THE SYNTHESIS AND REACTIVITY OF
3,7 1,3 TETRACYCLO ^3.3.1.1 .0 J DECANE
by
EDWARD JOHN THORPE
B.Sc. (Hons.) University of British Columbia, 1965
M.Sc. University of British Columbia, I968
A THESIS SUBMITTED IN PARTIAL FULFILMENT OF'
THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
in the Department
of
Chemistry
We accept this thesis as conforming to the required standard
THE UNIVERSITY OF BRITISH COLUMBIA
August, 1975 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study.
I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the Head of my Department or by his representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission.
Department of
The University of British Columbia Vancouver 8. Canada
Date it, H-u^jf IVi I - ii -
ABSTRACT
Supervisor: Dr. R. E. Pincock
The structures and some properties of adamantane (lb), strained cyclopropanes (23), and certain small ring propeller• like molecules (28) are reviewed. The synthesis of a new type of compound containing a combination of such structures and properties is presented. This compound tetracyclo
more simply 1,3-dehydroadamantane
(DHA) contains a very strained cyclopropyl group within an adamantane skeleton and was produced by bonding two bridge• head (tertiary) carbons together across the normally extremely rigid structure of adamantane. (This new compound, DHA, is shown below.)
In the synthesis of DHA using alkali metal (or alloys) with 1,3-dibromoadamantane (37)> the reaction times and relative yields of adamantane and DHA were extremely variable. The former difficulty was resolved - iii -
by the addition of an initiator (usually t_-butyl alcohol), while the yields were increased and made consistent by substituting sodium naphthalide or n-butyl lithium - hexamethylphosphoramide for the alkali metals. DHA and adamantane were also isolated as the major products from the reaction of 1,3,5-tri- and 1,3,5,7-tetrabromoadamantane with alkali metals or alloys.
DHA is one of the few organic molecules which possesses a so-called inverted geometry about the internally bonded bridgehead (quaternary) carbons. Wiberg, Hiatt and 55
Burgmaier have defined an inverted carbon as one "in which all atoms joined to the bridgehead atoms (inverted carbons) lie in one hemisphere, (i.e. in one plane or on one side of a plane passing through the bridgehead atoms)."
The inversion of the DHA bridgehead carbons results in a highly strained bond and an unusually great reactivity for a formally saturated hydrocarbon. DHA reacts spontaneously with oxygen at room temperature to give a peroxy polymer Ad - 0 -f 0 - Ad - 0 OAd which explodes at o X ca. 1A-6 C. DHA also reacts rapidly with halogens, acids, and mercuric acetate to yield halides, esters and alcohols, respectively. Although the direct reaction of DHA with - iv -
alcohols is slow (more than Zl\ hr to complete), Lev/is
acid catalysts promoted rapid addition of both alcohols
(to give ethers) and benzene (to give phenylated adamantanes).
Adam's catalyst promoted the rapid (30 min) addition of
hydrogen to DHA in n-heptane solution to produce adamantane. o
In the solid phase DHA polymerized readily at ca. 160 C
to give a highly insoluble product, polyadamantane
Ad-(Ad) -Ad which possesses great thermal stability
(decomposition point ca. 500° C under nitrogen). In
n-octane solution under nitrogen the half life of DHA was
if,45 hr at 195 °C,
The reaction of DHA with halogens in ether gives
(3-halo-l-adamantanyl)-diethyl oxonium trihalide. The reaction of this unstable intermediate with nucleophiles, for example
H2O or NaCN, is discussed as a potential source of unsym- metrical 1,3-disubstituted adamantane derivatives.
1 - V -
TABLE OF CONTENTS
Page
INTRODUCTION 1
A. Adamantane 2
B. Cyclopropanes and Small Ring Propellanes 16
C. Adamantane Molecules containing Cyclopropyl Bonds 23
RESULTS 28
A. Preparation of Brominated Adamantanes 28
B. Preparation of 1,3-Dehydroadamantane 30
C. Structure of 1,3-Dehydroadamantane 32
D. Reactions of 1,3-Dehydroadamantane 33
DISCUSSION 46
A. Synthesis i+6 ,
B. Structure of 1,3-Dehydroadamantane 59
C. Reactions of 1,3-Dehydroadamantane 68
D. Conclusions 103
EXPERIMENTAL 105
A. Preparation of Brominated Adamantanes 109
B. Preparation of 1,3-Dehydroadamantane - Representative Reactions llif
C. Reactions of 1,3-Dehydroadamantane 129
BIBLIOGRAPHY 161 - vi -
LIST OF TABLES
Table Page
I Representative Syntheses of 1,3- 55 Dehydroadamantane
II Microanalytic Results for the Intermediate 75 Compound Formed from 1,3-Dehydroadamantane v/ith Bromine in Ether
III Substitution of (3-Bromo-l-adamantanyl)- 82 diethyloxonium tribromide with Nucleophiles
IV Substitution of (3-Bromo-l-adamantanyl)- 82, 141 diethyl oxonium tribromide in Solvent Mixtures
V Normalized 1,3-Dehydroadamantane Trace 160 Weights for Samples after Various Times at 195°C - vii -
LIST OF FIGURES
Figure Page
1. The NMR Spectrum of 1,3-Dehydroadamantane in Benzene at 100 Mcps 60
2. The NMR Spectrum of 3,7-Dimethy1-1,3- dehydroadamantane in Benzene at 100 Mcps 61 3. The NMR Spectrum of (3-Bromo-l-adaraantanyl)- diethyl oxonium tribromide in Acetone-d,- at 100 Mcps "D 77
k. The NMR'Spectrum of l-Bromo-3-ethoxyadaman- tane in CDCl^ at 100 Mcps 78
5. The NMR Spectrum of l-Bromo-3-hydroxy- adamantane in CDCl^ at 100 Mcps 81 - viii -
ACKNOWLEDGEMENTS
I would like to express my sincere gratitude to Dr. R. E. Pincock for his patient and continual help during the course of this v/ork.
I would also like to thank Dr. R. Stewart,
Dr. D. E. McGreer and Dr. E. Piers for their helpful suggestions and comments.
I dedicate this thesis to my long suffering wife, Bonnie, without whose encouragement and assistance
this thesis would not have been finished. INTRODUCTION
This thesis reports a study of the synthesis and reactions of the compound tetracyclo j~3.3.1.1^'^.O^'^ decane (la) or more simply 1,3-dehydroadaraantane (DHA).
This compound can be viewed both as a modified adamantane
compound and as a strained cyclopropane compound. Thus,
the introduction to this work is divided into three sections.
The first section describes adamantane, its synthesis and
properties. The second section briefly relates the
development of the theory of the cyclopropyl bond and the
alteration in the properties of this bond when other small
ring groups are fused with the cyclopropane molecule. The
final section reviews those adamantane derived compounds
which contain cyclopropyl groups and are therefore closely
related to 1,3-dehydroadamantane (DHA). - 2 -
A. Adamantane
Adaraantane is the common name for the roughly
2 3 7 spherical or globular molecule, tricyclo 3.3.1.3 ' decane (lb).
Diagram 1
Two dimensional representations of adamantane do not do justice to the high symmetry of this molecular structure.
The molecule possesses a tetrahedral symmetry identical with the bonding orbitals of a sp3 hybridized carbon atom. This symmetry can be verified by drawing imaginary planes through each of the four cyclohexane rings so that these planes pass through the tertiary carbon atoms to form an imaginary tetrahedron with each of the bridging or tertiary carbon atoms at a vertex.
Theoretically, an adamantane compound with four different bridgehead substitutents should be resolvable into optically active isomers. Firstly, Hamill and McKervey have synthesized the analogue or adamantalogue (2a) of lactic acid (2b).
They have shown that the bromination product (2a) does indeed possess a small but measurable increment of optical activity.- - 3 -
Diagram 2
The structure of the optically active adamantalogue
(2a) was confirmed by treatment with sodium hydroxide solution. The product (2c) was identical with a product obtained from an unrelated unambiguous synthesis. Finally,
Stetter, Bander and Neumann-^ have observed and studied a vicinal dichloro-allene (2a) type of optical isomerism in the following adamantalogue (2b).
a b
Diagram 3
Rearrangements enlarging or breaking the adamantane r skeleton have been reported with increasing frequency despite the generally acknowledged thermodynamic stability of this skeleton.7
F' - 4 -
By further pursuing the analogy between the tetra- hedrally hybridized carbon atom and adamantane, several groups have synthesized adamantalogues of simple aliphatic hydrocarbons. To date, the adamantalogues for ethane, methane and propane have been synthesized. The synthesis 8a of higher hydrocarbon adamantalogues remains under study.
Neither the high symmetry nor the related high thermodynamic stability' of adamantane was utilized in the early syntheses and studies of the compound. The yields of these syntheses were poor. Despite their low yields, these total syntheses were important because they were the only source of secondary and tertiary substituted adamantane derivatives. The importance of these synthetic routes did not diminish substantially after Stetter and V/ulf^ developed a method for progressively increased bridgehead substitution of adamantane. The symmetry of adamantane made dissimilar substitution difficult to achieve by the Stetter and Wulf approach.
Early efforts to synthesize adamantane were stimulated v/hen it was realized that the sole source of this interest• ing compound was controlled by a strong monopoly which released it only in minute amounts. Since its discovery in the petroleum from the Hodinin fields of Czechoslovakia, only very small amounts of the compound found their way out of Landa's laboratory.To correct this artificial - 5 -
scarcity many attempts were made to synthesize adamantane. 11 The first attempt on record is attributed to Meerwein (4).
R=C02Me CH20+CH2(C02CH3 )2
R Diagram k
Kleinfeller and Frercks.1 2 attempted two entirely different approaches to the problem both of which also failed (5).
N02C(CH2Cl)3 + | •
H
3(Et02C )CH2C
Diagram 5 - 6 -
Bottiger13 was the first to successfully synthesize the adamantane skeleton (6), however, adamantane itself was not realized. Again, the Meerwein ester was the key intermediate in this scheme.
Prelog and Seiwerth ^ were the first to synthesize the parent hydrocarbon (7). The overall yield from the
Prelog and Seiwerth y later were able to increase the overall yield to 1.5% by improving the decarboxylation steps (8). The Hunsdiecker pathway gave an 11% yield based on the diacid while the Hoffmann reaction gave a Zk% yield
from the same starting material. Stetter, Bander and Neumann - 7 -
have reported the best total synthesis via the Meerwein ester route (9). The work of Stetter, Bander and Neumann introduced a modification into the Prelog scheme which increased the overall yield of this scheme to 6.5%.
Diagram 9
More recently Landa and KamycekXD have reported improved
conditions for the synthesis of the Meerwein ester, the key
intermediate of almost all adamantane total syntheses. The
improved yield of 85% furthers the feasibility of the
existing total synthesis. 17 Stetter and co-workers also have developed an elegant total synthesis of 2-substituted adamantanes (10). Their
approach resembles the unsuccessful attempt of Kleinfeller 12 and Frercks. However, the final product could not be
Curran and Angier have developed a method to synthesize 1,2-disubstituted adamantanes. This type of compound was previously very difficult if not impossible to obtain. - 8 -
converted to adamantane. Despite this, the sequence provided an efficient synthesis of 2-substituted adamantanes which previously were available only from the synthetic schemes involving the Meerwein ester. This was also true for the majority of tertiary and higher polysubstituted adamantanes until adamantane became readily available.
The most elegant of all adamantane total syntheses were reported by Schleyer (11).^ This sequence depended on the adamantane structure having a very low internal
(strain) energy. The Lewis acid catalyzed isomerization of endo-tetrahydrodicyclopentadiene resulted in fair yields of adamantane in essentially two reactions, although the mechanism of the second reaction was comprised of many steps.
Diagram 11
The advent of this novel synthesis ended the virtual monopoly of Landa on the world supply of adamantane. - 9 -
Even before the general availability of the parent hydrocarbon, it was realized that the globular or roughly
spherical shape of the adamantane molecule gave it some 2
unusual physical properties such as high volatility and
dissolution in a surprisingly wide range of solvents. Much
later the globular shape of this skeleton was used advanta•
geously in studies of solvent participation during solvolytic
reactions.^ (Clearly, bimolecular nucleophilic substitu•
tion cannot occur at the bridgehead carbons (12a) and a
similar mechanism is seriously impeded at secondary carbon
by the 1,5-axial hydrogen atoms (12b).)
X
a b
Diagram 12
The globular structure also had a marked effect on the
reactivity and stability of adamantane and its derivatives.
Though substitution of adamantane occurred fairly readily,
these substitution reactions occurred primarily in inorganic
solvents under conditions which would destroy the structure - 10 -
of most organic compounds. For example, exposure of o most organic chemicals to 96% sulphuric acid at 70 C almost always resulted in the decomposition of these compounds into a tarry black mass, but Geluk and Schlatmann noted that adamantane was primarily oxidized to the ketone
(13) under these conditions.
a b
Diagram 13
Another example of the stability of the adamantane o structure was presented by Stetter and Wulf. In liquid bromine at room temperature, adamantane reacted fairly rapidly to give 1-bromo-adamantane (l/+a). Even under forcing conditions no further substitution took place unless Lewis acid catalysts were added. Addition of the suitable Lewis catalysts to the above reaction mixture resulted pre- dominently in production of di or tri bridgehead brominated compounds (lifb,c respectively). - 11 -
BBro— b,X=Br. Y=Z=H
, ALR V^X=Y=Br; Z=H ( 2.2°C ) ALU3 \a,A=Y=Z=Br (forcing conditions)
a Diagram Ik
The synthesis of the fully "bridgehead-substituted tetrabromo derivative (lifd) required high temperatures and pressures in addition to the presence of the strong Lewis acid catalyst, AlBr^.
Diagram 15
The above reactions demonstrated the unusual stability of the adamantane structure. This stability was a direct result of not only the essentially stainless structure but also the inflexibility of the adamantane skeleton. The skeletal rigidity of the ring structure of adamantane could be illustrated by the relation between adamantane (15a) and diamond (15b), a very hard and durable substance. Both the structural unit of diamond and the skeleton of adamantane shared the same structure. Models of this structure (15a), - 12 -
even if composed of flexible plastic, demonstrated a marked resistance to compression and torque. Thus, it is not surprising that the adamantane skeleton was assumed to be basically a very rigid structure.
Investigations in the following three areas have also supported the concept of a rigid adamantane skeleton. 22
Firstly, nmr studies have indicated that regardless of the nature and number of substituents, the skeleton is not distorted significantly since chemical shifts of protons in polysubstituted adamantanes are calculable with considerable accuracy by addition of the shifts caused by single sub• stituents. Unfortunately, the existence of many "W" relationships^'^ which have been implicated in long range coupling2^*3 apparently was responsible for obscuring the expected well-defined coupling constants in this rigid system.
In an explanation of this phenomenon Padwa et al. suggested that the "direct overlap of the small posterior lobes" was responsible.These long range coupling constant values which appear to vary inversely with distance have been invoked to explain the "washed-out" appearance of many nmr spectra in cyclic systems including that of adamantane, ' 4 22
Fort and Schleyer have also shown that the Karplus equation2^ agrees with the observed coupling constants in the adamantane system. They concluded that this experimental- theoretical correlation was obtained only because the usual - 13 -
variations in bond lengths, in substituent electronegatives and in other bond angles were virtually absent in adamantanes. 25
Secondly, simple 1,2- shifts which occur intramolecularly in most other compounds have been shown to occur only through a intermolecular route in adamantane because of 2fi 26a the structural rigidity of this skeleton. Schleyer e_t al. concluded that unfavourable and fixed dihedral angles were responsible for the alteration of the 1,2-hydride shift from the normal intramolecular to an unusual intermolecular mechanism.
