLiary
ni 'croso compounds in which oxime forma don is impossible
31.
dimerize readily. The unusual property of nitroso com-
pounds to dimerize has made at temp 'GSGO de Germine the
infrared absorption of monomeric nitroso groups qui~e
difficul'c. Luttke (14) s'cudied~,he changes in the infra-
red spectrum which occurred with time when primary and
secondary nitroso compounds were volatilized and studied
'i:.erLiary ni'Groso compounds in dilute solution and in the
vapor state in which ~hey exist in 'eha monomeric form.
Wich niGrocamphor anhydride, however, the nitroso group
can be direcG1y meas~red in the solid s~ate. The exis'cence
of vhe anhydride as the monomer is readily explained by
Gfle steric environment of 'Ghe ni Groso group which prevents
dimeriza-vion.
The infrared spectrum of the nitrocamphor anhydride,
m.p. 170.5-1~1.5° (dec.), (Fig. 4) contained two bands
in the carbonyl region a0 5.65 and 5.71u. Carbonyl absor~-I
tion in 3-ni trocamphor (Fig. 2) occurred a'", 5. 71/{,(, and a
similar structural fea~ure is indica~ed for the anhydride.
l'he band in "he anhydride at; 5.65u mUSG be due ',,0 \;he/
carbonyl on the adjacent carbon atom bearing the nitroso
group. 'rhe parent ke tone, camphor, showed carbonyl absorp-
tion a~ 5.74~(. The very slight shift cowards shorter
#ave length for the absorption of the carbonyl group due
to Lhe nitro group, and the substantial change in the
0a~honyl absorption due to the nit;roso 0rouP must be
ana10;ous to the shifGing of the carbonyl absorption of
32.
cyclic ketones in their ~-halo,:seil derivatives which has
been studied extensively (15). The band at 6.12;U was
assiGned to the nii.:.roso group in accordance with sugges-
0ions by Bellamy and Williams (16), and Jander and Haszel-
dine (17). The bands at, 6.45 and 7.41fl corresponded to
Ghe niGro group (18). The infrared spectrum clearly
supports structure (IV) for the nitrocamphor anhydrides.
Absorption in the carbonyl region is not in accord with
s ·,-,ruc 'cure (V).
The nitrocamphor anhydride, m.p. 170.5-171.50
(dec.), showed absorption in the ultraviolet region at
240 m,p (log E 3.89) and 381 m,U (log E 198) (Fig. 5 and 6).
The spectrum appears to be consistent with the absorption
reported for C-nitroso compounds (13) and the bathochromic
shift of both bands in the spectrum of the anhydride may
be due to the proximity of the carbonyl group.
The nuclear magne0ic resonance spectrum of 3-nitro
camphor (Fig. 1) showed a peak at <.r.=. 5.1 which was split
in~o a doublet and musL:. be due to the hydrogen on the
carbon atom bearing the nitro group. The resonance of the
neighboring proton occurred a~ or: 2.75, and the 1hree
methyl groups gave peaks at ~ 0.91, 0.98, and 1.07.
The spectrum of the nitrocamphor anhydride, m.p. 170.5
171.50 (dec.) showed the absence of the proton on the
carbon bearing the nicro group (Fig. 3). A peak ac
J~ 2.72 corresponds closely to the peak at 2.75 in
33.
3-ni trocamphor. 'rhe peak observed at cr-=3.28 may be due
to the bridgehead proLon adjacen0 to the nitroso group.
The nuclear magnetic resonance spectral data are consistent
with structure (IV), but do not exclude V.
The nitrocamphor anhydride, m.p. 158-1600, gave
an infrared spectrum (Fig. 7) which was essentially iden-
tical with the speccrum of the isomer melcing a~ 170.5
171.50 (dec.), and 0he ultraviolet spec~ra (Fig. 8 and
9) of the two isomers were exceedinsly similar. The
substantial difference in optical rotations of the two
compounds and the similarity of their spectra indicate
Ghe anhydrides to be s0ereoisomers.
