PROTON MAGNETIC RESONANCE STUDIES
OF SPECIFICALLY DEUTERATED
CYCLOHEXANE COMPOUNDS
J. D. REMUNSE
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CYCLOHEXANE COMPOUNDS
BIBLIOTHEEK TU Delft P 1934 6255
PROTON MAGNETIC RESONANCE STUDIES
OF SPECIFICALLY DEUTERATED
CYCLOHEXANE COMPOUNDS
PROEFSCHRIFT
TER VERKRIJGING VAN DE GRAAD VAN DOCTOR IN DE TECHNISCHE WETENSCHAPPEN AAN DE TECHNISCHE HOGESCHOOL DELFT,
OP GEZAG VAN DE RECTOR MAGNIFICUS IR. H. R. VAN NAUTA LEMKE, HOOGLERAAR IN DE AFDELING DER ELEKTROTECHNIEK,
VOOR EEN COMMISSIE UIT DE SENAAT TE VERDEDIGEN OP WOENSDAG 8 DECEMBER 1971 TE 16.00 UUR
DOOR
JOHANNES DAVID REMUNSE
scheikundig ingenieurgeboren te Amersfoort
/ < ^ 0 . .^.^' ^ ^
1971
DIT PROEFSCHRIFT IS GOEDGEKEURD DOOR DE PROMOTOREN PROF. DR. IR. B. M. WEPSTER en PROF. DR. IR. H. VAN BEKKUM
Contents
Page 1 Introduction 1.1 Scope 7 1.2 Synopsis 9 1.3 Nomenclature 9 Literature 10 2 Cyclohexane and methylcyclohexane2.1 Introduction 11 2.2 Preparative work 12 2.3 Proton magnetic resonance 12
2.4 Experimental part 16
Literature 17 3 r-Butylcyclohexane
3.1 Introduction 19 3.2 Preparative work 20 3.3 Proton magnetic resonance 21
3.4 Results and discussion 24 3.5 Experimental part 26
Literature 27 4 1,1-DimethyIcyclohexane, 1,3- and 1,4-di-r-butylcyclohexane (cis and trans),
and cis,cis-l ,3,5-tri-NbutyIcyclohexane
4.1 Introduction 29 4.2 Synthetic methods 29 4.3 Proton magnetic resonance 32
4.4 Results and discussion 34 4.5 Experimental part 39
Literature 41 5 Long-range couplmgs C*/HH) ^" cyclohexane
5.1 Introduction 42 5.2 Results and discussion 42
5.3 Experimental part 44
Literature 45 6 Geometry of cyclohexane and alkylcyclohexanes
6.1 Introduction 46 6.2 Cyclohexane 47 6.3 Alkylcyclohexanes 50 Literature 57 Summary • 59 Samenvatting 61
Drawings: J. M. Dijksman Cover design: J. M. van der Toorn
1 Introduction
1.1 Scope
The widespread interest in saturated six-membered ring compounds can be ex-plained by the fact that they play a prominent part in very divergent fields of organic chemistry. They occur in many and Varied compounds, including relatively simple cyclic monosaccharides and rather complex steroids. Research into the saturated six--membered ring therefore is of great importance to organic chemistry. The acquain-tance with the actual shape of the ring and its relation to the properties and reactivity of simple derivatives has led to a systematic interpretation of much chemical know-ledge of complex compounds as well as to the prediction of physical and chemical properties.
The most obvious example of a saturated six-membered ring is cyclohexane. This compound therefore has attracted attention almost from the outset of stereochemistry. Von Baeyer^ (1885) and especially Sachse^ (1890), who postulated the conformations of cyclohexane without which a good understanding of a substantial part of the organic chemistry would not have been possible, represent the beginning of a new series of developments. Particularly the exposition of Barton^ (1950) concerning the consequences which conformation has on the stability and reactivity of cyclohexane derivatives, has given those interested in natural products or mechanistic studies a deeper understanding. The interest in saturated six-membered rings got a new im-pulse when, beside the information from heats of combustion, chemical behaviour etc., such physical tools like ultra-violet, infra-red, and nuclear magnetic resonance spec-troscopy were developed and became available to the ordinary organic chemist.
Among these methods it is especially nuclear magnetic resonance which has be-come of great importance to the configurational as well as to the conformational analysis of cyclohexane compounds. From proton magnetic resonance (PMR) spectra of derivatives of cyclohexane the number of remaining ring protons together with their relative position can sometimes be obtained and thus the configuration can be derived. Furthermore information can be obtained on the environment of the various protons and consequently on the preferred conformation. In the case of an equilibrium of conformations proton magnetic resonance can provide information on the thermodynamical parameters of such an equilibrium. Extensive reviews in the literature* on the application of PMR to configurational and conformational pro-blems in cyclohexane chemistry show the value of this physical tool.
obtain the exact PMR parameters, necessary for such analyses, from the PMR spectra. The chemical shifts of and the coupling constants between the ring protons are often hidden in many-spin systems which cannot be resolved due to the small differences in chemical shift and the extensive spin-spin coupling.
Nevertheless much progress has been made in this field. This can be traced back to the following developments:
1. The chemical shifts of the ring protons are markedly influenced by a neigh-bouring polar substituent. In many cases the signals of such protons are then first--order analysable. This well-known phenomenon is the reason that much attention of the conformational analysts has been directed to cyclohexane compounds with polar substituents. Even then, however, additional deuterium substitution is often necessary in order to reduce the complexity of the spectrum. A difficulty in this pro-cedure is that the PMR parameters of such compounds do not only refliect the influ-ence of the polar substituent on the conformation but also the (mostly unknown) influence on the coupling constants between neighbouring protons. The parameters obtained from these compounds therefore do not hold for and are not strictly com-parable with other cyclohexane derivatives.
2. The latest developments in NMR have also opened new possibilities in this field of research. The applicability of higher field-strengths (up to 75 kGauss) has solved many problems, which were too complex at lower field. So far '^C magnetic resonance has been applied only sporadically to the analysis of cyclohexane pounds, but it certainly is very promising for the future. The use of lanthanide com-plexes, which recently were shown to be able to cause dramatic shifts of the protons of a complexed compound^, is mainly restricted to alcohols, amines, ketones, and esters.
In spite of these developments the PMR analysis of cyclohexane and alkylcyclo-hexanes remained an insuperable problem. The use of 220 MHz apparatus hardly simplifies the spectra and lanthanide complexes are useless in this case. Still these compounds are of basic interest in cyclohexane chemistry and the knowledge of its PMR properties should form the basis of the PMR work on other cyclohexane derivatives.
A promising way to tackle the problem would seem to be the investigation of com-pounds in which a number of the ring protons is substituted by deuterium. This sub-stitution is not expected to have an appreciable effect on the ring conformation, where-as the PMR parameters will be influenced only very slightly. In fact the determination of the chemical shifts of the ring protons of cyclohexane by this method is described by several authors*. The preparation of suitably deuterated cyclohexane derivatives however, as is required for the determination of the coupling constants, is a sub-stantial challenge even to a synthetic chemist.
The main objective of the present investigation was to develop synthetic routes to specifically deuterated cyclohexanes and alkylcyclohexanes and to obtain exact PMR
data for these compounds. These parameters can fill up the gap of knowledge on the PMR of cyclohexane compounds. Furthermore the exact values of the coupling constants should provide insight into the deformation of the cyclohexane chair by equatorial alkyl groups. This deformation is a current topic; much theoretical work has been done^, but there is only little experimental evidence for it. Moreover the PMR parameters can contribute to the discussion on the conformation of heavily substituted cyclohexanes which may prefer a non-chair conformation.
1.2 Synopsis
Chapter II ^ of this thesis describes the development of suitable synthetic methods leading to specifically deuterated cyclohexane compounds. The results of the PMR analysis of deuterated cyclohexanes and methylcyclohexanes are given.
Chapter 111^° gives similar investigations on deuterated ?-butylcyclohexanes. The impact of an equatorial ?-butyl group on the chair conformation of cyclohexane is discussed.
Chapter IV'^ discusses corresponding studies on deuterated 1,1-dimethyl-, di-?-butyl-, and tri-f-butyl-substituted cyclohexanes. From the PMR parameters the influence of an axial methyl group and of equatorial and axial /-butyl groups on the ring shape is derived.
Chapter V^^ gives the determination of the ^Jan long-range coupling constants in cyclohexane.
Finally Chapter VI gives a review of the theoretical and experimental data on the geometry of cyclohexane and alkylcyclohexanes. A comparison with and an evalu-ation of the present results is given.
1.3 Nomenclature
Two methods were used for the nomenclature of the deuterated cyclohexane com-pounds :
1. The compound is considered to be a cyclohexane in which ring protons are replaced by deuterium. The deuterium atoms are substituents and their position as well as that of other substituents is indicated according to the lUPAC rules*.