HC02H and / or OH 96% H2SOz, 28°C
a Diagram 16
This group observed that dilution decreased the rate of an apparent 1,2-hydride shift during a Koch-Haaf reaction
(16). At low dilutions such as 0.004 M and less in sub• strate no rearrangement product (16c) was observed. Conversely, at higher concentrations such as 0.21 M and greater in substrate, only the rearrangement product was observed (16c).
A parallel result was obtained for the equilibration of
2-hydroxyadamantane (13b) to 1-hydroxyadamantane (13a).
Majerski, Schleyer and Wolf also showed that an apparent 1,2-methyl shift involved skeletal rearrangement (17). - 14 -
Diagram 17
The reason for these changes of mechanism must be that the dihedral angle between the secondary hydrogen atoms and the p-orbital of the tertiary carbonium ion in adamantane was fixed at 60° (18a) because of the skeletal rigidity.
c c a b Diagram 18 o
Furthermore, an even larger dihedral angle (90 ) existed between a secondary carbonium ion and an adjacent hydrogen atom (18b) than in the above situation (18a). It is well known that 1,2-shifts occurred most easily when this o dihedral angle was 0 , an angle nearly impossible to attain in the adamantane system.
Finally, the unfavourable and fixed secondary- tertiary dihedral angles in the rigid adamantane skeleton not only prevented 1,2-shifts but also the formation of - 15 -
27 double bonds. Recent syntheses of bicyclo >.3.l] non-l-ene (19a) by two groups encouraged further attempts 29 to synthesize adamantene (19b). 7 Evidence for the apparent synthesis of this compound was disclosed very recently by several laboratories. As expected, the compound was not stable even at very low temperatures.
Diagram 19
10 ^1 ^2
Several groups '-^'^ observed indications of possible interaction between the bridgehead carbon atoms of adamantane compounds. A positive internal energy for adamantane might be interpreted to result from internal crowding in addition 33 to external H-H interaction. Originally it was assumed^ that adamantane had a zero energy for two reasons. Firstly, a growing number of C]_QH16 isomers of adamantane were converted 5 to adamantane under conditions of thermodynamic equilibrium.^
Secondly, the ideal sp-^ geometry of carbon atoms and ideal dihedral angle of H-C-C-H bonds were present in this skeleton. 35
However, recent studies by Schleyer, Williams, and Blanchard^ have attributed a small but significant strain to adaman• tane (6.48 Kcal/mole). The cause'of this strain was not delineated; however, this disclosure appeared to collaborate with other observations to possibly indicate some form of - 16 - interaction between the four tertiary carbon atoms.
The most striking example of tertiary non-bonding
lobe interaction was reported by Fort and SchleyerThe
nuclear magnetic resonance (nmr) spectrum of the 1-
adamantanyl carbonium ion revealed the bridgehead protons
to be displaced further downfield than the adjacent
methylene protons (20). Carbon-carbon hyperconjugation did
not contribute significantly to this result,so "backside"
interaction was hypothesized between the empty p-orbital and
the non-bonding lobes of the tertiary hydrogen atoms.^
relative areas of the x S nmr peaks
a z 5.50 4.50
1 4.58 5.42 H Y 2 7.33 2.77 8 Diagram 20
B. Cyclopropanes and Small Ring Propellanes*
The major problem of this thesis was the synthesis of
a compound with a cyclopropyl moiety within an adamantane
skeleton. The cage-like adamantane skeleton would be
Propellane is the simple name given to tricyclic compounds in which three rings share a bond in common.3o For example, jl.m.n| propellane would have the general formula shown be-lo w (21).
Diagram 21 - 17 -
severely distorted by the formation of the 1,3-cyclopropyl moiety. Thus certain properties of the title compound,
DHA, would be expected to be similar to those of strained cyclopropanes. Furthermore, the formation of the internal bond might result in an inverted configuration about the participating carbon atoms. This second section of the introduction presents three types of structures, each type more complex than the preceding one. The first subsection reviews simple cyclopropane with special emphasis on its structure and bonding. The second subsection relates the effects of increased strain on the reactivity and bonding of the cyclopropyl ring. The final subsection introduces small ring propellane compounds which may possess inverted bonds.
Cyclopropane
The cyclopropane molecule fascinated early chemists not
only because of its Bayer strain and olefin-like properties but also because its existence was a strong challenge to
the theories of chemical bonding of that time. During
the 1940's two opposing models were proposed for cyclopropan
Walsbr' (22a) supported the dative (sp ) olefin-methylene
complex model while Robinson3^ (22b) supported the •z tetrahedral hybridization (sp ) model in which the valence
angles were distorted because this model best fit the •50 experimental data. ' - 18 -
H —• C—?v~Cv
Diagram 22
Coulson and Moffitt^0 resolved these untenable views by reasoning that carbon atoms which do not possess tetra- hedral valence angles could not possess tetrahedral hybridization. Their calculations based on this reason- o ing gave a value of 116 for the H - C - H angle which agreed well with experimental observations.^ They further reasoned that strained bonds should be less stable than unstrained bonds and should thus have weaker force constants and be longer than unstrained bonds. Saksena^2 and Skinner^ obtained experimental force constants for c-c bond stretching*1"2 and thermochemical^ values respectively, which agreed with the predictions of
Coulson and Moffitt.^ However, Bastiansen and Hassel^"*" - 19 -
showed by electron diffraction the c-c bond length of 0 cyclopropane (1.54 A) was almost identical with that of ethane (1.55 A). Coulson and HoffittZf0b,^Zf reconciled these apparent contradictions by proposing a bent or
"banana" bond model for cyclopropane. By separating the concepts of bond length and internuclear distance, this model permitted a bond longer than 1.54 A while the inter• nuclear distance may be less than this value. 45
From this model, Ingraham^"^ calculated the hybridization of the cyclopropane carbon bonds. The annular bonds were
found to be sp4"* while the external bonds evaluated to 2 2R ^5 2 be sp . Current theory attributed sp-^ and sp hybridization respectively to these bonds.^ The annular bonds were thought to be spread between 104° and 106 (23).^
104-6" N
Diagram 23
The large p component in the cyclopropyl bonding
orbitals helped to explain the long observed similarities
between cyclopropanes and ordinary unsaturated groups, for
example, electrophilic addition, and catalytic reduction.4'
The partial transmission of electronic effects through - 20 -
cyclopropyl groups 7 and the effectiveness of the terminal cyclopropyl group in extending the conjugation of an 50 unsaturated group also have been demonstrated by nmr, ultraviolet-^ and Raman spectroscopy.^ Furthermore, nmr spectroscopy indicated that the cyclopropane ring can support a ring current as indicated by a 0.5 ppni shielding of the ring protons and the converse for protons oriented 52 over the face of the ring.
Strained Cyclopropanes
The strain in a selected bond of cyclopropane can be increased by making it part of an adjoined strained ring.
This sharing of a common bond forces further deviations of bonding carbon orbitals from tetrahedral hybridization angles
thus further altering the proportion of s and p-orbital
mixing in the hybrids of the shared carbon atoms. These
alterations in hybridization have been correlated in a
general way to the reactivity of edge fused or bridging 53 bonds.^
Studies have shown that decreases in ring size of
^n.l.cTj bicyclanes (24) result in an increase of the
internal bond reactivity.
Diagram 24 - 21 -
This reactivity has been used rather loosely to compare the strain inherent in the bridging bonds of these com• pounds with the bridging bonds of other compounds (25).
Diagram 25
Small Ring Propellanes
A propellane has been defined previously as a compound in which three rings are fused to a common or internal bond (26). As these rings are reduced in size, the external
Diagram 26 bonds of the bridgehead carbon atoms must deviate from the ideal sp^ hybridization angle (109° 28 ) (27a) toward sp2 hybridization (120°) (27b) and possibly beyond to an inverted hybridization (27c,d). - 22 -
-Ch•C
V b'
Diagram 27
Wiberg, Hiatt and Burgmaier>y have defined an inverted carbon atom as one "...in which all atoms joined to the bridgehead atoms lie in one hemisphere (ie. in one plane or on one side of a plane passing through the bridgehead atoms)." Thus, the last two carbons shown above (27c,d) may be clearly classified as inverted by this definition.
Three hydrocarbons which might possibly possess inverted carbon atoms have been synthesized and studied 56a
(28a,b,c). Unlike the first compound (28a) shown below, the internal bond of the second compound (28b)^^31 did not show an enhanced reactivity compared with bicyclopentane
(25).^" The most recently synthesized compound 3«3«1
5J 7 — — propellane (28c), ' showed a reactivity somewhere between these two extremes (28a,b) but less than that of bicyclo• pentane .
.OAc
Diagram 28 - 23 -
Surprisingly, oxygen did react at room temperature or lower with [3.2.1] propellane (28a)-^a but did not react 56c with its epoxide analogue (28d).y Such sensitivity to oxygen by a formally saturated hydrocarbon is an unusual occurrence. This sensitivity was attributed to the inverted geometry of the ^3«2.lj propellane bridgehead carbon atoms, but an inverted geometry appeared not to be the only requirement. Additionally, the recently synthesized
^2.2.2J propellane (29)^ also believed to possess inverted bridgehead carbon atoms, did not react with 58a oxygen. Thus, the presence of a cyclopropyl group appears to be essential for the reaction of oxygen with an inverted carbon of a strained propellane.
R = CON(CH3)258a
= H58b,c
R Diagram 29
C. Adamantane Molecules Containing Cyclopropyl Bonds
Other superstructures are available for extending the study of strained hydrocarbon atoms and their bonds. Of
these, the adamantane molecule has held the most interest. - 24 -
As described above (P-14) neither the structure nor the rigidity of the system favoured the introduction of a double bond. Nordlander, Jindal, and Kitko 7 attempted to homoenolize 2-adamantanone with little success (30).
Diagram 30
Baldwin and Fogelsong^0 synthesized the first dehydroadamantane compound. They sought to establish the existence of a degenerate carbonium ion intermediate (31c) by studying the solvolysis of a labeled tosylate derivative (31b).
Diagram 31
Next, Udding, Strating and Wynberg reported the synthesis of 2,4-dehydroadamantane (32a) in high yield. This synthesis elegantly utilized the high symmetry of adamantane to a - 25 - singular advantage. (The substituted secondary carbon atom is equidistant from each of its four homoadjacent methylene groups*.)
Diagram 32
This DHA isomer (32a) responded rapidly to electro- philes by undergoing an aadditio< n reaction at the newly 62 formed dehydro-bond (33)
CH, X2/AgClO^
CH3CN
Diagram 33
Only two of the possible three isomers were produced in all of the reported addition reactions, ie. the diaxial
(2a,4a) addition product v/as conspicuously absent*. It was found that the more stable equatorial-equatorial isomer
(2e,4e) usually predominated over the less stable addition isomer (2a,4e). More recently Geluk and de Boer^3 have disclosed the synthesis of a doubledehydroadamantane compound, 1,2,4,5-didehydroadamantane (34a). Curiouslyj when this compound is treated with hydrogen under catalytic conditions, one of the original adamantane carbon-carbon bonds undergoes hydrogenolysis (34t>).
Recently, Lenoir and Schleyer ^ and Cuddy, Grant and McKerveyo4h have reported the synthesis of a 2a,4a - disbustituted adamantane compound by a roundabout route. - 26 -
Diagram 34
The syntheses of 2,4-dehydroadamantane compounds
(31a,32a)^0,^'J" supra vide, presented a new question. Could the rigid adamantane skeleton be distorted further? It became interesting to introduce a new dehydro bond between a pair of tertiary carbon atoms of the adamantane skeleton.
Diagram 35
The new internal bonding carbon atoms of DHA (35) might possibly possess an unusual if not unique geometry similar to that described for small rings. This geometry - 27-
would indicate, according to the theory of Coulson and
Moffitt,^ the occurrence of an unusual hybridization in
the carbon atoms forming the internal bond. Evidence for
an unusual type of hybridization might appear in the form of
a high or unusual reactivity. To test these hypotheses, the
synthesis of tetracyclo j~3.3.1.1"^,'^.0"I",^j decane (35) was
undertaken.
The purpose of this research work was to synthesize
the new compound tetracyclo decane (DHA)
and to investigate its properties. When this work was initiated the synthesis of the three small ring propellane
compounds described in the second section of the introduction
(28a,b,d) had not yet been reported. - 28 -
RESULTS
The first of the ensuing sections presents the prepara• tion of various brominated adamantane compounds. The second section reviews the efforts to optimize the yield of DHA by treating 1,3-dibromoadamantane with a variety of reagents under various conditions. The reactions of 1,3,5-tribromo- adamantane and l,3,5>7-tetrabromoadamantane under similar conditions are given. The final section reviews the results of the treatment of DHA with various reagents and its thermal stability. In each section the characterization or identifi• cation of the reaction products is cited briefly.
A. Preparation of Brominated Adamantanes
Commercial adamantane (36a) was treated with bromine and aluminum tribromide by a modified procedure of Stetter and q
V/ulf. This process gave a high yield of analytically pure
1,3-dibromoadamantane (36b) (92%). (Further refinement of this modified procedure by Scott^ showed that a five-fold reduction in the catalyst could be made without decreasing the high yields of the dibromide.)
The reported compound appeared to have two different melting points (108-109°C, 112-113°C),^ both these extremes were observed on various occasions; however melting points with ranges between the two extremes were most common. For b; X=Br, Y=Z=H
c, X= Y=Br, Z=H
d X=Y=Z=Br
Diagram 36 example, the melting point for an anlytically pure sample of 1,3-dibromoadamantane resulting from the modified reaction o was found to be between those reported (mp, 108-111 C).
The compound 1,3,5-tribromoadamantane (36c) was prepared by the previously described modified procedure of Stetter and Wulf followed by stirring at room temperature until the
1,3-dibromoadaraantane was converted entirely to the desired tribromo derivative (3 days). Due to the formation of by• products, a reduced yield of the analytically pure tribromide
(73%) v/as obtained. None of the many by-products was identi• fiable, and 1,3,5,7-tetrabromoadamantane was shown to be absent by glpc superposition.
The synthesis of 1,3,5,7-tetrabromoadamantane (36d) was performed by another modified Stetter and Wulf procedure (supra vide) so that the transformation could occur directly from 65 commercial adamantane as the starting material. ^ Using this procedure, the overall yield of 1,3,5,7-tetrabromoadamantane Q obtained by Stetter and Wulf7 was realized but only one reaction vessel was used.
The substitution of the tertiary hydrogens of adamantane under Lewis acid catalyzed conditions has been well established; however, in addition, each of the above structures was confirmed by nmr spectroscopy. - 30 -
B. Preparation of 1,3-Dehydroadamantane
X= Br, Na-K
a, X=Br c b, X = I Diagram 37
The title compound of this thesis, DHA (37c) was first synthesized in n-heptane by the action of liquid potassium metal on 1,3-dibromoadamantane (37a). The presence of a very reactive intermediate (37c) in the product solution could be detected by rapid titration with iodine or bromine to give colorless solutions of 1,3-di-iodo and 1,3-dibromo• adamantane (37a,b), respectively. The reduction by-product, adamantane (37d), was not affected by titration of the reaction solution with halogen.
The conditions of the above reaction were modified when a liquid sodium-potassium alloy was introduced as the debrominating agent. The use of this alloy allowed the debroraination to occur at room temperature, therefore more volatile solvents could be used. The change of reaction solvent from n-heptane to ether facilitated the isolation of the volatile products, adamantane and DHA, by a vacuum distillation-sublimation procedure. The initial reactions using the suspended alkali metals as the debrominating agent had variable induction and reaction
times.* Therefore, an alcohol initiator (usually t_-butyl
alcohol) was added. The addition of the initiator eliminated
both of the above inconsistencies in the above debromination
reaction.
The degree of reduction versus internal bond formation
was another important variable which was beyond control.