The nitrocamphor anhydride, m.p. 190.5-1920 (dec.),
gave an infrared spectrum (Fig. 10) in which there
were slight differences from the spectra of the two iso-
meric anhudrides. The well defined absorption in the
carbonyl re~ion establishes the structural similarity of
the three anhydrides. In 0he ultraviolet spectra (Figs.
11 and 12) at 380 m,u a clear maximum was not shown; the
absorption gradually increased to the maximum a L 238 m((./
The nitrocamphor anhydride, m.p. 190.5-1920 (dec.), was
probably described by Lowry (1). The small amount isolated
in the present sLudy did not permit a comparison of its
optical rotation with the value reported by Lowry.
The co~de~s~tio~ of
occurred to form a nitrone, structure (VI). The closest
34.
analogy (VII) has spectral properties completely different
from the spectra of the nitrocamphor anhydrides (19) •
VI
.0::- 0
t/.
N·,0-
VII
The two new anhydrides, m.p. 158-1600 and 170.5
171.50 in the present study and the two anhydrides, mop.
18~·0 and 1900 , describQld by Lowry (1,3) represen'c the
four possible stereoisomers for structure (IV). In the
present investigation the stereochemical structures have
not been assigned to the anhydrides, but possibly the
assignment could be done by optical rotatory dispersion
or X-ray analysis.
2. ~he Possible Nitro-Nitroso Intermediate in che
Conversion of Nitro Compounds to Furoxanes
The condensation of two molecules of 3-nitrocamphor
to give nitrocamphor anhydrides, nitro-nitroso compounds,
demonstrates a new reaction which is feasible for nitro
alkanes. In the case of primary nitro alkanes the anhydro
35.
intermediate would be expected to proceed further to form
a furoxane.
Cr-H -C - C-C,~H
b 5 II II 0 5i'J N
EO/' '0 'OH
) C,~H5CH - CHCI'H5
+ H20o I I t)
N02 NO
\C6H
5C=N-0 -t C6H
5CH2N0
2
/C:::~~N-O
C6H5- n- ~-C6H5
N,O)~'O
The sequence of reactions finds support in Wieland's
research which demonstrated a new route to furoxane from
nitro-nitroso compounds (20).
1
36.
The cleavage of nitro oxime tc the corresponding nitrile
oxide (VIII) and nitro alkane would also lead to the
expected product because nitrile oxide readily dimerizes
to furoxane (21).
Recently Parker and his co-workers (22) obtained
dicyanofuroxane from the nitration of cyanoacetic acid
with nitric acid in the presence of sulfuric acid) but
the me~hanism of its formation was not investigated.
2 NC-C - C-CNII IIN N,"01 0
The mechanism can readily be rationalized as proceeding
through the nitro-nitroso intermediate.
The first produclJ of Lhe niGrat;ion of cyanoacetic
acid would be nitrocyanoacetic acid (IX) which would
then decarboxylate to the corresponding nitroacetonitrile
(X). The decarboxylation of :x.. -ni trocarboxylic acid
occurs readily (23) 24, 25). Analogous to the decarbo
xylation of ~-ketocarboxyliC acid which leads directly
to the enol forn~ of tIle reaction product (24), the decar-
boxyla tion of '=" -ni trocarboxylic acid leads to aci-
form, of the ni tro compound. The aci-form would be favorable
for the condensation reaction to give the corresponding
nitro-nitroso intermediate (XI). The formation of furoxane
(XIII) can occur then ei ther by tautomeriza tion U1 lJ.l tl'0
and nitroso group (route a), or by ~he decomposition of
nitro oxime intermedia~e (XII) to nitrile oxide (XIV)
and nitroacetonitrile (route b). Both reaction routes
find support in Wieland's research (20,21).
37.