2. The compound is considered to be a perdeuterocyclohexane in which deuterium atoms are replaced by protons. Now the protons are the substituents and their position in relation to each other and to other substituents is defined in the same way.
Two deuterated compounds, described in Chapter II and IV, respectively, are given below with their names according to the two methods:
1) l,2,2,3,3,4,4,f-5,f-6-nonadeutero-r-l-trideuteromethylcyclohexane 2) c-2,c-3-diproto-r-l-perdeuteromethylcyclohexane
1) f-l,N4-di-?-butyl-2,2,3,3,4,5,5,c-6-octadeuterocyclohexane 2) r-1 ,/-4-di-/-butyl-l ,/-2-diprotoperdeuterocyclohexane
In the following chapters the two methods are used alternately, dependent on the extent of deuteration of the cyclohexane compound.
LITERATURE
> A. Baeyer, Ber. Deut. Chem. Ges. 18, 2277 (1885).
"" H. Sachse, Ber. Deut. Chem. Ges. 23, 1363 (1890); H. Sachse, Z. Phys. Chem. 10, 203 (1892). =• D. H. R. Barton, Experientia 6, 316 (1950).
•* H. Feltkamp and A^. C. Franklin, Angew. Chem. 77, 798 (1965); L. M. Jackman and S. Sternhell, Applications of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry, 2nd edition, Pergamon Press, Oxford (1969); R. D. Stolow, in Conformational Analysis, Scope and Present Limitations (ed. G. Chiurdoglu), p. 251, Academic Press, New York (1971).
' J. K. M. Sanders and D. H. Williams, Chem. Commun. 1970, 422. • Chapter II, references 6, 15, 17, 18.
' Chapter III, references 5-10.
' lUPAC Tentative Rules for the Nomenclature of Organic Chemistry. Section E. Fundamental Stereochemistry, J. Org. Chem. 35, 2849 (1970).
' J. D. Remijnse, H. van Bekkum, and B. M. Wepster, Reel. Trav. Chim. Pays-Bas 89, 658 (1970). " Idem, ibid. 90, 119 {197i).
*' Idem, ibid., submitted.
2 Cyclohexane and methylcyclohexane'
2.1 Introduction
Proton magnetic resonance (PM R) spectral data are of considerable importance in the study of the conformational equilibria of substituted cyclohexanes. AG-values for many substituents, among which are alkyl groups, have been determined by this method^' ^. Apart from the conformational analysis in terms of chair-chair equilibria, little attention has been paid to the influence of alkyl subsituents on the conformation in terms of changes in dihedral angles. For example, an axial methyl group may cause a flattening of the ring as a result of the interaction with the 3,5-axial protons*, and there exists some evidence that an equatorial /-butyl group causes a distortion of the ring'.
There can be little doubt that these phenomena will have an effect on the PMR parameters of the ring protons, especially on the vicinal coupling constants. However, the determination of possible ring distortions by PMR techniques has been hampered by the complexity of the spectra. In the case of alkylcyclohexanes especially it is vir-tually impossible to obtain exact chemical shift values for the ring protons due to the small differences in chemical shifts and the large amount of spin-spin splitting. No PMR parameters are known for simple alkylcyclohexanes, and cyclohexane has been fully investigated only very recently*. The situation is somewhat more favourable for polar substituted cyclohexanes, although, even in this case, partial deuteration of the ring was often necessary^"'".
The present study of specifically deuterated cyclohexane compounds was under-taken in order to reach a better understanding of the PMR spectra of alkyl substituted cyclohexanes. In this paper we communicate the preparation and PMR investigation of m-l,2-diprotoperdeuterocyclohexane (I), cw-l,2-diprotoperdeuteromethylcyclo-hexane (II), m-2,3-diprotoperdeuteromethylcyclocw-l,2-diprotoperdeuteromethylcyclo-hexane (III), and c/j-3,4-diproto-perdeuteromethylcyclohexane (IV). Of these latter two compounds both isomers were examined.
y CD3 H 9D3 CD3 CD3 CD3
ér" $-"
&; a ; ^„ c^„
H H
2.2 Preparative work
The synthesis of the deuterated compounds I-IV is given in Scheme 1. The tetra-chlorocresols were prepared following the chlorination methods of Zincke et a l . ' ^ ' ' ^ . A new procedure was developed for deuteration. The substrate was mixed with deuter-ated sodium hydroxide in an autoclave, nickel-aluminium alloy was added and the autoclave was closed. In this way the Raney catalyst was prepared in situ and the deuterium generated in this process was used for the deuteration of the substrate. The methyl protons were scrambled all over the mixture as was observed by PMR and mass spectrometry.
er'
CD3X
0
CD3 II CD3Dj " n
C D T Dl . E Scheme 1The dehydration of the deuterated cyclohexanols was performed by using 90% trideuterophosphoric acid. The final step in these syntheses was a diimide reduction of the deuterated cyclohexenes with ;?-toluenesulfonylhydrazine'^. This reduction is known to proceed by a synchronous cw-addition of neutral hydrogen to the olefinic bondi-^.
It will be clear that the reduction of 3- and 4-methylcyclohexene gives rise to the formation of two isomers. PMR investigations showed that the isomers were formed in about equal proportions.
All compounds were over 90% isotopically pure as was established by mass spectro-metry and elemental analysis.
2.3 Proton magnetic resonance Cyclohexane-diQ (/)
disulfide (20 vol %) and at 39 ° in carbon tetrachloride (20 vol %) with deuterium decoupling adjusted to give minimal peak widths. The peak positions were measured by the conventional side band technique and the spectrum of 1 at low temperature was treated as an AB-system. Satisfactory accuracy was attained by averaging the values from several spectra. Table I shows the chemical shifts and the coupling constant y„^ thus obtained, together with the values of the other investigators of cyclohexane.
After the first attempt to determine the chemical shifts of the ring protons from the proton spectrum of cyclohexane'', several deuterated cyclohexanes were inves-tigated. The chemical shifts and the geminal coupling constant were obtained from undecadeuterocyclohexane'*"'^ and 2,2,3,3,5,5,6,6-octadeuterocyclohexane'^. Dur-ing our investigations Garbisch^ published the preparation of 3,3,4,4,5,5,6,6-octa-deuterocyclohexane and exactly determined the geminal and vicinal coupling con-stants and chemical shifts of the ring protons. Our values are in good agreement with those of the other investigators.
Table I«
Low temp. CS2 Norm. temp.
Temp. Hax ^ea ^^ CS2 CCI4 Jgem Jae Jee ^aa Lit.
3.56
-- -- -- -- 15
17
12.6 - - - 18
13.05 3.65 2.96 13.12 6
" Chemical shifts are given in Hz downfield from TMS (60 MHz). Our values for the chemical shifts are considered accurate to 0.2 Hz, the value for the coupling constant to 0.05 Hz.
By comparison of the chemical shifts for compound I and cyclohexane at normal temperature, a deuterium isotope effect of about 3 Hz to higher field is observed in carbon disulfide as well as in carbon tetrachloride.
The same shift was observed for cyclohexane-dn while the other deuterated cyclo-hexanes show an isotope effect of only 1.5 Hz in the same direction. The relation be-tween the isotope shift of a ring proton and the amount and mode of substitution of other ring protons by deuterium is under further investigation.
The vicinal axial-equatorial coupling constant compares well with that observed by
( D ) H H H2^D^H ( D ) H - 90° 66.9 95.5 28.6 82.3 83.3 85.4 86.3 -105° 71.8 99.1 27.3 85.2 79° 67.2 96.0 28.8 82.2 95° 67.7 96.1 28.4 84.1 2 - 1 0 3 ° 68.2 97.0 28.8 83.9
Garbisch^, who calculated the bond angles of the cyclohexane ring from his values for the coupling constants (see later).
Methylcyclohexanes-di 2 (//, HI and IV)
We obtained 60 MHz spectra of II, III, and IV at 39° in carbon tetrachloride (20 vol %) in the same way as described for compound I.
On the basis of the known preference of the methyl group for the equatorial position only the following conformations will, in the first instance, be taken into account for the interpretation of the spectra:
I H H A~~--.^/^CD3 / K - / ^ ^ ' ^ ° 3 /^^^y^CDa A-^^_,^~-CD3 /j-^^^^^CDa
H 1^ ( H
H H
H M A H B l ï A H B The spectrum of II shows two doublets whilst the spectra of 111 and IV each consist of four doublets. All doublets could, without doubt, be assigned to the various axial and equatorial protons by comparison of the spectra and by proton-proton decoupling techniques. First one of the doublets of 11 had almost the same chemical shift as one of the doublets of 111; therefore these doublets must be assigned to the equatorial proton at position 2. The other doublet of II then belongs to the axial proton at position 1. The doublet of 111 belonging to the axial proton at position 3 could be assigned by proton-proton decoupling. The doublets belonging to the axial proton at position 2 and the equatorial proton at position 3 could be identified by comparison of the spectra of III and IV and again proton-proton decoupling resulted in the assign-ment of the doublets belonging to the protons at position 4.