Furthermore, the intermolecular or V/urtz coupling product
l,l'-biadamantane was identified many times in varying
amounts by glpc comparison. (Authentic 1,1'-biadamantane
was prepared as a glpc reference material from the 1-bromo-
adamantane by the Wurtz coupling method.) In many reactions
the above factors were responsible for reduced yields of
DHA. The synthesis of DHA by sodium naphthalide or n-butyl
lithium-hexamethylphosphoramide^ in ether improved the
yield of DHA (ca. 72%), but did not allow the isolation
of DHA and adamantane by a specially developed distillation-
sublimation procedure.
X a,X=Y=Br b c. X= Br. Y=H Diagram 38
A chronological survey of typical DHA syntheses with their various modifications to improve yields is presented in the DISCUSSION section (TABLE I). - 32 -
Treatment of 1,3,5,7-tetrabromoadamantane (33a) with sodium-potassium alloy in either heptane or ether did not give any detectable amounts of 1,3,5,7-didehydroadamantane
("Double DHA") (38b). The major products were adamantane and DHA. Similarly, treatment of 1,3,5-tribromoadamantane in n-heptane or in ether with sodium potassium alloy also gave a mixture of adamantane and DHA as the major products.
Treatment of an aliquot of 1,3,5,7-tetrabromoadamantane-
Na/K alloy product solution with iodine followed by glpc did not indicate that 1,3,5,7-tetraiodoadamantane was a product; thus, Double DHA (38b) was not likely present in the solution.
C. Structure of 1,^-Dehydroadamantane
b
Diagram 39
The new compound was isolated as an adamantane-DHA mixture (39a,b) (ca. if00 mg) by a vacuum distillation-
sublimation procedure. DHA (39b) also was isolated on a
small scale (ca. 10 mg) by preparative glpc using a 10 ft
column packed with fresh base washed Chromosorb "W"
supported Carbowax 20M (10%) at 110°C. DHA could be stored - 33 -
indefinitely as a solid or in solution if oxygen was absent from the sealed container.
The nmr spectrum of DHA in benzene showed an unusually lov; resonance value, 1.66 S , for the cyclopropyl protons.
The protons of carbons adjacent to those involved in the new internal bond resonated at 1.15 and 1.91 & . These assignments were supported by double resonance nmr studies Op of DHA and by the nmr spectrum of 5,7-dimethyl-DHA.
The sensitivity of DHA to oxygen prevented accurate microanalysis of samples; however DHA was converted to a polymer with the same empirical formula by heating an isolated sample of DHA in a sealed tube at approximately o
160 C. Microanalytic results for this modified DHA sample were consistent with the empirical formula C-j_o^l4* Further• more, this empirical formula for DHA was confirmed by high resolution mass spectroscopy of a DHA specimen. An m/e+ of
134.1086 i 0.001 was observed for this specimen and was con•
sistent with the value calculated for the empirical formula C10H14#
D. Reactions of 1,3-Dehydroadamantane R=0H,H, or solvent. x= 1,2,3,4...
Diagram 40 - 34 -
Treatment of DHA in n-heptane with oxygen gave a white waxy polymeric precipitate (40) (46%) which did not melt o but exploded on heating (ep c_a. 146 C). Glpc of the filtered supernatant liquid indicated many minor by-products were present. The foremost of these was identified as
1,3-dihydroxyadamantane (diol) by superposition with authentic material.* When the polymer was treated with lithium aluminum hydride, diol (50%) was identified as the major product in the above manner.* Furthermore, an isolated, recrystalized sample of the major polymer reduc• tion product had nmr and infrared spectra identical to those of authentic diol.
Treatment of DHA in n-heptane with bromine at room temperature gave 1,3-dibromoadamantane (41a, X = Br) in high yield. (Treatment with iodine gave the corresponding di-iodo product (41b, X = I).) Since the reaction proceeded very rapidly, the reagent could be used as a self-indicator when added in a titrimetric fashion. No noticeable decrease of reaction rate was observed when DHA o was titrated with bromine at -75 C. The. low solubility of 1,3-dibromoadamantane at this temperature was useful for isolating the reaction product in high yield by suction o filtration. The bromination of DHA in ether at -75 C resulted in the instantaneous formation of a floculent lemon-yellow precipitate in a very high yield. * Authentic diol was prepared from 1,3-dibromoadamantane by the method of Stetter and Wulf.9 Instability above -25 C and associated technical diffi• culties prevented the accurate microanalysis of the above compound (42a). The quantity of molecular bromine released during the thermal reaction of the precipitate was determined by ultraviolet (UV) spectroscopy to be 0.905 moles for each initial mole of DHA. HBr fumes also were detected
(moist blue lithmus turned red). The major thermal displace• ment product from the lemon-yellow precipitate suspended in ether was shown to be l-bromo-3-ethoxyadamantane (42b) by nmr spectroscopy. This study revealed the presence of the ethoxy methylene group integrating for 2 protons at 3.45 £ in the nmr spectrum and the ethoxy methyl group at 1.03 <£ . '
The relationship between the two resonances was confirmed by their identical coupling constants. The elemental analysis showed the presence of one atom of bromine in the molecule.
The structure of this compound was confirmed as l-bromo-3- ethoxyadamantane by acid cleavage of the ether to give 1,3- dibromoadamantane in excellent yield (74.8%). - 36 -
The low temperature nmr of the lemon-yellow intermediate
(43) in acetone-dg showed the presence of a quartet integratin for four protons at 5.19 £ and a resolved triplet superimposed on an unresolved multiplet integrating for 6 and 2 protons respectively at 1.71 C? • The quartet at 5.19 £ and triplet at 1.71 ^ had identical coupling constants. The magnitude of the downfield shift of the quartet suggested that the ethoxy methylene and methyl group was respectively OC and
y3 to a positively charged atom, most probably oxygen. This 22 result was consistent with the nmr spectrum expected for the compound (3-bromo-l-adamantanyl)-diethyl oxonium
tribromide shown below (43). gr~
Diagram 43
Similar and greater chemical shifts have been reported for secondary^3, and primary^*3 alkyl oxonium ion protons respectively, compared to the chemical shifts found for the protons of the ethoxy group of the oxonium compound (43).
The oxonium salt (42a) reacted in various solvent mixtures when warmed to room temperature. Unlike the reaction in diethyl ether where the bromo-ethoxy compound exceeded - 37 -
the dibromo compound (42c) by approximately 2:1 (67:33%), in 95% ethanol with K^CO-^ l-bromo-3-ethoxyadamantane (42b) was the primary product (93%). In acetone solutions the
oxonium salt (42a) reacted at -75°C in the presence of
sodium cyanide or iodide to give quantitative yields of the
bromo-ethoxy product (42b). When a solution of the oxonium
salt (42a) was allowed to reach room temperature, the 3-
bromo-l-adamantanyl moiety showed only a modest tendency
(33%) to be displaced by the anion of this salt, Br^~.
However, other strong nucleophiles, for example, PL^O (10%),
HOAc (0.7%), and H^SO^ (0.4%) in aqueous (ca. 10%) acetone
solutions of the salt were more successful (43, 53 and 61%,
respectively) yielding the bromo hydroxy compound (44a).
The quantitative formation of l-bromo-3-hydroxy-
adamantane was demonstrated when DHA was brominated in
aqueous acetone at room temperature (44).
0 b CH2
Diagram 44 - 38 -
The structure of this compound (44a) was verified by elemental analysis by infrared and by nmr spectroscopy and finally confirmed by a rapid base catalyzed rearrange• ment to 3-keto-7-methylenebicyclo jj^'-^'lj nonane (44b).
Using two different columns, an enhancement of the glpc
trace was observed after enrichment of the reaction
solution with the authentic compound. A minor compound resulting from the thermal displacement of the 3-bromo-l- adamantanyl moiety from the oxonium salt (42a) in acetone -
HOAc (25%) was tentatively identified using two different
glpc columns as l-acetoxy-3-bromoadamantane (45) by
comparison with the authentic material.
Diagram 45
Authentic l-acetoxy-3-bromoadamantane was prepared
by treatment of l-bromo-3-hydroxyadamantane with
concentrated sulfuric acid (ca. 0.05 ml) and acetic
anhydride (1 ml) overnight at room temperature. Puri•
fication by column chromatography gave an oil (49%)
from a specially selected middle fraction. Glpc, using two - 39 -
different columns, showed only one compound was present; the structure was confirmed by nmr and infrared spectroscopy.
Diagram 46
By iodinating DHA in ether at -75"C, a rusty-brown floculent precipitate (46a) was formed in a fashion parallel to that described in the bromination reaction (42). An acetone solution of this intermediate oxonium salt was o treated with a suspension of sodium cyanide at -75 C. This displacement reaction gave a high yield of a new compound identified as l-ethoxy-3-iodoadamantane (46b) by its infrared and nmr spectra as v/ell as by elemental analysis. The infrared spectrum possessed a distribution of absorptions very similar to that found for l-bromo-3-ethoxyadamantane.
The nmr spectrum displayed the ethoxy methylene resonance at 3.47 & and the methyl resonance at 1.06 £ . Their relationship was established by their identical coupling constants. The other resonances of the spectrum were in 22 accord with the calculated values. - 40 -
Diagram 47
Sulfuric acid catalyzed hydration of DHA gave a high yield of a compound (90 +_ 5%) identified as 1-hydroxy• adamantane by glpc comparison with the authentic product
(47)• No compounds corresponding to the ring opening of one of the exterior cyclopropyl bonds were observed; however, one unidentified by-product (ca. 5%) was observed. This could have represented the addition product of the 1- adamantyl carbonium ion to the tetrahydrofuran cosolvent.
The treatment of DHA with dilute HOAc in a hydrocarbon solvent at room temperature resulted in rapid formation of a single compound which was shown to be identical with authentic 1-acetoxyadamantane (48a).
a,R= OAc
b, R=0PNB
Diagram 48 - 41 -
\
The fairly strong organic acid, para-nitrobenzoic acid
(pK 3.41) reacted surprisingly slowly (6 hr) with DHA in benzene to give (l-adamantyl)-para-nitrobenzoate (48b) (82%).
The reaction product was identified by the following method. First, enrichment of the reaction solution with authentic (l-adamantyl)-para-nitrobenzoate caused an enhancement of the glpc trace. Second, the compound was isolated and the infrared and nmr spectra of the reaction product were found to be identical with those reported.
a Diagram 49
Treatment of DHA dissolved in tetrahydrofuran with an aqueous mercuric acetate solution followed by the rapid addition of 3 N sodium hydroxide and 1 N sodium borohydride aqueous solutions (49) gave 1-hydroxyadamantane (49a)
(47.7%) as the major product, 1,3-dihydroxyadamantane
(ca. 9%) and an unidentified by-product (ca. 18%). These values were determined using authentic 1-hydroxyadamantane as an analytical glpc standard. The identity of these two hydroxy compounds was determined by glpc trace enrichment studies. The major product was isolated by column chromato• graphy. The infrared spectrum was identical with that of the authentic compound. - 42 -
OMe Me OH
a
Diagram 50
When DHA (50a) was dissolved in dry methanol, the addition of the alcohol took place slowly (ca. 24 hr). This addition was accelerated by borontrifluoride, so that the addition reaction took place almost instantaneously to give
1-methoxyadamantane (50b) in high yield. This compound had a characteristic methoxyl resonance at 3.12 £ which integrated for three protons. Only one other compound with a very small yield was observed by temperature programmed glpc.
The identity of 1-methoxyadamantane was confirmed by an infrared spectral comparison with that of the authentic sample. This authentic compound (69%) was prepared from a sodium hydride promoted reaction of 1-hydroxyadamantane with methyl iodide and purified by fractional distillation.
H2 / Pt02
a
Diagram 51 - 43 -
Catalytic hydrogenation of DHA (51a) in n-heptane was marked by a rapid uptake of hydrogen. The major product
(79.5%) was identified as adamantane (51b) using glpc trace superposition with authentic material as well as by the infrared spectrum of the six-fold recrystallized product.
The infrared spectrum of the product was the same as the infrared spectrum of the authentic compound. A glpc unresolvable mixture (16.9%) consisting of at least four minor products also were observed. The nmr spectrum of this mixture showed a very sharp doublet in the methyl region.
Diagram 52
The aluminum chloride catalyzed phenylation of DHA (52a) in benzene proceeded rapidly (10 min) to give 1-phenyladaman- tane (52b) (39.8%). Under these conditions, it was shown that an equilibration of 1-phenyladamantane occurred to give adamantane (ca. 5-10%) and a compound (ca. 15-20%) which - Mi- -
is identified as 1,3-diphenyladamantane (5-c) by glpc and nmr. A glpc record also showed a trace in the area expected for 1,3,5-triphenyladamantane (52d) (< 5%). The major product of the reaction was identified by enhance• ment of the glpc trace upon enriching the solution with authentic 1-phenyladamantane and by their identical infrared spectra.
Authentic 1-phenyladamantane (38%) was prepared by the treatment of 1-bromoadamantane with aluminum chloride in benzene solution.
Diagram 53
The polymerization of DHA in the solid phase was achieved by heating at 145° C overnight (53)« The volatile compounds (primarily adamantane) were sublimed out leaving a o white material with a decomposition point of ca. 450 C o in air, ca. 500 C under a nitrogen atmosphere.
Analysis showed a higher value for hydrogen than is normal (ie. 0.3%) but the discrepancy was explained by the recognition that the oligomer occurs as a distribution of medium and short chains. The calculated values for
C10L, , however, are for an infinite chain. - 45 -
Thermal stability of DHA was studied in purified n- o
octane at 195.3 i 0.2 C under oxygen free conditions. The initial concentration of DHA was 8.56 x 10" moles/litre.
The extent of decomposition in each sample was determined
by analytical glpc and normalized with respect to the
constant value of an unreactive internal standard. The values of the glpc traces so normalized gave excellent
first order plots.
Two products of the thermolysis reaction, adamantane
(54a) and biadamantane, were identified by analytical glpc
trace superposition with authentic materials on two different
columns. The unidentifed products probably resulted from a
reaction between a radical or diradical intermediate and a
solvent molecule to give a mixture of n-(octyl)-adamantane
(54b) isomers. A preliminary investigation of DHA thermolysis
in cumene agreed with the above results. In addition to a
new unidentified product and previously identified products,
the presence of a major amounts of dicumene was demonstrated
by glpc trace superposition with authentic material.
a -*2 b
Diagram 54 - 46 -
DISCUSSION
For the purpose of clarity this discussion is divided into four sections. The first section describes the synthesis of tetracyclo 3.3.1.13,7.01'5 decane (DHA).
i— —
The second section presents the evidence for the proposed structure of DHA. The third section investigates the reactions of the title compound.
A. Synthesis
The first direct introduction of a strained cyclopropyl bond into the adamantane skeleton was demonstrated by Udding, 61
Strating and Wynberg in their elegant synthesis of 2,4- dehydroadamantane (32a); however, this strained bond was established between two secondary carbon atoms. In DHA the proposed bond would connect two tertiary or bridgehead carbon atoms and in order to form this internal bond, the geometry about the bridgehead carbon atoms might be expected to be inverted. Therefore it must be concluded that the strain in the internal bond of DHA would be significantly greater than in the strained cyclopropyl bond of the 2,4- dehydroadamantane isomer v/here no inversion is required.
Because the strain in DHA would be much larger than in
2,4-dehydroadamantane, it was highly uncertain whether the - V7 -
internal bond of DHA could be formed at all from a suitable adamantane derivative and once formed whether the compound 67 would be sufficiently stable to be detected. The reports '
that an adamantane derivative (56a) had undergone a
Favorskii rearrangement (56) encouraged an attempt to insert
the internal bond into the adamantane skeleton since the
intermediate of this rearrangement (56b) was believed to
closely resemble DHA (56c).
a b c Diagram 56
One of the most readily available and suitable disub-
stituted adamantane derivatives was 1,3-dibromoadamantane (57).