NCCH COOH2
+ HNO3
NC-CHCOOHi\T02
I\rC-CH::'lJ::::~H
+
NC-CH='N/~H
NC-CH-NOI
NC-CH-N02
---~;>
)
IX
lW_CR.::WiOH'"0
X
NC-CP.-HO
I
XI
11C-C=N"I OH
NC-CH-NO2
XII
+
I'\C-~':'N 'OH
NC-C-NOH 2
!(routeHC-C;:N-O
XIV+
NC-C,~N'OH(route a)---~') NC-C=N/OH
....0
b)NC-C-::N-O
>
XIII
rrhe condensa i-ion of ni tronic an acid (~~) is somewha t
similar ~o the Nef reaction (26). in which ni~ronic acid
is an intermedia~e. The Nef reaction involves conversion
of primary or secondary nitro compounds to the correspond-
ing aldehydes or ketones by addin~ Ghe alkali salv of the
former to aqueous mineral acid. An excellen~ mechanism
for Nef reaction has been proposed by van Tamelen and
Thiede (27).
Feuer and Nielsen (28), however, found tha~ 2-nitro-
oc~ane can be converted ~o 2-ocLanone without first formin~
an alkali salt of 2-nitrooctane. In other words, the
sauuomerism of 2-nitrooc0ane to the corresponding nitronic
acid is acid ca~alyzed. Acid catalysis of the nitro compound
Where B is base such as water or chloride ion.
to ~he nitronic acid and, furthermore, the activating
39.
cyano i~roup in ni troacetoni. ~rile strongly support ehe
hypothesis thaL Lhe condensation to the nitro-nitroso
intermediate proceeds via nitronic acid in the formation
of dicyanofuroxane.
'The condensation of nitro compounds to furoxanes
via a ni0ronic acid intermedia~e in acid medium is further
demonstraced by Alexander, Kinter and McCollum (29)0
'rhey ob"cained dibenzoylfuroxane by trea ting phenylme c.hyl-
carbinol, acetophenone, isonitrosoacetophenone or
LO-nitroacetophenone wi~h red fuming nitric acid in boiling
"_;lacial ace tic acid so lu tion. The proposed me chanism for
the conversion of phenylmethylcarbinol to dibenzovlfuroxane
suffers only one weakness in thau the condensation of
nitronic acid involves the carbonium ion which is adjacent
to the partially positive carbonyl carbon.
OHC6HSCHCH3
°C6HSCCH3 HONO)
ti°C6Hs6CH =-NOH
q +/OHC,HSCCH:::N,
o OH
1~ + _ /OH
C6H CCH-N,S OH
\ )
J -
, J0-° .. OH" e:-- '"C....-HSCCH::N
o '0\
Q +_/OHC....-HSCCH-N,
o OH
As itl the formatiotl of dicyatlofuroxatle, tbe con-
version of phenylmethylcarbitlol to the correspotlding
furoxane may have an alterna~ive mechatlism itlvolvitlg the
ni~ro-nitroso intermedia~e (XV).
oCbHsCCH-NO
) 01C6H
SCCH2N02
XV
40.
A reasonable mechatlism for the formation of diphenyl
furoxane was proposed by Kortlblum and Weaver (30) for
the reac1iotl of benzyl bromide with sodium nitrite in
dimethyl formamide (DMF) at -160 •
41.
HN02 +
C-l-i~9H-N02 ---7 HN02 '1- C6-HSC::N-O
o -'NO
XVII
) C,-HS-C - C-C,-HSOn.. 0
N, / N....
° °XVIII
The proposed mechanism was jusGified by the evidences
-chat the intermediaGe, nitro1ic acid (XVI), under the
same reaction conditions gave the correspondin; furoxane
(XVIII), and that benzonitri1e oxide (XVII) is known to
dimerize to form dipheny1furoxane (21).
~he presence of an intermediate, benzonitrile oxide,
in the forma~ion of diphenylfuroxane from phenylnitro-
methane was confirmed by Mukaiyama and Hoshino (31).