These conclusions are confirmed by the fact that without deuterium decoupling the axial protons showed much broader signals due to the greater axial-axial proton--deuterium coupling.
The spectra were treated as AB-systems. The chemical shifts and coupling constants thus obtained are given in Table II.
Table II « Position Kx 2e, 3ea ^ax 4 . , 4 a . Jae II 78.2 96.5 -3.56 III A _ 96.0 _ -70.7 -3.55 IIIB _ -50.8 97.7 -3.64 IV A _ -97.8 -65.0 3.73 IV B — -70.8 95.0 -3.60 Methyl-cyclohexane ^ 79 101 52 103 72 100 66 -<• Cf. legend Table I.
The following comments can be made on these data:
1. The experimental chemical shift values do not exactly represent the chemical shifts of the equatorial conformer. Two corrections are required to obtain these parameters.
In the first place, our values stem from the fast interconverting mixture with the methyl group in equatorial (95%) and axial (5%) position. As the chemical shifts of protons in axial and equatorial position differ by 30-50 Hz the protons of the equa-torial conformer will differ from the values listed by about 2 Hz (upheld for the axial protons and downfield for the equatorial protons).
Secondly, our values were obtained from deuterated compounds and consequently a deuterium isotope effect is involved. Assuming this effect to be the same as that observed for cyclohexane-d,o the values for methylcyclohexane will be about 3 Hz higher than our values. It should be noted that application of this correction for the methine proton of methylcyclohexane (78.2 Hz) gives good agreement with the value of 82 Hz, found by Anet^^.
Combining both corrections the chemical shift values for methylcyclohexane in the pure equatorial conformer are estimated to be 5 Hz higher for the equatorial protons and about 1 Hz higher for the axial protons (see Table II).
The corresponding corrections for the coupling constants are within experimental error.
2. The vicinal axial-equatorial coupling constants hardly differ from the cor-responding value for cyclohexane. This implies that no deviation from the cyclo-hexane chair conformation occurs under the influence of the equatorial methyl group since Jae is expected to be particularly dependent on the dihedral angle (p.
This can be seen from the values found by Garbisch^, who calculated the dihedral angles for cyclohexane from the theoretical relationship between dihedral angles and vicinal proton coupling constants in saturated systems^":
J = A(cos^ (p + n cos (p) (1) Solution of this equation for the three vicinal coupling constants gave: (pae = 57.2°
and (Peg = 60.8°, corresponding with /„^ = 3.65 Hz and J^^ = 2.96 Hz, respectively. This shows that the effect of the relatively small deviation from the ideal cyclohexane chair ((p^e = (Pee — 60°, from equation (1): J^e = ./^e = 3.11 Hz) on these coupling constants is considerable.
We assume that for an alkylcyclohexane the same values for A and n can be used, at least for the coupling constants between methylene ring protons, since the in-fluence of factors which affect A and n, such as the electronegativity of the alkyl sub-stituent, will be small. This assumption is supported by the fact that even the vicinal coupling constant of compound II does not differ from the value for cyclohexane.
We therefore conclude that the difference between the various dihedral angles in equatorial methylcyclohexane and the corresponding angles in cyclohexane is less than 1 °.
3. The equatorial proton signals do not shift appreciably from those of cyclo-hexane-dio under the influence of the equatorial methyl group. This is contrary to the view of Booth^^ who predicted a shielding of about 20 Hz for the equatorial pro-tons at position, based on values obtained from methylcyclohexanol and 2--methylcyclohexylamine.
Of the axial protons those at 2-position are shifted by about 18 Hz to higher field. In this connection the anomalous shift of axial ring protons vicinal to equatorial methyl groups observed by Muller and Tosch^^, and Segre and Musher^^, for c«-l,3--dimethylcyclohexane, m,cw-l,3,5-trimethylcyclohexane and other dialkylcyclo-hexanes may be mentioned. These authors explain this shielding in terms of a "sand-wich-effect" by the two equatorial alkyl groups. We conclude, however, that one equa-torial methyl group is sufficient to cause a considerable shielding of the axial protons at 2-position and that this is approximately doubled by an additional equatorial methyl group at the S-position^'^.
The origin of this effect is not clear. Anisotropy of the bonds involved might be invoked for an explanation but then it is surprising that the axial protons are affected to such an extent while the equatorial protons are not influenced at all. Alternatively, a ring current induced by the magnetic field^'''^* might be suggested as the cause of the abnormal shift. It is not possible at present to assess the magnitude of this influence.
2.4 Experimental part
The PMR spectra were obtained with a Varian A-60 Spectrometer equipped with a Varian V-6040 Variable Temperature System and a Varian V-6058A homonuclear spin decoupler. The side band technique was performed with a Packard Model 200 CD wide range oscillator and a Hewlett--Packard H 22 521 IB electronic counter. Deuterium decoupling was accomplished by a transmitter built in this laboratory and operating at 9.21 MHz. The oscillator was crystal-controlled and had a stability better than 1 :10' over one hour. We modified the V-6031B probe for dual-frequency irradiation " .
3,4,5,6-Tetrachloro-o-cresol
This compound was prepared from 3-chloro-2-methylaniline as described in ref. 12, in 30% yield; m.p. 189-190° (lit. 190-191°).
2,3,5,6- Tetrachloro-p-cresol
This compound was prepared from 4-methylaniline in accordance with ref. 11 in 60% yield; m.p. 190-191 "(lit. 190°).
Cyclohexanol-di j
Sodium 2,3,4,5,6-pentachlorophenolate (20 g) and sodium deuteroxide (100 ml 24% in deuterium oxide, min. 99% D) were introduced into a 500 ml autoclave. A sealed glass ampoule containing nickel-aluminium alloy (40 g) was put into the mixture and the autoclave was closed. The ampoule was then broken by starting the stirrer. The temperature rose to 150° and the deuterium pressure to 40 atm. The temperature was maintained at 150° for 8 h. After cooling, the reaction mixture was shaken with ether. The ethereal solution was dried over magnesium sulfate and the ether was distilled off. 3.2 g (47%) of perdeuterocyclohexanol were obtained. Gas-chromatographic analysis showed the purity to exceed 99%.
2-Methylcyclohexanol-dii and 4-methylcyclohexanol-dn
These compounds were prepared in the same manner as described above for cyclohexanol-dia, start-ing out from the sodium salts of 3,4,5,6-tetrachloro-o-cresol and 2,3,5,6-tetrachloro-;7-cresol, respectively.
Cyclohexene-dia
Cyclohexanol-di8 (2 g) was boiled with 90% trideuterophosphoric acid (0.5 g, prepared from phosphorus pentoxide and deuterium oxide) for 15 min. The mixture was distilled and 1.50 g (92%) of cyclohexene-dio, b.p. 82°, were obtained.
l-Methylcyclohexene-di2 and 3-methylcyclohexene-di2
2-MethylcyclohexanoI-d,4 (6 g) was dehydrated in the same manner as cyclohexanol-dj,. Gas--chromatographic analysis showed the product (4 g) to contain 75% of l-methylcyclohexene-dia, 18% of 3-methylcyclohexene-di2, and 7% of 4-methylcyclohexene-di2. From this mixture 1.75 g of l-methylcyclohexene-di2 and 0.2 g of 3-methylcyclohexene-di2 was obtained by preparative gas chromatography, using SE-30 as the stationary phase.
4-Methylcyclohexene-di 2
4-Methylcyclohexanol-di4 was dehydrated in the same manner as described for cycIohexanol-di2.
Cyclohexane-di„ (ƒ)
Cyclohexene-d,o (1.50 g) was dissolved in 18 ml of "diglyme". ;)-Toluenesulfonylhydrazine (12 g) was added and the mixture was heated to 70° for 5 h. The solution then was distilled and the 80-100° fraction was analyzed after the removal of "diglyme" by water. The product (0.5 g, 30% yield) contained 6% of cyclohexene according to gas-chromatographic analysis. This was removed by shaking with concentrated dideuterosulfuric acid.
Methylcyclohexanes-di2 (II, III, andIV)
These compounds were prepared in the same way as cyclohexane-dio (1), starting out from the corresponding methylcyclohexenes-di2.