This compound was synthesized recently in good yield by Stetter
and Wulf^ who used a boron tribromide catalyst in liquid
bromine. In liquid bromine aluminum tribromide was found
to be too reactive resulting in the predominence of 1,3,5-
tribromoadamantane. Since the boron trifluoride catalyst
method was found unreliable, other groups performed exten-
sive studies in this area. These studies, however, resulted
only in marginal improvements in the reproduction of this
reaction. This matter was resolved when consistently high - 43 -
yields of the dibromide were obtained by using aluminum tribromide in liquid bromine at 0°C. (Synthesis of tetra- bromine (57c) required extreme conditions.) a; X = Br,Y=Z=H b; X=Y=Br, Z=H c; X=Y=Z = Br
YJ Diagram 57
Warming this reaction mixture to room temperature or above o without first decomposing the catalyst at 0 C resulted in the synthesis of tribromide as reported by Stetter and Wulf9 (58).
Diagram 58
Dehalogenation reactions have been used in a large variety of halogen compounds to introduce strained bonds
(59). Wiberg^ has recently reviewed this reaction as a means for the synthesis of strained bonds in small rings.
Unfortunately, the mechanism of the dehalogenation reaction has not been established conclusively. Diagram 59 - 50 -
The reaction mechanism of the electrochemical dehalogena- 75 tion previously had been assigned a concerted mode;'-^ however, recent studies utilizing optically active compounds have been interpreted to favour a Y-halo carbanion inter- 77 mediate involved in a stepwise mechanism. These results were similar for the electrochemical as well as for the magnesium and sodium naphthalide dehalogenations. Notably, the results of these experiments depended on the free rotation of the reacting carbon atoms.
Another factor complicated the illucidation of the dehalogenation mechanism. This complication can be illustrated by the conclusions about dehalogenation by magnesium. The reaction between magnesium and a halogenated hydrocarbon results in the well known Grignard reagent. These compounds are represented cannonically with RX + Mg Mg X ^ *" R* "MgX , a 1 R- -MgX b Diagram 60 partial positive and negative charges respectively on the metal and carbon atom (60a); however, Dagonneau, Metzer 78 and Vialle have shown hemolytic cleavage can also occur (60b). This group has used this homolytic reaction to synthesize bicyclobutane. - 51 -
It is also known that diatomic halogen, oxygen, and
heavy metals promote this homolytic fission of Grignard
reagents (61). 79 Br. eg« M 0 PX
ox R Mg Br M * R-R • MgBr,
Diagram 61
Therefore it appears that the mechanism for the described
dehalogenation reactions (59) has yet to be established
conclusively, especially in the case of constrained,
ideally oriented molecules such as 1,3-dibromoadamantane.
+
—'n
n* 4,5,6,
Diagram 62
The treatment of 1,3-dibromoadamantane with magnesium
catalyzed by iodine appeared to yield only adamantane and
a white insoluble solid with a melting point in excess of o
350 C and an empirical formula of ^Q^lZf* ^he virtual
absence of DHA from this reaction was shown after synthesis
of DHA with sodium and potassium reagents to be due to the - 52 -
contamination of the glpc column by acids. Much later the reaction was repeated with a ten-fold decrease in sub• strate concentration to minimize polymer formation. At
50% completion, the compound thought to be DHA was shown
to be present by analytic glpc using a fresh base-washed
Carbowax column. Unfortunately, the concentration of this
product was less than that of the difficult to separate reduction by-product, adamantane. For this reason,
investigation of magnesium as a reagent for debromination
was discontinued in favour of molten sodium or potassium.
Treatment of the dibromide with these alkali metals gave
a much better yield of the desired compound and a greatly
reduced yield of adamantane (63).
Diagram 63
The reaction of molten sodium with 1,3-dibromo•
adamantane in heptane proceeded over a few hours resulting
in the loss of dibromide and the appearance of two new
peaks at low retention time in the glpc trace. One of - 53 -
these peaks was identified as adamantane. The other peak represented a very reactive compoundwhich was sensitive to acids, halogens and air.* The products of these reactions suggested that this new highly sensitive compound was indeed the desired title compound, tetracyclo
J3,3.1.15,7,01»5 decane or DHA (64a).80a For example, titration of the dehalogenation reaction solution with either bromine or iodine solutions resulted in compounds identified as 1,3-dibromoadamantane and 1,3-di-iodo- adamantane respectively (64).^
X = Br,I.
Diagram 64
Surprisingly, the new compound, DHA had fair thermal stability. It was isolated in small quantities by o preparative glpc at 110 C while the collector and detector manifolds were held in excess of 200 C.uuc*
These reactions will be detailed in the third section of the DISCUSSION.• - 54 -
The synthesis of DHA was performed many times
(TABLE I). The duration and yield of the alkali metal(s) debromination reaction was found to vary widely without any apparent reasons. At times reduction predominated giving large amounts of adamantane. At other times a very turbid solution resulted, presumably due to polymer formation. (The presence of l,l'-biadamantane was demon• strated in several of these solutions and sublimation residues by analytical glpc comparison with authentic material.) At still other times induction periods of up to several hours were observed before production of DHA commenced. During this period either no noticeable reaction or a very slow one occurred. The induction phenomenon was especially noted when the reaction solvent was changed from n-heptane to ether to allow sublimative isolation of the volatile reaction products. Attempts to control this erratic behaviour suggested that traces of moisture might have a catalytic effect on the reaction.
Moisture most likely reacted with the metal or alloy to remove the surface film but this was not established conclusively. A search for a less reactive initiator finally ended in the selection of t.-butanol as the most effective additive. Its slow reaction with the alloy required the addition of only several drops at the start of the reaction. Experi• Substrate Reagent Solvent Lag Initiator Temp. Time Yield 0/ /o mental 34 x 10-3M (g) (50 ml) (min). (ml) °C (min) ADAa DHA Sublimate sec. (t-BuOH) weight (g)
b B.4.(a) DBA K n-hep- 5-10 YES 100 35 0.3 59.2 __ (2.5) tane (0.05 ml) (b) DBA Na/K n-hep- 25 YES 100 43 4.8 50 (0.76) tane (0.05) (c) • DBA Na/K ether — NO 23 60 25.5 59 (0.392) (0.74) (60) (d) DBA Na/K ether 30 YES 23 55 16.7 60.5 (0.352) (0.74) (30 min) (2) dropwise (e) DBA Na/K, ether — NO -75 240 ca3-5 72.5 (0.66,2. 1) (f) DBA n-BuLi ether NO -32 8C cal-2 72 (20%) vn HMPA (4 ml)
d 5.(a) TTBA Na/K n-hep- NO 100 600 14.4 35 (1.215) tane (60 ml)e (b) TTBA Na/K E10 YES ether 23 90 5.8 33.8 f (0.176) (1.301) (75 ml) (0.03) (8.6)f
g 6.(a) TBA Na/K n-hep- _ _ NO 23 60 6.5 47.8 , (0.94D tane (8.3)f (b) TBA Na/K ether 20 YES (2) 23 65 9.9 63.5 (0.264) (2.67 x (0.74) dropwise 10-3M) a b 1,3-dibromoadamantane c The time of dropwise addition of the reagent. d 1,3,5,7-tetrabromoadamantane e The quantity of tetrabromide used is insoluble in 50 ml of these solvents, f This yield was determined by treatment of the distillate with bromine. 8 1,3,5-tribromoadamantane TABLE I. Representative Syntheses of 1,3-Dehydroadamantane - 56 -
In these reactions care was taken to exclude oxygen; however, traces of oxide and impurities in the metals could not be avoided. It is well known that intermolecular coupling via free radical intermediates is promoted by 79 traces of halogen, transition and heavy metal atoms/7 and oxygen. Thus, metallic impurities or oxides may have been responsible for aspects of the irreproducability of some of these reactions.
The unpredictable behaviour of the two phase alloy debromination could be overcome by first forming an alkali metal naphthalide. The yield of this reaction which required k hours to complete at Dry Ice temperature was slightly better
(ca. 72%) than that of the normal alloy debromination at room
temperature (ca. 60%); however this reaction was not a great improvement over the alloy reaction since the naphthalene
also sublimed during the sublimative isolation of adamantane-
DHA. Furthermore, the floculent naphthalide tended not only
to entrap the desired product but also to be a firehazard
n-BuLi / HMPA
-30°C
Diagram 65 - 57 -
during the manipulations during contact v/ith oxygen or 65 moisture. For these reasons, the discovery by Scott that debromination by n-butyl lithium occurred at low temperatures in ether-hexamethylphosphoramide (HMPA) solution (65) was welcomed. This reaction not only occurred in one phase, thus avoiding the erratic nature of two phase reactions, but also resulted in an improved yield of DHA (ca. 72.%) v/ith only traces of the difficult to separate side product, adamantane. In this reaction, only one other significant by-product* was observed by analytic glpc in small amounts (5%). The primary dis• advantage of this synthetic method was the contamination of the sublimate with HMPA and low boiling liquid by• products, for example, n-butyl bromide. For many studies this was a major problem.
* The by-product (ca. 5%) was isolated by column chromato• graphy and tentatively identified by nmr spectroscopy as l-bromo-3-(n-butyl) adamantane (66).
Diagram 66
The positions of its nmr resonances compared well with the resonances calculated for this derivative from the data given by Schleyer and Fort.22 - 53 -
The synthesis of the compound, 1,3,5,7-didehydro- adamantane, was attempted (TABLE I; 5,6). This compound was dubbed with the simpler name, doubledehydroadamantane
(67a). It could not be directly detected by either analytical glpc of the reaction mixture or indirectly detected by temperature programmed analytic glpc* of an aliquot treated with iodine. No compound with retention time corresponding to 1,3,5,7-tetraiodoadamantane could be observed. The major product of iodine titration in n-heptane was 1,3-di-ioadamantane. Two minor peaks v/ith
retention times corresponding to those expected for
l-bromo-3,5-di-iodoadamantane and l,3-dibromo-5,7-di-
iodoadamantane were observed.*
A similar iodination reaction was performed on the
l»3»5-tribromoadamantane debromination products. This
time only the traces corresponding to 1,3-di-iodo-
adamantane (major product) and to the compound tentatively * In addition to glpc on the carbowax column, these aliquots were also checked on the silicone elastomer column programmed to reach its maximum temperature (275°C). Again, no peaks corresponding to the tetraiodo-compound were observed. - 59 -
identified as l-bromo-3,5-di-iodoadamantane (minor product) were observed. Further isolation of these compounds was not pursued. The results from the debrom- ination of both tetra and tribromoadamantane (67b,c respectively) indicated that DHA and adamantane were
the major products (TABLE I, 5 and 6).
B. Structure of 1,3-Dehydroadamantane
Despite the surprising stability of DHA to heat
(isolation by preparative glpc at 110°C), the isolated
compound did not melt but polymerized at approximately
l60°C.^0a Due to technical difficulties (sensitivity to
oxygen), the microanalysis of the isolated compound was not
successful. However, the high resolution mass spectrum of
this compound was sufficient to identify the new compound
as a hydrocarbon with the empirical formula of C-J_QH^.
The new compound was identified more conclusively as
DHA (68a) by nmr in oxygen free benzene contained in a
sealed tube. (The nmr spectrum is shown in figure 1).
Diagram 68 1—~" 1 I I - 2.5 2.0 1.5 1.0 S FIG. 1. The NMR Spectrum of 1,3-Dehydroadamantane in Benzene at 100 Mcps
- 62 -
The initial assignment of the nmr resonances in figure 1 proved difficult. Because most hydrocarbon cyclopropyl protons were located upfield from hydrocarbon methylene 81* and methyl resonances, initially it was assumed that the furthest upfield peak v/as due to the cyclopropyl protons. Hov/ever, decoupling studies quickly proved this assumption incorrect.
When a decoupling signal v/as applied at 2.73 S simplification of the 2.05 S triplet to a singlet occurred.
The 1.66 S multiplet was also sharpened. Since the triplet could only result from the resonance of H^, the 2.73 S resonance was assigned to H^. (These assignments were confirmed by the nmr spectrum of 5,7-dimethyl-DHA (68b) 82
(figure 2). In this spectrum the resonance is absent and the resonance, though shifted slightly, is a singlet as would be expected.)
When a decoupling signal was applied at 1.15 S , a doublet (11Hz) at l.Qlobe came a singlet. Some simpli•
fication of the 1.66 S resonance also occurred.** This experiment indicated that the pair of coupled doublets The protons of cyclopropane resonate at 0.22 ** This simplification is the result of through-space coupling to remote methylenes oriented in "W" relationship22-2q- to the cyclopropyl protons as described in the INTRODUCTION, p - 12. - 63 -
were related; thus they were assigned to H^a ^. By the process of elimination the cyclopropyl hydrogens, EL,, v/ere assigned to the resonance at 1.66 £ , an unusually low value compared to cyclopropane (0.22 £ ).
Warner, LaRose and Schlies^^ suggested that this de-
shielding of the DHA cyclopropyl hydrogens, H2, was due to the H^ exo-axial hydrogens. (In the INTRODUCTION these hydrogens .were shown to interfere with S^2 reactions at a secondary carbon of adamantane by steric hindrance (12) - 20 a possibly analogous situation. ) The suggestion of
Warner et_ al.-^ was based on the lack of strong deshielding of cyclopropyl protons in the conformationally mobile compounds, 3.3.lj propellane (69) and J^3.2.lJ propellane
(70). The resonances of the cyclopropyl hydrogens were
0.45 and 0.68 £ , respectively. In these compounds the five membered rings presumably exist in the boat form thus removing the homoadjacent axial hydrogen interaction in the chair conformer. In contrast, DHA (68) is restricted to the double chair conformation by the bridging C-6 methylene.
The differenciation between the H. (exo-axial) £+a and H^ (endo-equatorial) hydrogens proved difficult. The H. (exo-axial) hydrogens appeared to be positioned closer M-a —— to the shielding area of the cyclopropyl group^"*" than were the H (endo-equatorial) hydrogens. Thus, the 1.15 &
doublet was assigned to H^a and the 1.91 £ doublet to
H^; hov/ever this assignment was tentative and may be revised subject to the results of further investigations. - 64 -
Diagram 70 - 65 -
The infrared spectrum for the new compound was compiled from a large number of rapid scans in different
solvents by observing the disappearance of the ^max as decomposition occurred. The most characteristic frequency for cyclopropyl hydrogen stretch is between 3040 and 3060 -1 83 cm . A weak but sharp absorption was observed at
3040 cm"""*". Other absorptions which were observed within or close to areas deemed characteristic of the cyclopropyl moiety were at 2900, 1450, 1035 (unsymmetrical ring vibrations) and 895 cm""*".
Diagram 71
DHA proved too reactive for X-ray analysis, however, the recently synthesized 5-cyanotetracyclo 3.3.1.13>7.01}3 decane (71) was sufficiently stable for this type of study. 34 35 Two interesting points were made in this study. ' Firstly, 0 the internal bond distance was found to be 1.643 A, the - 66 -
longest carbon-carbon bond on record! Secondly, the internal bonding carbon atoms v/ere found to be 0.11 A from a plane passing through their adjacent methylene carbons confirming the inverted geometry of the quaternary carbons. The only other compound reported to have a similar geometry around the corresponding atoms was the recently synthesized 8,8-dichlorotricyclo 3.2.1.0 octane (72a). In this case the distance was 0.09 A.
Diagram 72
Wiberg et al.OD decided that no conclusions about the nature of the internal bond of the above compound could be drawn because the exact position of the carbons could not be fixed precisely, a situation which appeared to be
paralleled in the cyano-DHA X-ray result. Therefore, no
conclusions about the nature of the internal bond in DHA
could be drawn from the X-ray study of 5-cyano-DHA (71).