In their studies of the reaction of primary nitropar-
affins with isocyanate and trialkylamine, they were able
to trap nitrile oxide with vinyl aceta~e to form isoxa-
zoline (XIX). The proposed mechanism by which diphenyl-
furoxane is formed is almost similar to ~he mechanism of
CH2~ CHOAc
+o
C6HSNHCNHC6HS +
AcO-CH-CH2I IO'N~O 'R
XIX
Kornblum and Weaver. Ins~ead of nitrite ion, phenyl
isocyanate reac~s wi~h nitronate ion to form an additio~
compound which wi 11 de compose 'co ni "cri le oxide and the
dimerization of the latLer will give the corresponding
furoxane.
oI q I
RNHCON:::CHRI
----7 RNHCOOHI !-
RI'JH 2
1FiNoC =0
1 01RNHCNHR
RC=.N-O
iRC=N-O
R-C - C-RN I~'0/ '0
The proposed mechanism by Mukaiyama and Hoshino is excellent,
however, an alternavive mechanis~' seems ~o be reasonable
via the nitro-ni~roso intermediate (XXI).
-RCH-NO
2
J -~ 0
RCH=N~ _o
+
TI
RN=C=O
Q q I
RCH'::N-OCNHR
+-RCH-N02
)
o 0 I
RCH:;I~-O~m-IR
XX
R-CH-NOI
R-CH-NO2
XXI
I
RNHCOOH
RCH-NOI
RCH-N02>
(route b)>
RC::;N'OH
IRCH-N02
1(route a)
R-C",N'OH
R-C::.N"OH'0
> R-C - C-R.~ ~.
l~ N'0/ '0
IRHNCOOH -~) RNH2 1-
L~J·c,oo
I U I
RNHCNHR
44.
Simi lar to 1-he me chanism of Mukaiyama and Hoshino, "I:he
ni~rona~e ion is formed in the presence of a basic
catalysL and one of lhe oxygen atoms of nitronaGe ion
combines with the positively charged carbon of ~he iso-
cyanate. Since the nitronate ion is an ambidGn~ ion,
the carbon of the nitronate ion would also combine with
\:,he isocyana te -co form """ -ni tro-amide (XXII). However,
the oxygen addition would be favored because of greater
electronegativi0y of oxy~en relative ~o carbon, and also
due to less steric hindrance (10), or if 1-he ~-nitroamide
is formed it would readily dissociate to its components
in ~he presence of trialkylamine (31). The formation of
nitro-nitroso inLermediate (XXI) would occur directly
~hrough the interaction of carbon of the niGrona~e ion
and compound (XX). The conversion of the nitro-nitroso
intermediate GO diphenylfuroxane would follow route a
or be as mentioned earlier in the mechanisms for the
formation of dicyano- and diphenylfuroxane. As according
to Mukaiyama and Hoshino, the decomposi tion of "~he
carbamic acid would lead to the corresponding diphenyl
urea and carbon dioxide.
o I
RCH~-NHR
IN02
XXII
It is interesting to note tha~ secondary nitro-
paraffins, such as 2-ni tropropane and --" -phenylni "croe
thane react with isocyanate in the presence of ~riethyla-
mine ~o ~ive sym- diphenyl urea wi~h evolution of carbon
dioxide, but Mukaiyama and Hoshino were no~ able to
isolate ~he corresponding dehydrated produc~. Since
secondary nitro compounds canno~ form furoxane, the de-
hydrated product would be undoubtedly the corresponding
nicro-nicroso compound (XXIII).
RR-C-N02
HT R'l\[=-C=O
RR-C-NO
IR-C-NO
I 2
R
XXIII
I q I
mmC-NHR
With the discovery tha~ the condensa~ion of 3-
nitrocamphor leads to the ni~rocamphor anhydrides, which
are nitro-nitroso compounds, it is imperative to re-examine
critically the mechanisms involved in the formation of
furoxanes from ni~ro compounds.
46.