Isotopic purity
All deuterated compounds had an isotopic purity exceeding 90% as was established by mass spec-troscopy. This was confirmed for cyclohexane-dm and the methylcyclohexanes-du by C-H-analysis.
Acknowledgements
We wish to thank Mr. A. Sinnema and Mr. A. van Veen for helpful discussions. We are grateful to Dr. W. H. de Jeu of the Department of Technical Physics for providing the scheme for the heteronuclear spin decoupler and to Mr. H. van Ruler and Mr. J. Vermaas for building the transmitter.
L I T E R A T U R E
1 J. D. Remijnse, H. van Bekkum, and B. M. Wepster, Reel. Trav. Chim. Pays-Bas 89, 658 (1970). ^ E. L. Eliel, Angew. Chem. 77, 784 (1965).
' H. Feltkamp and N. C. Franklin, ibid. 77, 798 (1965).
^ B. Waegell, P. Pouzet, and G. Ourisson, Bull. Soc. Chim. France 1963, 1821. * S. Wolfe and J. R. Campbell, Chem. Commun. 1967, 872 and refs. cited herein. 8 E. W. Garbisch and M. G. Griffith, J. Amer. Chem. Soc. 90, 6543 (1968).
' N. S. Bhacca and D. H. Williams, Applications of N M R Spectroscopy in Organic Chemistry p. 183, Holden-Day, San Francisco (1964).
« F. A. L. Anet, J. Amer. Chem. Soc. 84, 1053 (1962).
1» F. A. L. Anet and P. M. Henrichs, Tetrahedron Letters 1969, 741. " Th. Zincke, W. Schneider, and W. Emmerich, Ann. 328, 268 (1903).
" Th. Zincke and W. Pfaffendorf, ibid. 394, 3 (1912).
" E. E. van Tamelen, R. S. Dewey, and R. J. Timmons, J. Amer. Chem. Soc. 83, 3725 (1961). » E. W. Garbisch, S. M. Schildcrout, D. B. Patterson, and C. M. Sprecher, ibid. 87, 2932 (1965). " F. R. Jensen, D. S. Noyce, C. H. Sederholm, and A. J. Berlin, ibid. 84, 386 (1962).
" F. A. L. Anet and A. J. R. Bourn, ibid. 89, 760 (1967).
" F. A. Bovey, F. P. Hood III, E. W. Anderson, and R. L. Kornegay, J. Chem. Phys. 41, 2041 (1964). " N. Muller and P. J. Schultz, J. Phys. Chem. 68, 2026 (1964).
" F. A. L. Anet, Can. J. Chem. 39, 2262 (1961).
2» M. Barfield and D. M. Grant, Advan. Magnetic Resonance 1, 149 (1965). 21 H. Booth, Tetrahedron 22,615 (1966).
" N. Muller and W. C. Tosch, J. Chem. Phys. 37, 1167 (1962). 2» A. Segre and J. I. Musher, J. Amer. Chem. Soc. 89, 706 (1967).
^* During the preparation of this manuscript / . B. Lambert and R. G. Keske, (Tetrahedron Letters
1969, 2023) reported their preparation of 1,2,3,3,5,5hexadeuteromethylcyclohexane. They o b
-served the same shielding of the axial proton vicinal to the equatorial methyl group.
^^ J. A. Pople, W. G. Schneider, and H. J. Bernstein, High-resolution Nuclear Magnetic Resonance, McGraw-Hill Book Co. Inc., New York (1959), p. 183.
2« / . J. Burke and P. C. Lauterbur, J. Amer. Chem. Soc. 86, 1870 (1964). " Cf. A. Charles and W. McFarlane, Mol. Phys. 14, 299 (1968).
3 i-Butylcyclohexane'
3.1 Introduction
Recently accurate proton magnetic resonance (PMR) parameters of cyclohexane^'^ and methylcyclohexane^'* were determined by suitable substitution of the ring pro-tons by deuterium. The PMR analysis of methylcyclohexane showed that the effect of an equatorial methyl group on the shape of the cyclohexane chair conformation is negligible.
We now wish to consider the bulkier /-butyl group. Empirical valence-force calcu-lations by Allinger et al.' show that the internal angles of the ring may be affected to a considerable extent by this group (107-115° for /-butylcyclohexane compared with 111.5° for cyclohexane). Altona and Sundaralingam^ obtained more detailed figures on the geometry of the substituted cyclohexane ring, including values for the dihedral angles of/-butylcyclohexane which differ considerably from those of cyclohexane.
Ring-distortion has also been reported on the basis of experimental data. Utley et al.^ concluded from the rate of complex formation of substituted cyclohexane carbo-nitriles that the cyclohexane chair is flattened by a /-butyl group. From PMR calcu-lations on these compounds they derive a flattening of about 3° (internal ring angle)*.
Wolfe and Campbell'^ compared coupling constants in polar substituted cyclohexanes with or without a /-butyl group and deduced changes in the dihedral angles of the ring. Dallinga and Toneman'" from electron diffraction work on cis- and /ran.y-4-/-butyl-l--chlorocyclohexane concluded that the internal ring angles are considerably affected by the /-butyl group.
Finally, it may be recalled that there has been much discussion recently'^ on the validity of the PMR method for determining conformational preferences and A(?--values by using the /-butyl group as a holding group.
In this paper we report on the geometry of /-butylcyclohexane as derived from the PMR investigation of l-/-butyl(m-l,2-diproto)perdeuterocyclohexane (1), l-/-butyl-(cw-2,3-diproto)perdeuterocyclohexane (one isomer, II), l-/-butyl(cM-3,4-diproto)-perdeuterocyclohexane (III, both isomers), and l-/-butyl-3,3,5,5-tetradeuterocyclo-hexane (IV).
H
3.2 Preparative work
The preparation of the /-butyldiprotoperdeuterocyclohexanes is outlined in Scheme 1.
I
è.,-è- &:
\ = '
Scheme 1
Exchange of the 2-, 4-, and 6-protons of 3-/-butylphenol was accomplished under Clemmensen conditions (zinc amalgam) with deuterated acid. The deuterogenation was carried out following a previously described procedure^. The 5-proton of the phenol was exchanged during this reaction as shown by the PMR spectrum of the product. The mixture of alcohols was dehydrated by 85% trideuterophosphoric acid, yielding a mixture of the three /-butylperdeuterocyclohexenes which were separated by preparative GLC. PMR and mass spectra showed the absence of deuterium in the /-butyl groups of 3- and 4-/-butylperdeuterocyclohexene (11' and III'). The protons of the /-butyl group of l-/-butylperdeuterocyclohexene (1') however, were found to be exchanged to a considerable extent. Careful investigation by mass spectroscopy of the deuterium distribution in the product indicates that exchange has taken place be-tween the /-butyl protons, the deuterium atoms at the 2- and 6-positions, and the dehydrating agent. The participation of the deuterium atoms at the 2- and 6-positions cannot be explained by the well-known'^ mechanism of a protonated cyclopropane ring originating from the tertiary carbonium ion. We observed that in dehydration of l-/-butylcyclohexanol under the same conditions no exchange at all of the /-butyl protons occurred. The same contrast was observed in the dehydration of 2-isopropyl-cyclohexanol and 1-isopropyl2-isopropyl-cyclohexanol, exchange of the methyl protons occurring only in the reaction of 2-isopropylcyclohexanol. We propose therefore the inter-mediate formation of a protonated four-membered ring as shown in Fig. 1. A deute-ride shift in the primarily formed carbonium ion A moves the positive charge to position 2 (B). A 1,3-deuteride shift to the other side of the ring gives carbonium
A B E "/°
®
® "/°
C F
Fig. 1.
ion C. The formation of the protonated four-membered rings in E and F would enable exchange of the /-butyl protons. Proton abstraction from A yields 11' and III'. In the same way I' is formed from B and C.
The final step in this synthesis was the reduction of the cyclohexenes by diimide. PMR investigation of the products showed that one isomer of II is formed in large excess, while a mixture of about equal quantities of the two isomers of III was ob-tained from III'. We assume that formation of one isomer of II prevails for steric reasons. Molecular models show that the approach of the diimide reagent and the formation of a cyclic transition state according to Garbisch et al.'^ is more difficult on the /-butyl side of the preferred half-chair conformation of the cyclohexene (Fig. 2). The same holds for the mechanism proposed by Schaad and Kinser^*. A similar effect was observed by Pasto and Klein^^ in the hydroboration of 3-/-butylcyclo-hexene.
Fig. 2.
Due to this steric preference no value could be obtained for the chemical shift of the axial proton at position 2. Therefore l-/-butyl-3,3,5,5-tetradeuterocyclohexane (IV) was prepared starting out from 4-/-butylcyclohexanone. The protons vicinal to the carbonyl function were substituted by deuterium. Lithium aluminium hydride reduc-tion to a mixture of the alcohols was followed by tosylareduc-tion and a second reducreduc-tion with this reagent.