Despite the lack of precise information about the
nature of the internal bond in DHA a general assumption
can be formulated. It may be safely assumed that the
internal bond of DHA and its derivatives would possess
a high degree of p orbital character. A similar assumption
has been used for the strained bonds of bicyclanes to explain the stability of bonds with large bond distances
or awkward (large) angles between bonding orbitals and On OO the internuclear distance. Studies have supported
this assumption.
An important consequence of greater p orbital content
in a strained cyclopropyl bond is the increase in "size"
or electron content of the non-bonding lobes of this
bond compared to the non-bonding lobes of the carbons of
simple cyclopropane. This increase in non-bonding lobe
size appears to have a bearing on an addition reaction
mechanism - edge versus corner and electrophilic versus
free radical addition mechanisms in these cyclopropane
compounds. Strained cyclopropyl propellanes do not
present as many complications as only corner addition to
a strained internal bond seems likely. This seems
especially so in the case of the DHA structure. Recent OO Og
studies * ' predict a large p orbital component in the
internal bonds of strained bicyclanes and propellanes.
°2
Diagram 73
m-q ,s independent of the question whether the proton ^othe/flertrophile first attacks a bridging bond ed, then slides to a corner and results in the observed product.90 The hydrocarbon propellanes, DHA and J~3.2.]
propellane (68a and 72b respectively), share similar
fates when exposed to the same reagents and conditions.
In contrast, the very recently synthesized 3.3.lj
1, propellane, tricyclo 3.3.1.0 -M nonane (73), appe ars 57
to be very substantially less reactive, ' Therefore, in
the following section the comparison of the responses
of cyclopropyl propellane compounds when treated with
various reagents v/ill be examined and compared with DHA.
C. Reactions of 1,3-Dehydroadamantane
From the beginning DHA was found to be highly reactive. In addition to a very rapid reaction with halogens, the new compound reacted very rapidly with acids and somewhat more slowly v/ith hydroxy lie solvents. However, the most surprising observation was the sensitivity of DHA to oxygen. This was a most unusual sensitivity for a formally saturated hydrocarbon. It-was primarily this sensitivity which prevented the isolation of DHA by a normal workup procedure and resulted in the development of the distillation-sublimation method for the isolation of
DHA (see Experiment B.3.c).
Reaction with Oxygen-Peroxide Formation
On exposure of DHA solutions to air these solutions rapidly became cloudy, later resulting in a white floculent precipitate. The formation of the cloudiness was found to - 69 -
be due to oxygen and not moisture in the air. The free
radical nature of this reaction was indicated when 0.1/6
3,5-di-t-butyl-4-hydroxytoluene markedly retarded the
incidence of cloudiness.
At that time the only incidence of an oxygen mediating hydrocarbon polymerization on record was methyl bicyclo
1.1.0 butane carboxylate (74) reported by Wiberg et al.
R = COoMe
Diagram 74
This reaction (74) also could be controlled by free radical inhibitors; therefore it was surprising that the microanalysis of the isolated polymer indicated two atoms of oxygen for each DHA molecule incorporated into this polymer (75).
The polymeric substance (75) did not melt but exploded o at approximately 146 C - a characteristic of many per- 92 oxides.7 This explosion point was not fixed but varied with the conditions under which the polymer was formed.
For example, when the hydrocarbon solvent was substituted with ether or alcohols not only was a decreased yield of precipitate obtained but also much higher explosion points (ca. 170°C) were obtained. Furthermore, these - 70 -
higher explosion points (ep) were much more dependent on the rate of heating than were the ep of products from n-heptane solutions. R=0H,H, or solvent
02/n-heptane £gS3> n =1,2,3,4,...
Diagram 75
The polymeric material (75) was undoubtedly composed of short chains because the microanalysis was slightly high for hydrogen. The basic structure of the polymer was confirmed by treatment with lithium aluminum hydride (LAH) to give 1,3-dihydroxyadamantane as the major product.
Unsuccessful efforts v/ere made to detect the inter• mediates of the polymerization reaction by electron spin spectroscopy* since free radicals had been observed in other precipitated polymers. Detailed kinetic studies Op by Schmidt confirmed the free radical nature of this reaction (75). Shortly after the completion of the polyperoxyadaman- 55 tane studies, Wiberg, Hiatt and Burgmaier^^ reported that tricyclo 3.2.1.0 1,5 octane also formed a peroxy- 89c polymer by reaction with oxygen In contrast, neither 1,4 the recently synthesized tricyclo 2.2.2.0 octane
This study was expedited by D. Kennedy. - 71 -
derivative (76a) nor the very recently synthesized tricyclo
57y ; 3.3.1.01, 5 nonane hydrocarbon (76b) reacted with oxygen. ''
58a 57 R= CON(CH3)2
Diagram 76
However, the most surprising occurrence was the resistance
3 1 3 of 5-cyano tetracyclpi o 3.3.1.1 ^.O —' ' decane (76c) to attack by oxygen.4"3 This unusual stability was the major
factor which permitted a successful X-ray analysis of this 85
DHA derivative. ^ No explanation for this unusual stability
of the cyano compound (76c) was advanced. Thus, only three
formally saturated hydrocarbons are known to react wit89h d oxygen to give a peroxy polymer , 3.2.1 propellane,
DHA,80 and 5,7-dimethyl-DHA.82
Addition of Halogens
In connection with further confirming the structure
as well as determining the chemical properties of the new
dehydroadamantane, treatment of DHA with halogen was under•
taken (77). Because the addition to DHA occurred at the
bridgehead carbons, the result was easily verified by compari- - 72 -
son with a readily available well known compound, 1,3- dibromoadamantane (77a).
Br2or I2
-78 C, very rapid
a, X=Br Diagram 77 b, X=I
Simple cyclopropanes and small ring bicyclanes were thought to add bromine primarily via a broraoniura ion mechanism (78).^,(^3 The latter compounds were also known to undergo rearrangement and lysis of bridge as well as bridgehead-bridgehead bonds (78b).
Bi Br Br Cr* Br
Br Br Diagram 78
In one of the few examples of bromolysis of propellane
(59) internal bonds, Applequist and Searle7^ had established a free radical mechanism by free radical inhibitor-accellerator studies. Eaton and Nyi7^ invoked - 73 -
the above mechanism for the bromolysis of 3.2.2 and
.2.2 propellane since these compounds failed to react with hydrogen halides (78). V/iberg-^ noted a large decrease in the electrophilic mode of reaction between similarly strained cyclopropyl and cyclobutyl bicyclanes. This decrease was attributed to differences in the hybridization of the strained carbon atoms.
Br.
(CH9) (CH ) - 2 n 2 n
n=3,4.
HBr
JpH2>n
Diagram 78
Most recently, 3«3.lJ propellane (69) was shown to add bromine readily; however, Warner, LaRose and Schleis'^ stated they had evidence that the addition mechanism primarily involved free radicals.
The title compound of this thesis was the first 3.3.1 propellane type compound reported to add bromine. Even at Dry Ice temperature, a hydrocarbon solution of this compound could be titrated with bromine to yield only
1,3-dibromoadamantane (77a). Titration with iodine resulted in only the corresponding iodo-compound (77b). - 74 -
Both reactions v/ere too rapid to allow a testing of the mechanism with free radical inhibitors by the method of 71
Applequist and Searle;' however, bromination of DHA in ether at Dry Ice temperature resulted in a floculent lemon-yellow precipitate. Bromine, 1,3-dibromoadamantane, and the new major bromination product were shown to be soluble in ether under identical conditions. After the precipitate formed, no significant amount of products could be detected in the supernatant liquid. This preci- o pitate was found to decompose very rapidly above -20 C but it could be isolated easily and kept for four days in solution without noticeable decomposition well below o -20 C.
The yellow colour of this intermediate compound suggested an ionic nature, A literature search disclosed the existence of both a chloronium ion stable at low temperatures (79a)7 and a bright yellow insoluble brominium ion stable in refluxing CC1. (79b),^
Diagram 79 - 75 -
The structural illucidation of .the isolated yellow intermediate was encouraged further by the discovery of
these two ionic compounds (79a,b).
Due to technical difficulties, the microanalysis
of the intermediate compound was not successful; however, it revealed the presence of more than ten carbon atoms
and more than two bromine atoms.
TABLE II. Microanalytic Results for the Intermediate Compound formed from 1,3-Dehydroadamantane with Bromine in Ether
C H Sample Temp. °C Found: 30.4 6.80 -75 33.47 7.30 -75 33.04 4.81 23 31.82a 4.54a
Calculated for C^H^Br^.EtpO
Br\Et 0 — =-« -75°C
Diagram 80 - 76 -
An nmr spectrum of the intermediate in acetone-dg clarified the structure of the precipitate (figure 3).
The unmistakable quartet (4 protons) at 5.19 § and the triplet at 1.71 8 with identical coupling constants (7Hz) strongly indicated that the intermediate resulted from the addition of the ether oxygen to the "remotely generated" adamantyl carbonium ion (80a). The downfield shift of the ether methylenes was noted to be more than
1. 8 greater than in a representative sample of similar 98 ionic compounds.7 98c The first oxonium compound v/as recorded by Meerwein.
7 3 More recently, Klages et al. ,98a an^ Lamt>ert and Johnson* "^ have synthesized and studied this type of molecule. Both of the latter groups have utilized either antimony pentahalides or boron trifluoride to cause oxonium salt formation in solution.
The intermediate was shown to possess a tribromide 97 anion akin to Wynberg's bromonium ion compound.7
This was made possible by the isolation and characteriza• tion of the major decomposition product of the intermediate
(80b). The nmr spectrum of this major new product (figure k) agreed with the microanalytic results. The spectrum indicated the presence of an ethoxy substituent on a disubstituted adamantane skeleton. The l-ethoxy-3- bromoadamantane structure of the compound was con• firmed by HBr cleavage to yield 1,3-dibromoadaman• tane. Decomposition of the intermediate suspended in acetone solvent
FIG. 3. The NMR Spectrum of (3-Bromo-1-adamantyl) diethyl oxonium tribromide
in Acetone-d6 at 100 Mcps - 78 -
FIG. 4. The NMR Spectrum of 1-Bromo-3-ethoxyadamantane in
CDCl3at 100. Mcps - 79 -
CCl^ by raising to room temperature resulted in a red- brown solution of molecular bromine. The ratio of bromine to the organic decomposition products (80b,c) was shown to be 0.905:1.0 by ultraviolet spectroscopy and analytic glpc respectively. The missing bromine could probably be accounted for by further reaction with the by-products of decomposition. The presence of acid fumes in the decomposition mixture could be explained by the abstraction of a hydrogen atom from one of the methyl groups by a bromine anion (81) and possibly by hydrogen-bromine exchange at saturated carbons. Clearly,
either HBr or Br0 could add to the unsaturated molecule.
A
Diagram 81
Most recently, this proposed mechanism has been given further credence by the studies of Richmond and Spendel.^
In situ generated benzyne was found to cleave ethers in just this manner to give unsaturated carbon products
(82); however, nmr studies showed that more products than those suggested above (81) were formed when the oxonium salt reacted. - 80 -
Et OEt
+ + Et20 CH2
40% AO •/•
Diagram 82
The diethyl ether adduct of the oxonium compound could not be displaced readily (TABLE III). The attempts at displacement led primarily to very high yields of 1-bromo-
3-ethoxyadamantane (80b); thus the oxonium compound was not likely to be useful in synthesis. Alternately, bromina- tion of DHA in acetone solutions containing non-acidic nucleophiles resulted in the desired substituted adamantane.
For example, bromination of DHA in water-acetone solution resulted in a quantitative yield of l-bromo-3-hydroxyadamantane
(83a). The structure of this product was confirmed by a base catalyzed reaction to give 3-methylene bicyclo 3.3.lJ nonane (83b),
Br2 /H20 0H/H20
acetone
Diagram 83 - 81 -
III I H2H4J0H5,9 H H ~i—i—i—|—i—i—i—i—|—i—i—i—i——1 1 1 r 5.0 4.0 3.0 2.0 1.0 0 S FIG. 5. The NMR Spectrum of 1-Bromo-3-hydroxyadamantane in.
inCDCl3at 100 Mcps - 82 -
TABLE III. Substitution of (5-Bromo-l-adamantanyl)- diethyloxonium tribromide with Nucleophiles
a b Decomposing Solvent Scavenger DBA Yield of % EA3 ether Nil 28.7 67.8 ethanol 95% K2C03 1.5 93.0 acetone (wet) Nal — 100 NaCN — 100 a 1,3-Dibromoadamantane b Small amounts of l-bromo-3-hydroxyadamantane could not be detected on the carbowax column due to decomposition.
TABLE IV. Substitution of the (3-Bromo-l-adamantanyl)- diethyloxonium tribromide in Solvent Mixtures
Additives ' % Yield of Productsa
l-bromo-3- l-bromo-3- l-acetoxy-3- ethoxy- hydroxy- bromo- adamantane adamantane adamantane
b — 1) 2% H20 22.3 54.7
C 2) 10% H20 27.1 53.1 —
b 3) 0.7% H0Ac 33.1 43.8 0
c d 4) 25% H0Ac 33.4 6.1 6.3
5) 0.4% H^O^6 32.8 61.2 —
a by analytical glpc of product solutions, b with complex from 0.1698 g DHA. c with complex from 0.171 g DHA. d decomposes under basic conditions of the workup, e with complex from 0.157 g DHA. - 83 -
Comparison with the authentic compound by analytic glpc on two different columns strongly indicated identity for the two compounds. Efforts to increase the yield of l-bromo-3- hydroxyadamantane from the oxonium salt by increasing the water content of or adding acids to acetone solutions were not encouraging (TABLE IV). (The decomposition in 25% acetic acid (HOAc) did produce a compound in approximately 6% yield which appeared to be l-acetoxy-3-bromoadaraantane.)
I" n=lor3
Diagram 84
Both chlorination and iodination of DHA in ether led
to the expected respective oxonium salts. For example, the
iodination product v/as a dark red-brown precipitate which o
slowly underwent a displacement reaction even at -75 C. A
high yield of l-ethoxy-3-iodoadamantane could be obtained by
dissolving the precipitate in acetone and adding NaCN (84).
Other reactions of the iodoadamantyl oxonium salt were not
investigated because the excess iodine was very insoluble at
-75 C making the iodo-oxonium compound difficult to isolate. - 84.-
The chloro oxonium compound appeared to be quite stable. The compound required over 2.5 hr to decompose at room temperature. The exact nature of the anion in each case was not established.
It could only be concluded that bromine added to the
1,3 bond of DHA in polar solvents preferentially by a two- step electrophilic mechanism and that the resulting carbonium ion intermediate was trapped by ether to give an insoluble
(3-hromoadamantane-l-yl)-diethyl oxonium'tribromide salt (80a).