3. Miscellaneous
In connection with other problems it was of interes0
~;o prepare Ul -ni troace tophenone oxime. The compound
was previously prepared as early as in 189S by Sommer
(32) by acGion of arsenic and concentrated ni "ric acid
on styrene and in 1903 by Wieland (33) on trea0ment of
styrene in glacial acetic acid with concentrated sodium
nitrite. Hurd and Patterson (34) who studied 'uhe addition
of hydroxylamine to various unsaturated nitro compounds
prepared W -ni troace tophenone oxime by trea tin[:; u,)-
ni 'ero styrene wi th hydroxylamine. The re su1 ting reaccion
product was uhen oxidized wi~h chromic acid to the corres-
ponding nitro-nitroso dimer which in hot chloroform dis-
socia ted andcau tomerize d to w -ni troace tophenone oxime
(XXIV) •
---')') C6HSQH-CH2N02NHOH
2 C6HS
?H-CH2N02NHOH
H2
S04
+ Na2cr
207)
-- ~) 2 C6HSS-CH2N02NOH
XXIV
31r1(;8 w -ni tronce tcphCDcnc "v·JD.G
connection with the study of nitro ketones, it was hoped
L~'7 •
tha t perbaps Lv -ni troace tophenone oxime could be direc ely
prepared by treating ~be correspondins nitro ketone witb
hydroxylamine. However, the bond cleavage occurred between
~he carbonyl carbon and tbe carbon to which the nitro
group is at~ached and benzohydroxamic acid (XXV) was
obtained. Feuer and Anderson (35) have taken advanGage
of tbis type of bond cleavage by preparing
alkanes from the corresponding mono-potassium
c:ljw -dini tro-I
o<.tl-
dinitrocyclar.ones either in basic or acidic media.
NaHC03 °NH20H BCI ~ C6H5~-NHOH + CH3N02
xxv
Since ~he condensa~ion of two molecules of 3-nitro-
camphor ~o Ghe nitro camphor anhydrides i~ slightly basic
medium demonstra~es a new reaction which is feasible for
nitroalkanes, at~empts were made to condense phenylnitro-
me the.ne under ;,f"l8 same reac don conditions to tbe corre s-
ponding nitro-nitroso compound or to diphenylfuroxane.
Even thouGh there is a variety of methods described in
the literature for the preparation of diphenylfuroxane
(21, 30, 36-44), nevertheless, nobody has ever reported
attempts 'GO condense phenylnitromethane which misht lead
to furoxane. Preliminary experiments, however, were
inconclusive. A crystalline reaction product was isolated
which had the same empirical formula and the melting
point as sym- diphenyl urea, but their infrared spectra
were distinctly different and their mixture meltins
48.
point was depressed. No further efforts were made to
characterize the reaction product. However, isolation of
an unidentified reaction product and the interpretation
of the formation of furoxanes inspired by the structure of
the nitrocamphor anhydrides maJ be the basis for additional
re search.
As mentioned earlier in the introduction Lowry (2)
isolated a compound, m.p. 2200 , as a by-product in the
prepara tion of camphoryloxime from the trea tmen'(, of ni tro-
camphor with concentra~ed hydrochloric acid. The compound
was named camphoryloxime anhydride to which Lowry assigned
struc~ure (II). In the structural investigation of
II
camphoryloxime, Edward Wat (45) in this Laboratory did
not observe the presence of camphoryloxime anhydride in
the reaction mixture. Since Lowry preferred structure
(XXVI) for camphoryl oxime which is not correct on the
basis of new eVidence, it is obvious that structure (II)
does not correctly represent the camphoryloxime anhydride.
XXVI
D. SUMIvlARY AND CONCLUSION
Lowry's structures must be regarded as improbable
on the basis of the spectral and chemical evidence ob~ained
in the structural studies of the nitrocamphor anhydrides.
Since the structure of camphor and the reactions of
ni tro compounds were not known at l.,ha 1~ time, Lowry's
proposals coulr:'l. not be expected GO represent the structure
of the nitrocamphor anhydrides.