3.3 Proton magnetic resonance
M
D UFig. 3.
(20 vol %) with deuterium decoupling adjusted to give minimal peak widths. The spectra of I, II, and III are given in Fig. 3.
The undecoupled spectrum of I consists of two broad unresolved peaks of the ring protons and a sharp peak of non-deuterated methyl groups superposed over the multiplets of deuterated methyl groups. Deuterium decoupling of I resolves the peaks of the ring protons to an AB-system and gives rise to the formation of three sharp peaks originating from CHj-, CHjD-, and CHDj-groups, respectively, the latter one absorbing at highest field. The distance between the peaks is 1.1 Hz (0.018 ppm) and represents the isotope shift caused by substitution of a geminal proton by deuterium'^. The spectra of II and III prove that no exchange of the /-butyl protons has occurred in these compounds. Ill is a mixture of the two isomers as follows from the presence of two AB-systems. In the spectrum of II only one AB-system is observed which implies that one isomer predominates strongly.
The doublets in the spectra of I, II, and III are assigned to the various ring protons by comparison of the spectra and by proton-proton decoupling. One of the doublets of I also appears in II and is assigned to the equatorial proton at position 2. The doublet at higher field of I then belongs to the 1-axial proton and the high-field
dou-biet of II to the 3-axial proton. This one also occurs in III. Proton-proton decoupling proved that the inner doublets of this spectrum form an AB-system, which then be-longs to the 3-axial-4-equatorial isomer. The outer doublets then originate from the 3-equatorial-4-axial isomer. The low-field doublet of this AB-system is assigned to the 3-equatorial proton. Other assignments lead to results which are inconsistent with the PMR spectrum of IV.
The spectrum of IV was investigated in order to obtain the chemical shift of the axial proton at the 2-position and to verify the previous assignments. Direct analysis of the spectrum was not possible and recourse had to be taken to computer simulation. Simulated spectra of this seven-spin system were obtained by using the chemical shifts and the vicinal axial-equatorial coupling constant as derived from the spectra of I, II, and III. The geminal coupling constants and the vicinal axial-axial coupling constant were assumed to be the same as for cyclohexane'. The good fit between the experimental and the simulated spectrum, demonstrated in Fig. 4, was obtained by (a) iteration of the value for the chemical shift between 52 and 68 Hz resulting in a best value of 54 Hz and (b) accepting a long-range coupling between the equatorial protons separated by three carbon atoms. As to (b), in the first instance the two protons at
Fig. 4. (a) Deuterium-decoupled PMR spectrum of IV; (b) computed spectrum for the ring protons of IV (seven-spin system).
position 4 form an AB-system; the sharp peak near the centre of the experimental spectrum is part of the high field doublet of this system. The corresponding peak of the equatorial proton is seen to be split into a triplet by this long range coupling (VHH = 1 -4 Hz). The other part of this doublet is obscured by the rest of the spec-trum '^.
3.4 Results and discussion
The chemical shifts and coupling constants thus obtained for /-butylcyclohexane are given in Table I, together with the corresponding values for cyclohexane and methyl-cyclohexane^.
Table I" PMR spectral data for ^-butylcyclohexane, methylcyclohexane and cyclohexane
Position ^ax 2.a 2ax 3e, 3„. 4e, ^ax ^ ax~^eQ 2e«-3a. ^ax~^eQ 3 - 4 -^ eQ 'ax 3 -4 2 - 4 /-Butylcyclohexane J 3.03 3.61 -3.77 3.76 1.4 59 Hz 106 54 106 72 99 66 <P 60.4° 57.4° -56.6° 56.6° -Methylcyclohexane J 3.56 3.55 3.64 3.73 3.60 -79 Hz 101 52 103 72 100 66 9 57.7° 57.7° 57.2° 56.8° 57.4° -Cyclohexane J 3.56 3.56 3.56 3.56 3.56 -72 Hz 101 72 101 72 101 72 9 57.7° 57.7° 57.7° 57.7° 57.7° -Chemical shifts at 39° are given in Hz downfield from TMS (60 MHz) and corrected for the deute-rium isotope shift^. The values for cyclohexane at 39° in carbon tetrachloride were obtained by correcting the values at —90° in carbon disulfide for the temperature and the solvent effect^. The values for the chemical shifts are considered accurate to I Hz, the values for the coupling constants J to 0.05 Hz (corresponding to 0.3° in dihedral angles rp).
Dihedral angles cp (Table 1) were calculated from the modified Karplus equation,
J = A{cos^(p + ncos (p) (1) using the values for the constants A (12.95) and n ( — 0,02) as obtained by Garbisch^
for cyclohexane. The influence of an equatorial /-butyl group appears to be consider-able, in contrast with the effect of an equatorial methyl group. Whereas the dihedral angles of cyclohexane and methylcyclohexane differ by less than 1°, the /-butyl group enlarges the dihedral angle between the 1-axial proton and the 2-equatorial proton by about 3° and reduces the 3 ^ dihedral angles by about 1°.
The following comments are relevant to this application of the Karplus rule. The most important factors which influence the constants A and n of equation (1) are (a) the electronegativity of the sub-stituents, (b) the C-C-H bond angles, and (c) the C-C bond length'".
(a) It is known" that with increasing electronegativity of the substituent the vicinal coupling constant in saturated systems decreases. As can be seen from Table I substitution ol a proton of cyclohexane by a methyl group has no influence on the coupling constant J^ti^ieq- Therefore it is improbable that the certainly minor change in electronegativity by substitution of the methyl group by a /-butyl group would participate in the observed change in the coupling constant. Moreover the observed change is a decrease and not an increase as should be expected from the somewhat more electron-donating ?-butyl group.
ib) An increase of the C-C-H angles would give a decrease of the vicinal coupling constant. Cal-culations using the approximative quantitative rules given by Karplus^^ lead to a combined increase of the C-C-H angles of about 7 required to explain the observed decrease of the coupling constant. As Jigg-^ax is not influenced by the /-butyl group and therefore the situation at position 2 is hardly changed, the increase of 7° would have to come only from the 1-axial proton. This is an improbably large effect and also in contradiction with the r-butylcyclohexane model of Altona' which predicts a decrease oi 4°.
(c) Once more using the rules given by Karplus^' the observed decrease of the vicinal coupling con-stant would require an increase of the length of the C-C bond of about 0.1 A. Such an increase cer-tainly is unlikely. For example, the experimental values for the C-C bond lengths of cis- and trans--4-/-butyl-l -chlorocyclohexane given by Dallinga and Toneman '° do not differ more than 0.02 A from those of cyclohexane.
Summarizing we conclude that the most important contribution to the observed decrease of Jiax-zeq stems from the increase in the dihedral angle. This is in harmony with the recently published values for the dihedral angles of /-butylcyclohexane as obtained by empirical valence-force calculations*. The lax-^eq dihedral angle is cal-culated to increase by 4.5° when introducing an equatorial /-butyl group while the 2-3 and 3-4 dihedral angles show no important difference from those of cyclohexane. Our values for the 3-4 coupling constants of/-butylcyclohexane show a slight increase compared to cyclohexane and methylcyclohexane, corresponding to slightly smaller dihedral angles. The difference, however, is too small to allow for a further inter-pretation.
Our conclusion concerning the geometry of the ring is that the axial proton at position 1 is bent towards the centre of the ring. The inference is that at the /-butyl side the ring is somewhat more puckered than the ring of cyclohexane (and not flattened as has often been suggested). The other part of the ring is not noticeably affected.
The spectrum of IV shows a long-range coupling of 1.4 Hz between the equatorial protons at positions 2 and 4. For the simulation of the theoretical spectrum a coupling of the same magnitude was accepted between the equatorial protons at positions 2 and 6. An accurate value however could not be deduced. There is no observable long--range coupling between the 2,4-axial protons or between the axial proton at position 4 and the equatorial proton at position 2. These observations confirm the " W " rule, which demands a planar zig-zag conformation for effective coupling in the fully saturated system H-C-C-C-H^°. We suppose that this coupling between equatorial protons over four single bonds occurs in all cyclohexane derivatives with a chair con-formation and should be taken into account when interpreting their PMR spectra^'.
This phenomenon also may be one of the reasons of the complexity of the spectra of apparently simple spin systems of cyclohexane derivatives like c/j,m-l,3,5-tri-/-butyl-cyclohexane^^. Furthermore, the long-range coupling might be helpful in distinguish-ing between chair and twist conformations as the planar " W " conformation is no longer present in a twist conformation.