Addition of Acids
To date overwhelming evidence has been accumulated in favour of the edge protonation theory for simple cyclo- propanes."*"00 If steric factors are not involved, generally the degree of bond strain would be represented approximately by the reactivity of the bond toward protons. Thus, in bicyclopentane and bicyclobutane, the transannular bond was thought to be the usual site of reaction (85).69,101 However, the original mechanism of edge protonation appeared doubtful for some of these compounds (85c)Studies with the com• pound l-methyl-3-cyano-bicyclo j^l.l.oj butane (85) indicated that both the proton and the hydroxyl group added to the same side of the ring possibly by a collapse of the intermediate to a carbonium ion. Such an intermediate would result in two - 85 -
OH ft
+ CN
CN
Me OH H Diagram 85 isomers but only one isomer was produced. Thus, possibly the addition occurred almost simultaneously from the under• side (acute dihedral angle) of the ring. The propellane ring superstructure would prohibit edge protonation of the sterically hindered internal bond; thus the only reasonable mode of proton addition would involve the non-bonding lobes of this internal bond. As discussed previously, attempts to qi, add hydrogen halides to propellanes had failed^ while free radical bromination did occur readily.71»94
As indicated above, the title compound of this thesis can also be considered a propellane-type compound. It has been established that DHA added bromine by an electrophilic mechanism; thus, the addition of acids would be favoured more - 86 -
by this compound than by the propellanes. Exposure of DHA to 8.13 M sulfuric acid did result in the rapid (30 min) conversion of the compound to adamantan-l-ol. Exposure to lower concentrations of sulfuric acid resulted in progressively longer reaction times. For
10""^"M and 5 x 10~3M acid reagents almost 'two days and over
four days, respectively, were required, and the yields of
these reactions were progressively lower. 56a
Wiberg and Burgmaier^ reported that tricyclo
3.2.1.01,^~J octane reacts very rapidly with HOAc (86).
H0AC •• OAc
Diagram 86
Explicit conditions were not given so a precise comparison
with the reactivity of DHA could be made. The compound DHA
reacts totally (within 10 min) at room temperature in an
excess of 0.1M HOAc. The corresponding "fragment"
nexane bicyclo j^#l#^J (87a) was relatively stable in
glacial acetic acid. - 87 -
(Its behaviour is very similar to that of cyclopropane under identical conditions.) The most similar and therefore
lj significant "fragment" of DHA would be tricyclo 5.3.1.0^] nonane or £3.3.lj propellane (87b).^ This compound had a half life of 8 hr at 100 C when dissolved in acetic acid. ^ ^ HOAc
» Diagram 87
The major product (53.5%) was 1-acetoxybicyclo |~3.3.1~j nonane (87c), but the alternate ring opening product (46.5%)
(87d) which was readily eliminated (87©) also was formed.
The ' ^•^••^J Propellane was much less reactive toward HOAc than was DHA. This propellane appeared to be much less reactive than bicyclopentane (87b,f, respectively).
R= C02Et
R R
Diagram 88 - 88 -
102 The derivatives (88) have been shown to be quite resistant to dilute acids. The first compound (88a)102a was also stable to heat as the solvolyses were carried o out at 100-130 C. Gassman intimated that for this compound higher temperatures and higher concentrations of acids, ie. greater than 7 x 10~^M, yielded "a small amount of additional products." Unfortunately the nature of these products was not disclosed.
The title compound, DHA, also reacted totally with
6 x 10 M para-nitrobenzoic acid within 6 hr to give the
corresponding ester. This acid has made an excellent leaving
group and has been used widely in solvolytic studies."^3
Although in approximately ten-fold excess over the normal
catalytic concentrations, the rate of this reaction indicated
that its presence would certainly complicate solvolytic
studies involving derivatives of DHA, a suggestion Haywood-
Farmer^3 made in a preceeding dissertation.
As for the reaction with oxygen and the reaction with
bromine, the protonation of DHA proceeds exclusively via interaction with a non-bonding lobe. Recently this type of
addition has been suggested"^" or demonstrated for less 105 strained and less hindered compounds (89). - 89 -
Both Lalonde e_t al.'Lu:3a and Hendrickson and Boeckman,""""^" have suggested that corner protonation was favoured in the above compounds due to steric hindrance by the endo and exo hydrogen atoms, respectively; thus they concluded that the transition energy difference between the two intermediate could not be very large. Most recently, a theoretical study of two small ring strained bicyclanes has indicated that the corner protonation would be the preferred mode in these compounds. - 90 -
Addition of Mercuric Acetate
The mechanism of cyclopropane oxidation by heavy metal 107 salts has generated particular interest. This interest was initiated by the olefinic character of the three LR membered ring.
The treatment of olefins with various organometallic
acetate reagents of the general formula M(OAc) (M = H^. ,
Pd2+, Tl3+, Pb4'*) has an extensive history.108 The usual
trans mechanism of addition is generally noted but in cases
of strained and sterically hindered olefins varying amounts
of both cis and trans addition products are encountered. 109
Bach and Richter 7 postulated a cyclic transition
state for strained olefins on the basis of rate enhancement
by sodium acetate, but the addition of solvent molecules to
these bonds implies the existence of at least a partial
carbonium ion (90). Furthermore, Berger and Vogel110 noted
the addition of solvent molecules to unstrained olefins
attacked by mercuric salts; therefore, they supported the
partial carbonium ion mechanism. H
R HgON02 Hg(N03)2 '
R • R CN R ^NTV
0N02
Diagram 90 - 91 -
This hospitality of olefins toward solvent molecules was very similar to the behaviour of DHA during electro- philic addition of bromine in ether; however, the metalation of DHA with aqueous mercuric acetate produced an unusually complex result.
Additional to the major product, 1-adamantanol, 1,3- dihydroxyadamantane, an unidentified by-product and many minor by-products were observed in the reaction solution by glpc. Curiously, a dark precipitate was always observed within 3 min of adding the salt. This precipitate was identified as free mercury by its coalesence into a characteristic bead of shiny silver liquid metal. Further• more, the ratio of the reaction products to one another was found to depend strongly on the procedure used. The repetition of this reaction while varying the duration of the interval between the addition of mercuric acetate and initiation of reducing conditions, led to the following observations. An inverse correlation was noted between the length of this interval and the yield of the desired product, 1-hydroxyadamantane. A direct correlation was noted between the duration of this interval and the yield of 1,3-dihydroxyadamantane.
These observations could be explained primarily by a tendency peculiar to secondary and tertiary mercuric esters. - 92 -
Eisch111 noted that t-butyl and i-propyl mercuric tosylates were remarkably reactive and that a reduction-oxidation solvolytic cleavage.of the alkyl metal bond constituted the mode of this reactivity (91). The half life of t-butyl
R 9^^^
2^C+---Hg-"OTs »• Hg** ^t-OTs
R3 "a
Diagram 91 mercuric acetate in a mixture of dioxane and water at
25 C was estimated to be 3.5 i 0.5 hrs. x The half life
of the corresponding adamantanyl derivative was approxi- 11^
mately 5 min. Wittig y reported this reaction to be
strongly solvent dependent and that doner solvents promoted
this dissociation by altering the strength of the alkyl-
metal bond.
The solvolyzing intermediate possessed a significant
amount of carbonium ion character as was seen by the prefer•
ential formation of 1,3-dihydroxy adamantane, but this
positive charge was not sufficient to favour the general ring
opening rearrangement (2,Mt).^'^ Undoubtedly, small amounts - 93 -
of products corresponding both to attack by acetate and the ether solvent also were formed during the cleavage. Coupled with the possibility of attack by the solvent and acetate on the first carbonium ion, and the fact that the reduction reaction was initiated before completion of the metalation of DHA, the yield of 1-hydroxyadamantane v/as surprisingly high (47.7%). Other reactions also could reduce this yield, most notably disproportionation (92).114'
2 RHgX
Diagram 92
The resulting compounds would be most difficult to reduce due to the formidable steric hindrance of the twin adamantyl substituents. After several months the reduction reaction products did display new evidence of metalic mercury, presumably from the decomposition of these compounds. In
any case the reaction of Hg(0Ac)2 with DHA is surprisingly complex.
Addition of Alcohol
An attempt was made to purify the adamantane-DHA mixtures by recrystallization from methanol. Not only was the fraction recrystallization procedure not effective, but also DHA was found to react slowly with the solvent to give a high yield of 1-methoxyadamantane (93). The addition of - 94 -
Diagram 93 borontrifluoride accelerated the reaction drastically so that total conversion occurred within minutes. A similar result was obtained in ethanol. This reaction could be slowed but not stopped by adding trace amounts of sodium bicarbonate to the solvent several hours prior to the dissolution of
DHA. This attempt to control the addition of alcohol was part of a specific effort to find a more suitable medium than n-octane for studying the hydrogenolysis of DHA.
Hydrogenation 115
In his review, Newham ^ presented three general mechanisms for hydrogenolysis of cyclopropyl rings. He envisioned the possibility of one, two and possibly three adsorbed carbon radicals11^ interacting with the surface of the catalyst (94)»
Hydrogenolysis has tended to occur at strained bonds (95) »^"^ unless steric hindrance existed.11'''
Unfortunately definitive studies of the mode for hydro• genation of these compounds has not yet been performed. - 95 -
Mechanism Type
a be
Diagram 94
The results from the study of a small number of compounds seemed to indicate hydrogenolysis occurs by adsorption onto the catalyst from the top or bonding lobes of the strained bond (96); rather than the bottom ie_. non-bonding lobes of the strained bond. However, conclusive differentiation between mechanisms A and B has not been accomplished.
Attempts to hydrogenolyze the internal bond of propellane molecules was unsuccessful in the limited number of compounds reported;^°k>57,94 however hydrogenolysis of the internal bond of DHA occurred readily in n-octane near the standard conditions. Diagram 96 - 97 -
A high yield of adamantane was obtained. Several by• products (total yield ca. 15%) with a glpc retention time less than that of adamantane were also present. In many repetitions of this experiment with several different noble metal catalysts it was found difficult to reproduce either the rate of hydrogen uptake or the quantity and distribution of the by-product mixture. A direct relationship was noted between the duration of the reaction and the yield of by• products. The nmr spectrum of this intractable by-product mixture (isolated by preparative glpc) showed two sharp resonances in the methyl region, doubtlessly, the result of a molecular rearrangement (97). 127
In an effort to increase the reaction rate ' the experiments were repeated with ethanol as the solvent because the reaction of DHA with solvent was expected to be very slow.
The increase in the hydrogenation reaction rate was observed; however, increases in the yield as well as a change in the character of the by-products also was noted. Most notably, the reaction rate between the solvent and DHA was accelerated.*
Addition of sodium bicarbonate to these reactions had little noticeable effect on the ether-producing side reaction; however, the short retention time by-product mixture was
* The usual reaction time was ca. 24 hr but under hydrogena• tion conditions in ethanol reaction was complete within 30 min. The yield of ether was estimated to be 31 i, 5% by nmr integration. - 98 -
reduced somewhat. Again as with the synthesis of DHA, difficulties were encountered in reproducing the reaction rates. The character and quantity of the by-products also varied among repeated reactions.
The results of these reactions were most consistent with a modified TYPE A mechanism (no d - ff stabilization).
The by-products which showed the presence of methyl groups conceivably could arise from a TYPE B adsorption mechanism
(97a) followed by homolytic fission of a bridge-bridgehead bond; however, a TYPE A mechanism involving homolytic (97b) or more likely heterolytic (94a,c) fission would also be possible.^ h K
Diagram 97
The Platinum group metal catalyzed rearrangement of strained compounds has been well documented. The persistent - 99 -
slow uptake of hydrogen after the disappearance of DHA could be interpreted as evidence for, the existence of such a rearrangement. The formation of the ethyl-adamantyl ether might be attributed in part to traces of HC1 remaining in the catalyst or more likely the poisoning of the catalyst by traces of bromoadamantane compounds. This ether also might arise from platium catalyzed addition of ethanol to
DHA, possibly via a carbonium ion intermediate or free radical intermediate (98).
Diagram 98
Addition of Benzene
The addition of benzene to DHA occurred readily when catalyzed by aluminum trichloride (99). Under the conditions of the reaction, only a modest yield of 1-phenyladamantane was obtained. This was due to the existence of many side reactions. First, Lewis acid catalysts have been known to
co-polymerize with cyclopropyl compounds. Upon the workup
of the reaction, polymeric material was isolated. Micro•
analysis of this material indicated that the carbon and
the hydrogen content were lower than that expected for
polyadamantane; furthermore, a non-combustible residue - 100 - remained. Presumably, this residue was composed of aluminum salts. Second, the reaction was further complicated
by the equilibration of the reaction product. Not only was 1-phenyladamantane dephenylated giving adamantane but also another phenyl group was added resulting in the com• pound, 1,3-diphenyladamantane. Furthermore, mass spectro• scopic evidence indicated the presence of 1,3,5-triphenyl- adamantane. A similar distribution of the products was obtained in the preparation of authentic 1-phenyladamantane from 1-bromoadamantane under similar conditions.
The lower solubility of 1,3-diphenyladamantane compared with 1-phenyladamantane required extensive fractional recrystallization for purification of the 1-phenyl-compound.
In a similar fashion, the purification of 1,3-diphenyl• adamantane was extremely tedious. The best elemental analysis of this compound was not within the required limits; however, the nmr spectrum did integrate for 10 protons in the aromatic region. The mass spectrum showed a strong peak with m/e+ at
288 mass units and a very small peak with m/e+ at 364 presumably due to the 1,3,5-triphenyladamantane impurity (molecular weight, 364). - 101 -
Thermolysis of DHA
The mixed sublimate or pure samples of DHA did not o melt but polymerized rapidly at ca, 160 C to give a solid o. which did not melt up to 350 C (100). In air this solid o began to turn brown and decompose at ca. 450 C but was stable up to 500°C under nitrogen. A sublimate similar to that of adamantane was observed to form on the coverslip during decomposition. This product (100) had superior heat resis• tance (supra vide) to the polyadamantane compound prepared by Reinhardt from 3,3'-dibromobiadamantane via a Wurtz o 131 reaction (decomposition point 325 0).
ni2
Diagram 100
A dilute solution of sublimed DHA in degassed n-octane was studied at 195 0. Wiberg reported that tricyclo 3.2.1.0 octane possessed a half life of ca. 20 hr at this temperature
The half life of DHA was found to be 4.45 hr. Both adaman• tane and l,l'-biadamantane v/ere identified in the product solutions. An unidentified major product most probably resulted from reaction of DHA with solvent. The analytical glpc retention time and the breadth of the trace were con• sistent with the expected mixture of isomers. - 102 -
Preliminary studies with dilute solutions of DHA in cumene gave two new compounds in addition to adamantane and l,l'-biadamantane. One of these v/as identified as dicumene (101a) by comparison with an authentic sample and the other (101b) was apparently again the product of solvent reaction with the 1,3-diradical intermediate. The yield of adamantane from pyrolysis of DHA in this solvent was increased substantially.
Diagram 101
The 1,3-diradical species has been of interest for almost twenty years. Both calculations and experimental c studies agree that this species v/as the usual intermediate in thermolyses and pyrolyses of simple and strained cyclo- propanes. There could be little doubt that DHA undergoes homolytic cleavage during thermolysis to yield such an intermediate diradical (102).
®» products
Diagram 102 - 103 -
D. Conclusions
The molecule tetracyclo Jj5.3.1.1^,''.01'^J decane has been synthesized by dehalogenation of 1,3-dibromo,
1,3,5-tribromo, and 1,3,5,7-tetrabromoadamantane with a variety of metals and organo metallic compounds. This molecule belongs to a new class of compounds with inverted bridgehead carbon atoms. This membership has been demon• strated by the high reactivity of the new hydrocarbon compound toward both free radical and electrophilic reagents. This reactivity makes the new compound a useful intermediate for the synthesis of 1,3-disubstituted adaman• tane compounds. The structure and reactivity of the compound also suggests that the internal bond possesses a high degree of p-charac±er and that the reactivity must be due to an increased electron density in the non-bonding lobe exterior to the skeleton. This explanation is re- enforced by an X-ray crystallographic study of a derivative which shows the internal bond of the new compound to be very large (1.643 A). The DHA thermal polymer has proven to be stable at high temperature. This stability could further be increased by enabling crosslinkage between chains to occur. Compounds such as double-dehydroadamantane or l,l'-bi-DHA easily would promote crosslinking during
DHA pyrolysis. - 10k -
Recently adamantane derivatives have been shown to 132 possess medicinal properties. The simple compound
1-aminoadamantane as well as certain other of its derivatives have shown both antivirial and anti-Parkinson's syndrome effectiveness. The addition of the adamantanyl group to existing drugs and antibiotics has resulted in significantly altered spectra of activity and potency.