On the basis of spectral as well as of chemical
studies, structure (IV) was assigned to the nitrocamphor
anhydrides and not the alternative (V). The appearance
of two bands in the carbonyl region at S.64-S.67~ in
N04. NO
IV V
the infrared spectra clearly demonstrate ~hat ~he two
carbonyl groups have a diffe~2nt environment. Carbonyl
absorption in 3-ni trocamphor occurred a'l., S.711--1 and the
additional band in the anhydrides at S.64-S.67jA is due
to carbonyl adjacent to the nitroso group. The parent
ketone, camphor, showed carbonyl absorption at S.74;U •
50.
The very slight shift ~owards shorter wave length for the
absorption of the carbonyl group due to the nitro group
and the substantial change in the carbonyl absorption due
to the nitroso group is analogous to the shifting of the
carbonyl absorption of cyclic ke tones in their 'J\ -halogen
derivatives which has been studied extensively. The
appearance of two carbonyl bands, a nitro and a nitroso
band in Ghe infrared spectrum of nitrocamphor anhydrides
which agree closely with those in che literature favors
structure (IV). The ultraviolet spectra of the nitro
camphor anhydrides are consistent wi~h ~he ultraviolet
spec~ra of nitroso compounds in which a bathocromic shift
has occurred.
The unreactivity of the nitrocamphor anhydride to
ozone and potassium permanganate gives additional support
in favor of structure (IV). The resistance of the nitroso
group to potassium permanganate oxidation may be due to
protecuion provided by bulky neighboring groups. The
steric environment of the nitroso group also accounts for
its existence as the monomer which is indicated by ~he
molecular weight and is unusual for C-nitroso compounds.
Although there are numerous publications on nitro
and nitroso compounds in the literature, only a few
publications deal with nitro-nitroso compounds (20, 29,
33, 46-48). The scarcity of the latter is due to the fact
51.
thaG nitro-nitroso compounds are hard to prepare and to
isolate from the reac·~ion mixture. Upon heating secondary
nitro-nitroso compotinds are readily converted to the
corresponding nitro oxime or furoxane. The recognition
that the nitrocamphor anhydrides are nitro-nitroso
compounds miGht supplement the existing mechanisms proposed
for the formation of furoxanes from niGro compounds and
might open a new general route to the syn~hesis of nitro
nivroso compounds.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
52.
E. BIBLIOGRAPHY
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Nitrocamphor and iL,s deriva~ives. V. Sesquicamphorylamine, a product of the spontaneous decomposition ofnitrocamphor. VI. Camphoryloxime anhydride. VII.
(3 -Bromo- r:;;;..' -ni trocamphor. P and jj' Bromocamphoryloxime. T. Martin Lowry. ibid.~ 83, 953-68 (1903).
Nit,rocamphor and i'cs derivatives. Part VIII. Theaction of formamide on nitrocamphor. Thomas r~rtin
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The basis for the reported optical ac~ivity of thesalt of aliphatic ni~ro compounds: 2-nitrooctane.Na than Kornblum, Norman N. Lich'cin, John 1'. Pattonand Don. C. Iffland. J. Am. Chem. Soc., 69,307-13 (1947). -
Relations between acidi~y and ~automerism. Part III.rrhe ni'ero-group and the ni'~ronic esters. Fri tz Arndtand John D. Rose. J. Chem. Soc., 1-10 (1935).
A new method for the syn~hesis of aliphatic nitrocompounds. N. Kornblum, Harold O. Larson, RobertK. Blac~~ood, David D. Moorberry, Eugene P. Oliveto,and Galen E. Grahm. J. Am. Chem. Soc., 78,1497-501 (1956)~ -
The urea dearran~ement, II. Tenny L. DaVis and KennethC. Blanchard. ibid., 45, 1816-20 (1923).
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53.