The chemical shifts of the ring protons of /-butylcyclohexane give rise to the following remarks:
1. The striking shift to higher field of the axial ring protons at position 2 of methyl-cyclohexane^ is observed also with /-butylcyclohexane. The explanation in terms of carbon-carbon single bond anisotropics as suggested earlier^''* for methylcyclo-hexane cannot hold since the geometry is certainly different and yet the same shift is observed while the 2-equatorial proton remains relatively unaffected. Apparently the methyl and the /-butyl groups influence a possible ring current induced by the mag-netic field in a similar way and therefore bring about the same shift of the axial proton at position 2.
2. Table I shows that the chemical shifts of the ring protons at position 4 are really affected by the introduction of a methyl or a /-butyl group at position 1. The use of these groups as holding group when determining the chemical shifts of the 4-protons for the unsubstituted compound therefore is unjustified. With respect to the /-butyl group the observed ring distortion provides a further restriction as to the use of this group as holding group for other purposes.
3.5 Experimental part
The PMR spectra were obtained with a Varian A-60 Spectrometer equipped with a Varian V-6058A homonuclear spin decoupler. The side-band technique was performed with a Hewlett--Packard Model 200 CD wide range oscillator and a HewlettHewlett--Packard H22 521 IB electronic counter. Deuterium decoupling was accomplished by the transmitter previously described^. Peak positions were measured by the conventional side-band technique and the spectra of I, II, and III were treated as AB-systems. Computations for spectrum simulation were performed on an IBM 360/65 using the computer program LAOCN3^'.
m-t-Butylphenol-d,
»7-/-Butylphenol (20 g) was added to a mixture of zinc amalgam (100 g) and deuterium oxide (80 ml 99.7%D)^*. Acetyl chloride (300 g) was added dropwise while cooling the mixture with ice. The solu-tion was refluxed for 14 h, diluted with deuterium oxide (100 ml) and extracted with ether. The ethereal solution was treated with sodium deuteroxide (2^) in order to remove the acid. The ether was distilled off and 14.8 g (74%) of m-Z-butylphenol-dj were obtained. This procedure was repeated in order to obtain an isotopic purity of more than 95% as determined by mass spectrometry. The PMR spectrum showed one peak at 7.0 ppm due to the remaining aromatic proton.
3-t-Butylcyclohexanol-dii
Deuterated m-/-butylphenol (12 g) was dissolved in sodium deuteroxide (150 ml 24% in deuterium oxide, min. 99%D). This solution was introduced into a 500 ml autoclave together with a sealed glass ampoule containing nickel-aluminium alloy (40 g). The deuterogenation was carried out following the procedure described previously^. 9.9 g (76%) of 3-r-butylcyclohexanol-dii were obtained. The isotopic purity was more than 95% according to the mass spectrum.
Deuterated t-bulylcyclohexenes (/', / / ' , and III')
3-/-Butylcyclohexanol-du (9.9 g) was boiled with 85% trideuterophosphoric acid (2 g, prepared from phosphorus pentoxide and deuterium oxide) for 15 min. The mixture was distilled and 7.7 g of a mixture of deuterated /-butylcyclohexenes were obtained. From this mixture 1.0 g of deuterated l-/-butylcyclohexene (da-du), 0.5 g of 3-?-butylcyclohexene-d9, and 1.3 g of 4-/-butylcyclohexene-d9 were obtained by preparative G L C , using Apiezon as the stationary phase.
Deuterated t-butylcyclohexanes (/, / / , and III)
These compounds were prepared by diimide reduction of the corresponding cyclohexenes as described previously^.
t-Butylcyclohexane-df (IV)
4-/-Butylcyclohexanone (10 g) was refluxed with deuterium oxide (50 ml 99.7%D) and acetic an-hydride (20 ml) during 10 h. The mixture was extracted with ether. The ether was distilled off yielding
9 g (90%) of the deuterated compound. This procedure was repeated until the deuterium content of
the a-positions was greater than 95% according to PMR and mass spectrometry.
4-/-Butylcyclohexanone-d4 (3 g) dissolved in ether (50 ml) was added dropwise to a mixture of lithium aluminium hydride (1 g) and ether (50 ml). The mixture was refluxed for 1 h and the re-maining reagent was decomposed by water. The reaction product was filtered off. The ethereal solution was dried with magnesium sulfate and the ether distilled off to give 2.0 g (66%) of the deuterated cyclohexanol. 4-?-Butylcyclohexanol-di was tosylated in the usual way with p-toluenesulfonyl chloride in pyridine. The tosylate was reduced by the use of lithium aluminium hydride in the same way as described above. The isotopic purity of the product was better than 95% as shown bij mass spectro-metry.
Acknowledgements
We wish to thank Messrs. J. A. Peters and A. Sinnema for helpful discussions. We are grateful to Mr. J. H. Kelderman for assistance with the use of the computer program and to Mr. H. M. A. Buurmans for measuring the mass spectra.
L I T E R A T U R E
» / . D. Remijnse, H. van Bekkum, and B. M. Wepster, R e d . Trav. Chim. Pays-Bas 90,779 (1971). 2 / . D. Remijnse, H. van Bekkum, and B. M. Wepster, ibid. 89, 658 (1970).
' E. W. Garbisch and M. G. Griffith, J. Amer. Chem. Soc. 90, 6543 (1968). * J. B. Lambert and Y. Takeuchi, Org. Magn. Resonance 1, 345 (1969).
' a. N. L. Allinger, M. A. Miller, F. A. Van-Catledge, and J. A. Hirsch, J. Amer. Chem. Soc. 89, 4345 (1967);
b. N. L. Allinger, J. A. Hirsch, M. A. Miller, I. J. Tyminski, and F. A. Van-Catledge, ibid. 90, 1199(1968).
» C. Altona and M. Sundaralingam, Tetrahedron 26, 925 (1970). ' F. Shah-Malak and / . H. P. Utley, Chem. Commun. 1967, 69. « G. E. Hawkes and / . H. P. Utley, ibid. 1969, 1033.
» S. Wolfe and / . R. Campbell, ibid. 1967, 872.
1» G. Dallinga and L. H. Toneman, Reel. Trav. Chim. Pays-Bas 88, 1221 (1969). " a. E. L. Eliel and R. J. L. Martin, J. Amer. Chem. Soc. 90, 682 (1968);
b. F. R. Jensen and B. H. Beck, ibid. 90, 3251 (1968). " C. J. Collins, Chem. Rev. 1969, 543.
" E. W. Garbisch, S. M. Schildcrout, D. B. Patterson, and C. M. Sprecher, J. Amer. Chem. Soc. 87, 2932(1965).
" L. J. Schaad smd H. B. Kinser, J. Phys. Chem. 73, 1901 (1969). " D. J. Pasto and F. M. Klein, J. Org. Chem. 33, 1468 (1968).
" In an effort to determine this long-range coupling constant for methylcyclohexane we prepared l-methyl-3,3,5,5-tetradeuterocyclohexane. The PMR signal of the equatorial proton at position 4 is split into a doublet ( 7 = 1 3 Hz) by the coupling with the geminal axial proton. Unfortunately, as the chemical shift of the 2-equatorial proton is about the same (see Table I), the magnitude of J%eq-uq could uot be deduced from this spectrum.
'« M. Karplus, J. Amer. Chem. Soc. 85, 2870 (1963).
" L. M. Jackman and 5'. Sternhell, Applications of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry, p. 283, Pergamon Press, Oxford (1969).
" Ref. 19, p. 334.
''I This long-range coupling has not been observed for cyclohexane since no deuterated cyclohexane with 1-3 diequatorial protons has been synthesized until now.
"^ H. van Bekkum, H. M. A. Buurmans, G. van Minnen-Palhuis, and. B. M. Wepster, Reel. Trav. Chim. Pays-Bas 88, 779 (1969).
2' S. Castellano and A. A. Bothner-By, J. Chem. Phys. 41, 3863 (1964). " M. Fétizon and J. Gramain, Bull. Soc. Chim. France 1969, 651.
4 1,1-Diniethylcyclohexane, 1,3- and l,4-di-<-butylcyclohexane
(cis and trans), and cfs,c/s-l,3,5-tri-<-butylcyclohexane'
4.1 Introduction
In previous papers^ we described the synthesis and PMR analysis of a specifically deuterated cyclohexane and a series of deuterated methylcyclohexanes and /-butyl-cyclohexanes. It was found (i) that the chemical shift of the axial protons vicinal to an equatorial methyl or /-butyl group is considerably more affected than the other chemical shifts and (ii) that the vicinal axial-equatorial coupling constants in methyl-cyclohexane do not differ from those in methyl-cyclohexane, whereas in /-butylmethyl-cyclohexane the lax-^eq coupling constant has decreased appreciably. The application of a Karplus--like relationship to the change of this coupling constant led to the origin of this effect: the tertiary proton is bent towards the centre of the ring and the cyclohexane chair is presumably puckered at the /-butyl side.