For these reasons, the ready availability and reactivity of DHA may prove useful in the area of medicinal chemistry. - 105 -
EXPERIMENTAL
Infrared spectra were recorded on the Perkin-Elmer model 137-B Infracord spectrophotometer equipped with sodium chloride optics. Liquids were run as neat samples, solids, as nujol mulls or as solutes in chloroform.
Solution spectra were obtained using 0.523 am sodium chloride cells.
Nuclear magnetic resonance (nmr) spectra were recorded by Mr. R. Burton and Miss P. Watson of this department on Varian Associates A-60, HA-100 and T-60 spectrometers. Resonance peaks are given in & units, relative to tetramethylsilane (internal standard). The samples were usually run as 15-20% (w/v) solutions in deuterochloroform or carbontetrachloride. Spectra were also run in aromatic solvents to take advantage of the observed chemical shifts by susceptible protons. Pyridine and benzene were used for this purpose and for the dis• solution of compounds which were insoluble in the non- aromatic solvents. Commercially available 5 mm glass nmr tubes were used in all cases. Hydroxyl peaks were identified by observing their disappearance after addition of deuterium - 106 -
oxide or by observing the resulting change in their chemical shift following the addition of pyridine. Acceptable integrated peak area ratios were obtained for all compounds studied.
Microanalyses were performed by Mr. P. Borda of this department.
Melting points (corrected) were obtained in glass capillary tubes using an electrically heated, circuiting oil bath.
Distillations, unless otherwise specified, were carried out using a Bantom-ware short-path disillation unit.
It was noted that the boiling points (uncorrected) were affected by the still pot temperature; hence were not very accurate.
Preparative gas-liquid phase chromatography (glpc) was performed with a Varian-Aerograph 90-P, a Wilkins-
Aerograph A-90-P and a Wilkins-Aerograph A-700 Autoprep.
All used helium as the carrier gas and a thermal conductivity unit as a detector. ; These instruments used standard commercial lA in or 3/8 in copper or aluminum columns
(Aerograph). Analytic glpc was performed with a Perkin-
Elmer model 900 chromatograph using helium as the carrier gas and flame ionization as the detection method. The columns were standard commercially available 6 it by 1/8 in stainless steel columns (Perkin-Elmer). These analytic columns all used Chromosoro "W" 8u/100 mesh as the inert - 107 -
support medium. Three analytical columns v/ere used almost exclusively. These v/ere: Carbov/ax 20M (10%) on base washed Chromosorb "W"; Phenoxysilicone grease (8%) on acid washed Chromosorb "W"; and Silicone elastomer-30 (8%) on acid washed Chromosorb "W". The support in each case v/as
80/100 mesh.
The model 900 Perkin-Elmer instrument was capable of being temperature programmed. For the Carbowax column the most useful program consisted of the following: hold at o o 80 C for 8 min; then increase the temperature by 32 C per o o min to 200 C; and then hold at 200 C the maximum recommended temperature (usually 10 min) before returning the temperature to 80°C (80°C/8 min ?2 G/mirW200^/10 min). Unless other• wise specified this is the temperature program used. The helium flowrate varied with varying temperature but in all cases cited it remained betv/een 40 and 65 ail per min.
Bromine (J.T. Baker) (used both as solvent and reagent) was used directly from the bottle. Drying by snaking with concentrated sulphuric acid and/or phosphorous pentoxide and distillation was not found necessary.
Diethyl ether (Mallinckrodt AR Anhydrous) was used directly or stored over SA-5 molecular sieves until used.
Benzene was dried by azeotroping off tne water and refluxing over sodium. Distillation was effected by using an upright condenser and stillhead with stopcocked side arm. - 108 -
n-Heptane (BDH) was purified by shaking tnree times
with 10% (v/v) of concentrated sulphuric acid washing with
v/ater then drying over calcium chloride. The n-heptane
was dried finally by reflux over and distillation from
sodium metal with the aid of the modified stillhead
described above.
Glyme was dried by reflux over and distilled from
sodium.
n-Pentane (Eastman) was purified and dried in the same
manner as n-heptane.
Tetrahydrofuran was purified by reflux over sodium and
distilled.
Sodium hydride (a 54% dispersion in mineral oil from
Metal Hydrides Inc.) was washed free of oil with anhydrous diethyl ether quickly weighed and then used immediately.
Potassium (BDH) was purified under an atmosphere of nitrogen in n-heptane by heating the metal past its melting point gently swirling the metal free of its oxide "skin" and letting it solidify again. The metal was removed, weighed and then used immediately. (An alternate but wasteful method of purification was to cut the oxide coating away under xylene). Sodium (J.T. Baker) metal could be similarly purified.
Sodium-potassium alloy was prepared by melting together sodium (23 g) and potassium (119 g). The alloy was trans• ferred to a ground glass Erlenmeyer and stored under 1 cm - 109. -
of paraffin oil until needed. This alloy referred to as
"stock alloy" was used for all debrominations of the adamantane bromides.
All other chemicals used were reagent grade or better and were used directly, as received.
A. Preparation of Brominated Adamantanes
1. Preparation of 1,3-Dibromoadamantane
An anhydrous stirred solution of aluminum tribromide
(1.7 g) in bromine (105 ml) v/as prepared in a 250 ml two- necked round bottomed flask fitted witn a stopper and a condenser topped with a drying tube*. Due to the high exothermicity of tne reaction, the solution was cooled between 0 6
0 C and 7 0 in an ice-bath while commercial grade adamantane
(32.0 g) was added (1.3 hr;. The excess bromine v/as decom• posed v/ith excess sodium Disuifite (120 g) after pouring the reaction solution into ice water (900 ml) and carbon- tetrachloride (4/5 ml). The phases were separated, the aqueous layer back-extracted v/ith carbontetrachloride and the pooled organic phases dried over anhydrous calcium chloride. Rotary evaporation gave a slightly yellow, crystalline product (c_a. 69 g). Analytic glpc, using the o Carbov/ax column at 200 C, 52 ml per min, shov/ed only one
A hydrogen oromide gas trap v/as connected to the drying tube or paper towelling was wrapped in a cylinder around the end and the reaction v/as performed in the fume hood. - 110 -
major product, 7.0 min, in the trace. 'Four recrystallizations from cyclohexane gave analytically pure white crystalline solid (35 g, 92%), mp (sealed capillary tube) 108-111°C
(reported 112-113°C, also 108-109°C).9
The infrared spectrum (CHC1,) showed^ „ at: 2880 (s),
1450 (s), 1340 (s), 1320 (s), 1280 (s), 1100 (w), 1020 (s),
995 (m), 983 (w), and 955 cm"1 (s).
The nmr spectrum (chloroforra-d) showed the following resonances: 2.86, singlet, 2 protons of the C-2 methylene;
2.30, singlet, 10 protons of the C-4,8,9 and 10 methylenes and C-5 and 7 bridgeheads; and 1.72 S, singlet, 2 protons of the C-6 methylene.
c Anal. Calcd. for 10H1^Br2: C, 40.84; H, 4.73; Br, 54.36.
Found: C, 40.61; H, 4.83; Br, 54.54.
2. Preparation of 1,3,5-Tribromoadamantane
In the same apparatus used for the preparation of 1,3- dibromoadamantane an anhydrous solution of aluminum tribromide o (3.8 g) in bromine (63 ml) was cooled to 0 C before commercial adamantane (17.5 g) was added over 2 hr so that the tempera- o ture did not exceed 6 C. The reaction was allowed to reach room temperature and continued for 3 days before analytic glpc showed no 1,3-dibromoadamantane, 7 min, remained.. o
The base-washed Carbowax column at 200 C indicated the presence of only one major product, 19 min. A minor - Ill -
by-product, 34 min, was shown not to be superimposable
upon the authentic 1,3,5,7-tetrabromoadamantane trace.
The reaction product was poured into ice water (1000 ml)
and carbontetrachloride (350 ml). The excess bromine was
decomposed with sodium bisulfite (80 g) by adding small
portions (c_a. 1 g) over 4 hr so that the temperature did o not rise above 6 C. The two phases were separated, dried,
and the solvent distilled off as described for the prepara•
tion of 1,3-dibromoadamantane. A pale yellow crystalline
solid (47.8 g) was obtained. Four recrystallizations
from methanol and two from n-hexane gave an analytically
pure white crystalline solid (36.1 g, 75%), mp (sealed
tube) 121.5-124°C (reported 126-127°C).9
The infrared spectrum (KBr disc) showed 1? at: 2880 max
(s), 1450 (s), 1345 (m), 1325 (w), 1310 (s), and 1280 cm"1
(s).
The nmr spectrum (chloroform-d-^) showed the following resonances: 2.78, singlet, 6 protons of C-6,8 and 10 methylenes; 2.35, singlet, 1 proton of C-7 bridgehead; and
2.25 5 , singlet, 6 protons of C-4,6 and 8 methylenes.
c Anal. Calcd. for ^1Q\^y , 32.26; H, 3.38; Br, 64.35. Found: C, 32.28; H, 3.51; Br, 64.28.
3. Preparation of lt|3 ,5,7-Tetrabromoadarnantane
The compound 1,3,5,7-tetrabromoadamantane was prepared - 112 -
directly from adamantane by a modification of the Stetter and Wulf9 method, developed by Scott.^
The apparatus and the first part of this procedure v/a identical to that described for the preparation of 1,3- dibromoadamantane. Commercial grade adamantane (10 g) was added to a solution of aluminum tribromide (0.18 g) in bromine (45 ml) which was cooled sufficiently to control the vigorously exothermic reaction. The reaction mixture was refluxed (6 hr) and allowed to stand overnight.
Analytic glpc using the Phenoxysilicone grease column*, o at 240 C, 54 ml/min, of an aliquot decomposed by sodium bisulfite and neutralized with sodium bicarbonate showed only one major product, 3.2 min. Authentic 1,3,5-tribromo adamantane had an identical retention time.
The bromine solution containing the 1,3,5-tribrorno- adamantane was quickly transferred with a micropipette to anhydrous, nitrogen filled Carius tubes of two sizes.
Each of the two large tubes was filled to 1/3 of capacity
(15 ml) as were the eight small tubes (1.5 ml).
The remaining portion of this reaction solution (5.5 : for which no tubes were available was treated as described in the preparation of 1,3,5-tribromoadamantane and this
* The maximum recommended temperature for this column was 275 0. This column was used for compounds which had an inconveniently long retention time or decomposed on the Carbowax column. - 113 -
crude tribromide compound (5.43 g) was isolated. After
freezing the contents in liquid nitrogen, the tubes were sealed under high vacuum and were enclosed in brass bombs. o The bombs were heated to 165 i 2 C (2.5 da) before analytical glpc indicated the reaction was complete. The tubes were opened after freezing their contents once again in liquid nitrogen. The product suspension was divided into two parts. Each was emptied into ice water (900 ml) and carbontetrachloride (1500 ml). Sodium bisulfite (30 g) was added (1 hr) while keeping the contents cool with an ice bath. The workup was identical to that described for
the preparation of 1,3-dibromoadamantane. This procedure yielded crude 1,3,5,7-tetrabromoadamantane. Analytical o
glpc using the Phenoxysilicone grease column at 240 C,
54 ml/min, showed one major product, 4.6 rain. Several minor products; 3.2 (1,3,5-tribromoadamantane), 7.0 and
9.5 min were also observed. Fractional recrystallization
from carbontetrachloride gave (18.3 g, 46%) of an analytically pure white granular solid, mp (sealed tube)
246-8°C (reported 246-7°C).9
The infrared spectrum (nujol) showed the following
1) : 1320 (s), 1220 (m), 990 (m), 848 (s), and 720 cm"*1
(s).
The nmr spectrum (chloroforra-d-^) showed only one
resonance: 2.70 £ , singlet, 12 protons of the methylenes. - 114 -
Anal. Calcd. for C^H^Biy C, 26.55; H, 2.65; Br, 70.79. Found: C, 26.73; H, 2.56; Br, 70.51.
B. Preparation of 1,5-Dehydroadamantane - Representative
Reactions
1. Treatment of 1,5-Dibronioadamantane i-n fflyme with
Lithium aluminum hydride
An anhydrous three-necked flask (100 ml) was fitted with a condenser and a drying tube and stoppers. Lithium
aluminum hydride (1.0 g) was added to a solution of
dibromoadamantane (2.0 g) in glyme (50 ml). After several
days of reflux one-half of the starting material had been
consumed. The only visible product of this reaction was
identified as adamantane by superposition v/ith the authentic
compound.
2. Treatment of l,3-Di"bromoadamantane with Magnesium
A solution of 1,3-dibromoadamantane (0.50 g) in
anhydrous ether (5.0 ml) v/as added from a dropping funnel
with side arm into a dry, nitrogen flushed three-necked
100 ml flask containing powdered magnesium metal (0.15 g)
and a stirrer. Anhydrous conditions v/ere maintained by a
drying tube on the condenser. A crystal of iodine (ca. 10 mg)
was required to initiate the reaction; then the reaction - 115 -
mixture was diluted with anhydrous ether (45 ml). The
reaction was followed by analytic glpc using the Carbowax o o column at 80 C and at 200 C. The reaction was almost
half completed (15 hr) when glpc showed the ratio of the
desired compound to that of the reduction by-product was
less than unity; thus, the reaction was abandoned in favour
of tne alkali metal debromination method v/hich already had
produced much better yields of the desired compound.
5. Preparation of DHA from 1,5-Dibromoadamantane
The following reactions were repeated many times for
the preparation and study of DHA. Only those reactions
which gave the most representative yields were recorded
below as representative reactions.
a) Potassium metal in n-heptane
An anhydrous 250 ml three-necked rlask was fitted with a drying tube and dry nitrogen inlet; each was separated
from the flask with a 10 cm "extension" tube. The central
B-24 joint received the water cooled collar of the rheostat- controlled high speed stirrer*. The above apparatus will
De referred to as the usual apparatus in the following related experiments.
Lab Line Instruments, Inc. - 116 -
The system was purged with nitrogen. Under these anoxious and anhydrous conditions, 1,3-dibromoadamantane
(1.00 g) was dissolved in dry n-heptane (50 ml) before freshly cut potassium (2.5 g) was added. The temperature o v/as raised above the melting point of the metal (100 + 3 C) which v/as then dispersed by high speed stirring, then stirred more slowly. The reaction was followed by analytical glpc using the base-washed Carbowax column* v/ith a tempera- o ture program, (80°C/6 min 32 C/mirW200°C)**.
No significant reaction took place until tertiary- butyl alcohol (ca. 0.05 nil) v/as added. Analytical glpc o (35 min) with temperature programming (80°C/6 min , J>- C/min^ o
200 C) showed the reaction was complete by the absence of 1,3-dibromoadamantane, 17.2 min***, and the appearance of two major peaks, 4.3*** and 5.3 min. The second peak, 5.3 min, disappeared when the system was titrated with o bromine at -75 0. 1,3-Dehydroadamantane decomposed on all acid washed or contaminated columns. ** The carrier flowrate was found to vary v/ith temperature. *** Established with authentic 1,3-dibromoadamantane and adamantane respectively. - 117 -
Analytical glpc using the Carbbwax and the Phenoxysilicone grease columns, identified the bromination product as 1,3- dibromoadamantane by superposition of the respective traces with authentic material.
The yields of adamantane (0.060 g, 13.0%) and 1,3- dibromoadamantane (0.593 g, 59.2%) were determined by comparison with solutions of the authentic compounds.
From the above data the yield of the new compound DHA
(0.270 g, 59.2%) was calculated.