11. RearrangemenGs of some new hydroxamic acids related toheterocyclic acids and to di-phenyl- and Griphenylacetic acids. launder W. Jones and Charles Do Hurd.ibid., 43, 2422-54 (1921).
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1. Mitteilun~: Die charakteristischen Infrarotbanden der monomeren Nitrosoverbindungeno Wolf~ang
Luttke. Z. Elel{crocr.em., 61, 302-13 (1957).
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16. Infrared spectra and polar effects. Part VI. Internaland external spectral relationship. L. J. Bellamyand R. L. Williams. J. Chem. Soc., 863-8 (1957).
Ii. Reactions of flurocarbon radicals. Part XIV. Hexafluroazoxymethane. J. Jander and R. N. Haszeldine.ibid., 919-25 (1954).
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19. Experimentsl.:;owards '~11e synthesis of Corrins. Part IV.rrhe oxidation and ring expansion of 2,4,4-trimethyl- d pyrroline-l-oxide. R. F. C. Brown, V. M. Clark andSir Alexander Todd. J. Chern Soc., 2105-8 (1959).
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21. Zur Kenntniss der Nitriloxyde. Heinrich Wieland.Ber., 40, 1667-76 (1907).
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54.
23. An improved synthesis of esters of nl~roace~lC acidoHo Feuer; Ho B. Hass and Ko S. Warren. J. Am. Chern.Soc., 71, 3078-9 (1949).
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29. A mechanism for 0he formation of dibenzoylfurozaneoxide from phenylmethylcarbinol o EllioL R. Alexander,Mark R. Kinter and John D. McCollum. ibid., 72, 801-3(1950). - -
30. The reaction of sodium nl~rl~e with eL;hyl bromoacetateand benzyl bromide. Nathan Kornblum and William M.Weaver. ibid., 80, 4333-7 (1958).
31. The reactions of primary nitroparaffins with isocyanates.Teruaki Mukaiyama and Toshio Hoshino. ibid., 82,5339-42 (1960). -- -
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35. A new synthesis of o:.<,UJ -dinir,roalkanes. Henry Feuerand Roy Scott Anderson. ibid., 83, 2960-1 (1961).
55.
36. Uber die Reaktionsweise des Hi trosy1ch10rids. II.Einwirkung von Nitrosy1ch10rid auf aromatischeAldoxime. Heinrich Rheinbo1dt. Ann., 451, 161-78(1927). -
37. Zur Kenntniss der Benznitro1saure. Heinrich Wielandand Leopold Semper. Ber., 39, 2522-6 (1906).
38. Zur Isomerie der Benza1doxime IV. Ernst Beckmann.ibid., 22, 1588-97 (1889).
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40. Uber Nitrosoverbindunzen, I. Mittei1.: Bildunggemina1er Ch10r-nitroso-Verbindungen durch Radika1reaktionen. Eugen Muller and Horst Metzger. Chern.Ber., 87, 1282-93 (1954 ).
41. C.A. 47, 2688e (1953). Action of oxides of nitrogenand nitric acid on mercury-paraffin compounds. Theapplication of the reaction to the study of thenitration of paraffins. A. I. Titiv and D. E.Rusanov. Dok1ady Akad. Nauk S.S.S.R., 82, 65-8(1952). --
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44. Reactions of dinitroolefins with nucleophilic reagents.William D. Emmons and Jeremiah P. Freeman. J. Org.Chern., 22, 456-7 (1957).
45. Unpublished work of Edward Wat.
46. The infrared spectra of nitro and other oxidizednitrogen compounds. John F. Brown, Jr. J. Am. Chern.Soc., 77, 6341-51 (1955).
The reaction of nitric oxide with isobuty1ene.F. Brown, Jr. ibid., 79, 2480-8 (1957).-- --
John
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ACKNOW LEDGEy,lENT
'The author wishes to express his gratitude to
I. Lynus Barnes for the help in taking and interpreting
the ultraviolet spectra, to Mrs. Vira Walker for typing
the manuscript and to the National Institute of Health