We now present our investigations on cyclohexanes with two or three alkyl groups together with our conclusions concerning the impact of these groups on the geometry of the cyclohexane ring.
The introduction of additional equatorial methyl groups is not expected to reveal new aspects as no distortion is caused by an equatorial methyl group. Furthermore it is already known from the PMR spectra of c/j-l,3-dimethylcyclohexane'' and cis,-c/5'-l,3,5-trimethylcyclohexane* that the anomalous shift of the axial protons at position 2 of methylcyclohexane is about doubled by the introduction of a methyl group at position 3. We therefore want to focus our attention to the introduction in /-butylcyclohexane of additional /-butyl groups at the 3-, 4-, or 3- and 5-position. In these cases a further distortion of the cyclohexane chair might be expected.
Axial alkyl groups may cause a more severe deformation of the cyclohexane chair. An axial methyl group may flatten the ring' and a /-butyl group may even cause the ring to adopt a non-chair conformation*'^'*. For synthetic and PMR reasons 1,1--dimethylcyclohexane was chosen for the study of the influence of an axial methyl group. It is obvious that the impact of an axial /-butyl group can best be measured in trans-1,3- and c(5'-l,4-di-/-butylcyclohexane. Both compounds have been investigated previously by other physical methods^'*. No definite decision could be made con-cerning the conformation but both compounds are reported to exist for the greater part as twist conformers.
4.2 Synthetic methods
Routes were developed for the synthesis of the deuterated compounds, leading to specific patterns of ring deuteration. These methods are summarized below.
I. A deuterated (o- and /7-positions) phenol is deuterogenated following the Raney-alloy/deuterated sodium hydroxide method, reported previously^. Thereafter two routes can be followed. The perdeuterated cyclohexanol is dehydrated by di-methyl sulfoxide to a cyclohexene which by diimide reduction is converted into a m-l,2-diprotoperdeuterocyclohexane (Scheme I, A). Alternatively the cyclohexanol is oxidized to the corresponding cyclohexanone. Thereupon reduction with lithium aluminium hydride, dehydration (DMSO), and diimide reduction gives a 1,1,2-tri-protoperdeuterocyclohexane (Scheme 1, B).
\ Q OH H H H
R R R Scheme I
II. The a-protons of a cyclohexanone are exchanged with deuterated acid. Reduc-tion with lithium aluminium deuteride, tosylaReduc-tion of the cyclohexanol and subsequent
OTs D
D 2 ^ - ' ^ D 2 D 2 ^ / \ D 2
D D2 D 2 / - ^ D D2^^X^D2
4 1,1-Diniethylcyclohexane, 1,3- and 1,4-di-Nbutylcyclohexane
(cis and trans), and cfs,cis-l,3,5-tri-<-butylcyclohexane'
4.1 Introduction
In previous papers^ we described the synthesis and PMR analysis of a specifically deuterated cyclohexane and a series of deuterated methylcyclohexanes and /-butyl-cyclohexanes. It was found (i) that the chemical shift of the axial protons vicinal to an equatorial methyl or /-butyl group is considerably more affected than the other chemical shifts and (ii) that the vicinal axial-equatorial coupling constants in methyl-cyclohexane do not differ from those in methyl-cyclohexane, whereas in /-butylmethyl-cyclohexane the \ax-^eq coupling constant has decreased appreciably. The application of a Karplus--like relationship to the change of this coupling constant led to the origin of this effect: the tertiary proton is bent towards the centre of the ring and the cyclohexane chair is presumably puckered at the /-butyl side.
We now present our investigations on cyclohexanes with two or three alkyl groups together with our conclusions concerning the impact of these groups on the geometry of the cyclohexane ring.
The introduction of additional equatorial methyl groups is not expected to reveal new aspects as no distortion is caused by an equatorial methyl group. Furthermore it is already known from the PMR spectra of m-l,3-dimethylcyclohexane^ and cis,-m-l,3,5-trimethylcyclohexane* that the anomalous shift of the axial protons at position 2 of methylcyclohexane is about doubled by the introduction of a methyl group at position 3. We therefore want to focus our attention to the introduction in /-butylcyclohexane of additional /-butyl groups at the 3-, 4-, or 3- and 5-position. In these cases a further distortion of the cyclohexane chair might be expected.
Axial alkyl groups may cause a more severe deformation of the cyclohexane chair. An axial methyl group may flatten the ring' and a /-butyl group may even cause the ring to adopt a non-chair conformation*'^'*. For synthetic and PMR reasons 1,1--dimethylcyclohexane was chosen for the study of the influence of an axial methyl group. It is obvious that the impact of an axial /-butyl group can best be measured in trans-\,3- and c/5'-l,4-di-/-butylcyclohexane. Both compounds have been investigated previously by other physical methods^'*. No definite decision could be made con-cerning the conformation but both compounds are reported to exist for the greater part as twist conformers.
4.2 Synthetic methods
Routes were developed for the synthesis of the deuterated compounds, leading to specific patterns of ring deuteration. These methods are summarized below.
I. A deuterated (o- and /^-positions) phenol is deuterogenated following the Raney-alloy/deuterated sodium hydroxide method, reported previously^. Thereafter two routes can be followed. The perdeuterated cyclohexanol is dehydrated by di-methyl sulfoxide to a cyclohexene which by diimide reduction is converted into a c/5'-l,2-diprotoperdeuterocyclohexane (Scheme I, A). Alternatively the cyclohexanol is oxidized to the corresponding cyclohexanone. Thereupon reduction with lithium aluminium hydride, dehydration (DMSO), and diimide reduction gives a 1,1,2-tri-protoperdeuterocyclohexane (Scheme I, B).
II. The a-protons of a cyclohexanone are exchanged with deuterated acid. Reduc-tion with lithium aluminium deuteride, tosylaReduc-tion of the cyclohexanol and subsequent
2 ^ : OD D ^ A OTs D D 2 / ^ D 2 D 2 / \ D 2 R R Scheme II
Product
Table I. Synthetic methods and products. Starting Material , H2 / \ CH3 H2 0 C H , Synthetic Method II A' M2
0<c:
H2 CH3 I A H2 H2 .CH3 •CH3 H A /Bu 'Bu H A /Bu—( D X . (CIS + t r a n s ) ^ H D H tQu-( O V ' B u D OD I A D H / \ ' B u^Bu—<^ D yC (cis + t r a n s ) rBu—( O >—'Bu H2 D OD I B /Bu 0 7 r B u - ( D K ( c i s + t r a n s ) t%u-\ >—/Bu ( c i s + t r a n s ) I B H2 H2 10 11 D V : (cis + t r a n s ) >Bu 'Bu 'Bu 'Bu<p^2 ' B u D K (cis + t r a n s ) H2 'Bu D OD ' B u ' B u ' B u 'Bu r 'Bu
V
I
'Bu°f
'Bu 'Bu°\
'Bu H V'Bu V-'Bu (cis+trans) V/Bu l A I A I B E Breduction with lithium aluminium deuteride gives a hexadeuterocyclohexane (Scheme II, A). When tosylation is difficult due to large vicinal substituents, a dehydration (DMSO) followed by reduction with dideuterodiimide gives the desired compound (Scheme II, B).
A list of the deuterated compounds is given in Table I, together with the compo-sition of the products, the starting materials and the methods of synthesis. A detailed description of an example of each method is given in the experimental part of this paper.
4.3 Proton magnetic resonance
P M R spectra of the products 1-11 were obtained at 100 MHz in carbon tetrachloride with deute-rium decoupling adjusted to give minimal peak widths. Products 2 and 3 were also measured in carbon disulfide at —120' in order to slow down the chair-chair equilibrium. In most cases computer simu-lation and iteration was necessary in order to obtain exact chemical shifts and coupling constants.
A brief description of the spectra and their analysis is given below. The values for the chemical shifts are not corrected for the deuterium isotope effect. Corrected values are given in Tables II-V. The values for the chemical shifts are considered accurate to 0.01 ppm, the values for the coupling constants to 0.1 Hz, unless stated otherwise.
m 1 This compound was investigated in order to obtain values for Aax-2oa:> H I Jieq-iax-: ^ i d Jieq-ieci- The 4-protons form an AB-system. Jii,u^iax was
CH3 determined accurately from the axial part of this system. The equatorial part is not only broadened by the long-range coupling with H.^^, and Hec,, H but it is also overlapped by the multiplets of these protons. Therefore no accurate value for J^q-iea could be obtained''. From the H^eq- and He^,--multiplet a value of —13.0 Hz was derived for Jieq-iax- The H2„j.-signals are partly obscured by the methyl signals but simulation as a 5-spin system (ignoring the 4-protons and the methyl protons and using the chemical shifts and coupling constants obtained earlier'^) gave a satisfactory fit for the Hiax-signal with Jiax-2ax = 11.5 ± 0.3 Hz. This value agrees very well with the value of 11.6 Hz, obtained recently by Garbisch et al.°.
~u 2 The room temperature spectrum shows two singlets with intensity-H I -ratio 4:6. At — 120' the signal of the methyl groups is still a singlet but the
CH3 signal of the ring protons is split into an AB-system. The values for the chemical shifts were calculated to be 1.08 and 1.32 ppm (corrected for the '^H temperature and solvent effect'') and the geminal coupling constant was measured to be —12.9 Hz;. The high-field doublet is assigned to the 2- and 6-axial protons as it shows a much larger H-D coupling than the low-field doublet without deuterium decoupling.
QH3 3 The room temperature spectrum shows an AA'BB'-system for the ring protons. Chemical shifts and coupling constants for this system were LpCH3 obtained by computer simulation and iteration, starting with the
para-meters derived from 2 and with estimated values for the other parapara-meters. The final values are: SA = 1.22 ppm (2-protons), 8 B = 1.42 ppm (3-pro-tons). JAB = JA'B' = 4.0 Hz, ^AB' = JAB = 8.1 Hz and JAA' = JBB' =
= - 1 3 . 0 Hz.
The spectrum at —120° is very complex. Analysis of the ABCD-system was impossible due to the relatively small differences in chemical shift, the extensive spin-spin coupling, and the reduced resolution of the spectrum at this temperature.
H 4 The spectrum of this compound shows a multiplet at 1.5-1.9 ppm from the equatorial protons and a multiplet at 0.7-1.2 ppm for the axial protons. The latter is partly obscured by the r-butyl peak (0.85 ppm). A spectrum was computed using the values obtained earlier^ and estimated values for Jta3^2ax and J^gg—iax- An iteration of this spectrum on the equatorial signals and the observable part of the axial multiplet, yielded the parameters for this five-spin system (Jiax~2ax = 11.6 ± 0.3 Hz and Jiea-iax = —13.3 Hz).
' B u - < D X 'Bu H
(cis + trans)
5 Two AB-systems are shown by the PMR spectrum. One of them (chemical shifts 0.87 and 1.78 ppm, coupling constant 3.1 Hz) was assigned to the /ra/!i-component and the other one (chemical shifts 1.19 and 1.43 ppm, coupling constant 5.8 Hz) to the c/.!-component of this product. This assignment was based on spectra of pure trans- and pure cw-1,4-di-/--buiylcyclohexane, which show the ring protons in a wide (0.8-1.9 ppm) and narrow (1.1-1.6 ppm) range, respectively.
/ \ 'Bu
H2
(cis* trans)
6 The spectrum of the /ra«5-component of this product forms an ABX--system. The AB-part (axial protons) is almost completely obscured by the peak of the /-butyl groups, but from the X-part all parameters of this system could be derived. In addition to the already known chemical shifts of Hj^j. and Haeg and the coupling constant Jiax-^eq (product 5), Sj,,^ was calculated to be 0.84 ppm. For Jiajmax and J^gq-^ax values of 11.7 ± 0.3 Hz and — 13.3 ± 0.3 Hz, respectively, were obtained.
The spectrum of the cw-component shows an ABC-system. Computer simulation starting with the parameters from product 5 gave a value of 10.0 ± 1.5 Hz for the coupling between the /rani-1-2-protons (82 = 1.30 ± ± 0.04 ppm) and a value of —13.0 ± 0.5 Hz for the geminal coupling constant at position 2. In this case no further refinement of the values could be obtained since the ''C-satellite of the /-butyl peak and isotopic impurities confuse the spectrum.
H2 H2
(cis * trans)
7 The spectrum of this product supports the assignment of the values of the parameters obtained from the products 5 and 6. The accurate deter-mination of the various 2-3 coupling constants, however, was not possible since the five-spin systems are lacking symmetry and the coupling constants involved are large in both the cis- and the /ro/ij-component. Computer simulation of the spectra of the cis- and the trans-component, however, using the values already known (compounds 5 and 6) and suitably chosen values for the other parameters (/^ea-sarc = Jia^ug = 3.6 Hz, J^eq-^eq =
= 3.0 Hz, and J^ax-sax = 13.1 Hz for the /ro«j-component; / „ ^ = J trans = 7.0 Hz"for thec(i-component;7jg„ = —13.0 Hz for both components) gave a fair fit with the experimental spectrum.
\ / 'Bu /Bu
(cis * trans)
8 Two AB-systems are shown by the PMR spectrum of this product. One of them (chemical shifts 0.92 and 1.66 ppm, coupling constant 3.0 Hz) was assigned to the c/i-component and the other one (chemical shifts 1.31 and 1.42 ppm, coupling constant 2.1 Hz) to the /röni-component. This assignment was based on the spectra of pure cis- and pure /ran.s-l,3-di-/--butylcyclohexane, which show the ring protons in a wide (0.5-1.9 ppm) and narrow (1.0-1.6 ppm) range, respectively.
'Bu 9 The spectrum of this compound shows an AjBX-system. Computer analysis, starting with parameters estimated from the spectrum and judici-ously assigned to the various protons, yielded the following parameters: Sloa; = Ssax = 0.97 ppm, 82^3 = 1-83 ppm, 8203. = 0.64 ppm, Jiax-2eq = = 2.8 Hz, Jia^iax = 11.7 Hz, and J^eq-^ax = -12.4 Hz.
10 For the c/.?-component of this product only the chemical shift of Hen3^ and the coupling constant /,„3_e(,a; are unknown. Spectra were com-puted for this five-spin system using the values for the other parameters, obtained from compounds 8 and 9, and varying the values of 8^^^ and Jiax-dax- The best fit with the experimental spectrum was obtained with a ' value of 0.87 ppm for S^ax and 3.0 Hz for Jiaj^sax- The spectrum of the /ranj-component could not be analyzed.
11 The spectrum of this compound could be analyzed roughly by a first-order treatment. A further refinement of the parameters was obtained by computer simulation and iteration. The final parameters were: ^lax = 0-97 ppm, 82e9 = l-'79 ppm, 82^^ = 0.57 ppm, Aa:t-2M = 2.7 Hz, Jiai^iax =11-8 Hz, and J^^^^ax = —12.3 Hz.
4.4 Results and discussion
A. THE INFLUENCE OF EQUATORIAL SUBSTITUENTS
Table II shows chemical shifts and coupling constants of cyclohexane (ref. 2 and 11), methylcyclohexane (ref. 2 and compound 1), /-butylcyclohexane (ref. 2 and com-pound 4), //•art.s-l,4-di-/-butylcycIohexane (products 5, 6, and 7), c/i-l,3-di-/-butyl-cyclohexane (products 8, 9, and 10), and m,m-l,3,5-tri-/-butylc/i-l,3-di-/-butyl-cyclohexane
(com-pound 11).
Mono-alky Icyclohexanes
We discussed the mono-alkylcyclohexanes in previous papers in this series^ but we have to reconsider the 1-2 coupling constants, since in the present work not only the values of Ji^^^ieq' but also of yi„-2<ix have been determined.
No change is observed in Jiax-ieq going from cyclohexane to methylcyclohexane, but J lax-lax is showu to dccreasc by 1.6 Hz. If we interpret this decrease in terms of a change of the corresponding torsion angle, the decrease would be at least 15° (the
Karplus curve is almost flat around (p = 180°). This seems very unlikely. Moreover, if indeed the torsion angle were responsible for this decrease of J\ax-2ax' ^ further change would be reasonable for /-butylcyclohexane. No difference however is observ-ed. We therefore have to conclude that the second important factor, the nature and relative position of the substituent, is responsible for this decrease. This trend is well confirmed by recent theoretical calculations by Pachler^^ on vicinal coupling con-stants of monosubstituted ethanes. He found that the substituent effect is strongly angle-dependent. An extrapolation of his results to the introduction of a methyl group in cyclohexane would lead to an increase of Jlax-ieq by 0.1-0.2 Hz and a decrease of •flax-lax by 0.7 Hz. The observed decrease of J^ax-iax being 1.6 Hz, Pachler's data would lead to an increase of Jiax-ieq with 0.2-0.4 Hz. The absence of this increase could be interpreted as meaning that the influence of the electronegativity change on this coupling constant is compensated by a decrease due to an increase in torsion angle. This would lead to the conclusion that the ring is already somewhat puckered at position 1 in methylcyclohexane. H2 / " \ 'Bu r./ H2 'Bu ^ (cis + trans) 'Bu 'Bu