This compound, 9.5 min, was separated from the adamantane by-product by preparative glpc using a 10 ft x 3/8 in Carbowax 20M (10%) on base washed (60/80 mesh)
Chromosorb "W" in an aluminum column at 110°C, 86 ml/min.
Each injected aliquot (2 ml) of the product solution
(ca. 4 x 10~3M) allowed the isolation of a colorless volatile solid (4-6 mg) having no distinct melting point
(sealed tube). o When heated, the neat compound polymerized at ca. 160 C o giving a colorless solid which did not melt below 350 C. o This solid turned brown in air above 450 C. Under nitrogen o and above 500 C, it remained colorless, but a white sublimate condensed on the cover slip, showing decomposition occurred.
The compound decomposed in all solvents used (for example, CS^, C^, CHCl^, CCl^) for infrared analysis. - 118 -
The infrared spectrum (CSp) showed the following 1? nici x 3040 (w), 2900 (s), 2055 (m), 1285 (s), 1270 (w),
1100 (m), 1080 (s), 1030 (m), 995 (m), 942 (m), 900 (m),
790 (s), 745 cm"1 (s). The infrared spectrum (CC1, ) showed
The nmr spectrum (degassed benzene) showed the
following resonances: 2.73, broad singlet, 2 protons of
the C-5,7 bridgeheads; 2.05, triplet, J = 1.2 Hz, 2 protons
of the C-6 methylene; 1.66, closely spaced multiplet, 2 protons of the C-2 methylene; 1.91, doublet, J = 11 Hz,
4 protons of C-4,8,9 and 10 (endo-equatorial protons) methylenes; and 1.15 £ , doublet, J = 11 Hz, 4 protons of
0-4,8,9 and 10 (exo-axial protons).
The high resolution mass spectrum showed a peak
+ c H with m/e at 134.1086 + 0,001; calculated for 10 lif*
134.1095.
The high reactivity of DHA with oxygen precluded accurate and consistent analytic results. However, analysis
of the thermally treated DHA sample compound gave the following results:
C H ; Anal. Calcd. for 10 14 C, 89.49; H, 10.51.
Found: C, 89.30; H, 10.90.
b) Sodium-potassium alloy in n-heptane
The usual apparatus was dried and purged with nitrogen.
In this apparatus a solution of 1,3-dibromoadamantane - 119 -
(1.00 g) was prepared in n-heptane (50 ml) near its boiling point. Sodium-potassium alloy (0.76 g, 1:5.17 by weight) v/as delivered from a tarred nitrogen filled ary micropipette and was dispersed.
The reaction progress was monitored by analytical o glpc using the Phenoxysilicone grease column at 240 C to observe the disappearance of 1,3-dibromoadamantane, ca. 1.2 min. No reaction occurred (25 rain) until tertiary-butyl alcohol (ca, 0.05 ml) v/as added. Only a trace of the 1,3-dibromo compound remained (35 min) after the reaction was initiated. Further reaction (8 min) removed this trace.
The yield of DHA (0.23 g, 50.3%) was determined by titration v/ith iodine (0.43 g) and by analytical glpc comparison of tne reaction product with a standard solution of authentic 1,3-di-iodoadamantane using the base-washed o
Carbowax column at 200 C. The yield of adamantane
(0.0224 g, 4.8%) was determined in a similar fashion.
c) Sodium-potassium alloy in diethyl ether
A solution of 1,3-dibromoadamantane (1.01 g) and dry diethyl ether (60 ml) v/as prepared under nitrogen in the usual apparatus. This solution v/as treated at room temperature v/ith sodium-potassium alloy (0.74 g, 1:5.17 by weight) which was dispersed by high speed stirring.
Analytical glpc (1 hr) showed that no 1,3-dibromoadamantane remained. - 120 -
The procedure described in the following two paragraphs
will be henceforth referred to as distillation-sublimation.
The reaction flask was attacned to the distillation-sub•
limation apparatus*, then cooled to Dry-Ice temperature.
The ether was distilled from tne reaction vessel under a
high vacuum at room temperature and lower as evaporation
occurred. The entrainment of tne volatile reaction product
and by-product was minimized by a mixture of carbon- o tetrachloride and Dry Ice (a temperature of ca. -15 C) in
the tip of the condenser.
The sublimation was performed in the same apparatus immediately after distillation by replacing the carbon-
tetrachloride-Dry Ice in the tip of the condenser with acetone-Dry Ice. The sublimation (ca. L hr) could be
^—B-19 to hose-adaptor l-*—high vacuum hose
to vacuum
clam ps tip
magnetic V—~~^ reaction mixture
stirring bar L- _i: , i III — ^ — * • • • — This modified Dry Ice condenser and flask was used whenever distillation-sublimation was performed. - 121 -
accelerated by application of warm water baths. Upon
completion, the tip was allowed to reach room temperature
in isolation before breaking the vacuum, scraping off the
sublimate, weighing without delay, and storing under an
inert atmosphere.
The weight of the crystalline volatile white sublimate
(0.392 g, 84.5%) was determined. Repeated injections showed
that the ratio of adamantane to DHA was 1:2.28; thus, the
yields of adamantane (0.119 g, 25.5%) and DHA (0.272 g,
29%)* v/ere calculated.
d) Sodium-potassium alloy in ether initiated by alcohol**
The usual apparatus v/as assembled. Under anhydrous and anoxious conditions, a solution of 1,3-dibromoadamantane
(1.00 g) in ether (50 ml) was treated v/ith a large excess of finely dispersed sodium-potassium alloy (0.739 g,
1:5.17 by weight). No significant reaction took place
(30 min); therefore t-butyl alcohol (ca. 2 ml) was added
(0.05 ml/15 sec) from a dropping funnel with a side arm.
Analytical glpc showed no 1,3-dibromoadamantane v/as present
(55 min).
*• The accuracy of these figures depends upon two assump• tions: 1,3-dehydroadamantane does not decompose or react significantly during glpc analysis, and ionizes to the same extent as adamantane wnen combusted by the hydrogen flame. Tne validity of these assumptions was confirmed by bromination of DHA and isolation of the dibromide. The hydrogen flame was found to be sufficiently hot to ionize even OCl^ to a small but significant extent.
** Small amounts of hydroxlic solvents removed the erratic initiation and reaction times for this reaction. .- 122 -
Distillation-sublimation yielded a white volatile solid mixture (0.352 g, 77%). Gas chromatography established the ratio of adamantane to DHA (1:3.64). The yield of DHA
(0.276 g, 60.5%) and that of adamantane (0.076 g, 16.7%) was calculated from the above data.
o
e) Sodium naphthalide in ether at -75 0
The naphthalide was prepared at room temperature from dispensed alloy (0.633) and naphthalene (2,1 g) in the usual apparatus except for a larger flask (250 ml). The usual dry an anoxious conditions were maintained throughout the experi- o ment. At -75 0 the 1,3-dibromoadamantane (0.50 g) in anhydrous ether (5.0 ml) v/as added (5 min). The reaction (4 hr) was followed by a glpc using the Carbov/ax column. The yield of -
DHA (0.165 S» 72.5%) was determined by analytical glpc trace comparison of the reaction solution v/ith a standard solution of adamantane, since distillation-sublimation was not feasible due to co-sublimation of naphthalene.
An equally efficient and consistent yielding method for the synthesis of DHA utilized the n-butyl lithium and hexamethylphosphoramide (HMPA) debrominating reagent in ether infra vide; however similar to the above reaction, contamina• tion of the sublimate occurred by HMPA and low-boiling by• products so that the sublimate at times was a semi-solid.
For studies which required the purist possible sublimate, eg. thermal decomposition kinetics, the lower yielding less consistent more time consuming Na-K alloy in ether debroraina- - 123 -
tion reaction v/as used. The glpc analysis of the latter
sublimate showed only adamantane as the only significant
by-product.
f) n-Butyl lithium and hexamethylphosphoramide in
diethyl ether
An anhydrous solution of 1,3-dibromoadamantane in
ether (25 ml) and HMPA (3.0 ml) v/as prepared in 100 ml
three-necked round bottomed flask under an inert atomosphere.
The solution was cooled to -30°C before 0.88 M n-butyl
lithium in n-hexane (5.0 ml) v/as added (5 min) to the
rapidly stirred solution by syringe through a serum cap.
After adding n-butyl lithium solution (1.5 ml), a thick
and milky phase formed, only to disappear after more n-butyl
lithium solution (4.0 ml) was added.
The reaction mixture v/as allowed to reach room tempera•
ture before it v/as extracted four times with deoxygenated, nitrogen saturated water (total, 40 ml). The organic
layer was diluted (50.0 ml) in a volumetric flask after
drying v/ith magnesium sulfate under a nitrogen atmosphere
and filtering off the drying agent. Comparison of this
solution with an authentic adamantane solution by analytical
glpc using a base-washed Carbowax column at 80°C, disclosed
the yield of DHA (0.328 g, 72%). Using this procedure, only a trace of adamantane was produced. In a typical experiment
1 to 2% of the starting material remained. A by-product - 124 -
(ca. 5%) was isolated by column chromatography on Woelm
grade I neutral alumina. Its nmr spectrum (CCl^) had the
following resonances: 2.24, sharp singlet, 4 protons of C-8
and 9 methylenes; 2.16, obscured singlet, 2 protons of C-2
methylene; 2.06, sharp singlet, 2 protons of C-6 methylene;
1.66, unresolved multiplet, 2 protons of C-5 and 7 bridgeheads;
1.50, sharp singlet, 4 protons of the C-4 and 10 methylenes;
1.20, sharp unresolved multiplet, 6 protons of the n-butyl methylenes; and 0.88 £ , triplet, 3 protons of the n-butyl methyl group.
4. Preparation of DHA from l,5,5»7-Tetrabromoadamantane
a) Sodium-potassium alloy in n-heptane
The usual apparatus was dried, assembled, and purged with nitrogen gas. A solution of 1,3,5,7-tetrabromoadamantane
(1.537 g, 3.4 x 10*~3 moles) in dry n-heptane (60.0 ml) at o
100 + 3 C was prepared in this apparatus before the sodium- potassium alloy (1.215 g, 1:5.17 by weight) was added to
the flask from a dry nitrogen gas filled micropipette.
The alloy was dispersed into a very fine suspension by high
speed stirring (3-4 min). This uninitiated reaction (10 hrs) was monitored by observing the disappearance of starting material by analytical glpc using the Phenoxysilicone grease o column at 240 C# - 125 -
Upon completion, analytical glpc using the Carbowax o column at 80 C, indicated that adamantane (O.O664 g,
and DHA (0.155 g, 35%) were tne only visible compounds produced. These peaks v/ere identified by superposition with authentic material. The presence of the sought symmetrical 1,3,5,7-dehydroadamantane compound was not observed. Similarly, no compounds corresponding to
5,7-dibromo-DHA or 5-bromo-DHA were observed by glpc.
During the reaction, only the glpc traces of 1- bromoadaraantane, 1,3-dibromoadamantane and 1,3,5-tribromo- adamantane were observed and identified by superimposition with the authentic compounds. Temperature programmed glpc v/as performed using the Phenoxysiliccne grease column, 0 (240°C/20 min 20 C/mxrW275°C), and the silicone elastomer column (240°C/15 min 20 C/min»».2750C), and the base- o washed Carbowax column at 200 C for more than 90 min.
Analytical temperature programmed and regular glpc of aliquots treated witn iodine showed no peak v/ith a retention time corresponding to that of the 1,3,5,7-tetraiodoadamantane.
The major product, 1,3-di-iodoadamantane, was identified on the Carbowax column by superimposition with authentic material.
b) Sodium-potassium alloy in diethyl ether
A solution of 1,3,5,7-tetrabromoadamantane (1.537 g) in dry diethyl ether (75 ml) was prepared in the usual - 126 -
apparatus. Under anhydrous and oxygen-free conditions sodium-potassium alloy (1.301 g, 1:5.17 by weight) was delivered from a dry nitrogen flushed micropipette and dispersed into a fine suspension.
Tertiary-butyl alcohol (ca. 0.05 ml) was added to initiate the reaction.
The reaction was monitored by analytical glpc using o the Phenoxysilicone grease column at 2^0 C. During the reaction, decreasing trace areas were observed for 1,3,5- tribromoadamantane, 1,3-dibromoadamantane, and 1- bromoadamantane. At completion (1.5 hr) no companion peaks which might indicate the presence of 5,7-dibromo-
1,3-dehydroadamantane and 5-bromo-l,3-dehydroadamantane were observed using the base-washed Carbowax column at o 200 C. Adamantane and DHA were observed using this o
Carbowax column at 80 C. The prime object of this experi• ment, 1,3,5,7-didehydroadamantane was not observed. An examination of aliquot, titrated with iodine and bromine in the manner described in the preceding experiment
failed to indicate the presence of 1,3,5,7-tetraiodoadamantane, or 1,3,5,7-tetrabromoadamantane on either the carbowax or silicon elastomer columns at their maximum temperatures. The reaction product (0.176 g) was isolated by distilla• tion-sublimation. Analytical glpc using the Carbowax o column at 80 C determined the yield of adamantane - 127 -
(0.026 g, 5.8%) and DHA (0.150 g, 33.8%). Additional
DHA (8.6%) was found in the distillate.
5. Preparation of DHA from 1,3,5-Tribromoadamantane
a) Sodium-potassium alloy in diethyl ether without
initiator
Dry nitrogen was used to clear the oxygen from the anhydrous apparatus which is described in the procedure for preparing DHA from 1,3-dibromoadamantane with potassium in n-heptane. A solution of 1,3,5-tribromoadamantane
(1.265 g, 3.4 x 10*~3 moles) in dry ether (50.0 ml) was prepared in this apparatus. A dry oxygen-free micropipette was used to deliver the sodium-potassium alloy (0.941 g,
1:5.17 by weight) into the reaction flask. Several minutes of high speed stirring dispersed the alloy into a fine suspension.
The disappearance of 1,3,5-tribromoadamantane, 3.1 min, was followed by analytical glpc using the Phenoxy-
O o / silicone grease column at 240 C, 48 ml/min. No 1,3,5- tribromoadamantane was evident in the glpc trace (1 hr).
The reaction products were isolated by distillation- sublimation. The usual crystalline white solid (0.248 g) was obtained. By analytical glpc, using the Carbowax column, the ratio of adamantane (0.031 g, 6.5%) to DHA - 128 -
(0.218 g, 47.8%) in the sublimate was found to be 1:7.21.
Entrainment by the distillate accounted for an additional amount of DHA (8.3%).
b) Sodium-potassium alloy in diethyl ether v/ith an
initiator
Anhydrous and oxygen-free conditions v/ere established in the usual apparatus. The 1,3,5-tribromoadamantane
(1.00 g, 2.67 x 10"3 moles) was dissolved in dry ether
(50.0 ml). The sodium-potassium alloy (0.74 g> 1:5.17 by weight) was added to the apparatus from a dry inert atmosphere filled micropipette. After negligible progress
(20 min), the tertiary-butyl alcohol initiator (ca. 2 ml) was added (0.05 ml/15 sec) from a dropping funnel with side arm. The reaction was stirred for a further period
(25 min; total, 65 min) before analytical glpc, using the o
Phenoxysilicone grease column at 240 C, 48 ml/min, showed no starting material, 3.1 min, remained.
The colorless volatile mixture (0.264 g) was isolated by distillation-sublimation. A tiny sample was dissolved 0 in ether. Using the Carbov/ax column at 80 C, analytic glpc of this solution shov/ed the ratio of adamantane
(0.036 g, 9.9%) and DHA (0.228 g, 63.5%) to be 1:6.5.
The yields were calculated from this ratio and the sublimate weight. - 129 -
C. Reactions of 1,3-DQhydroadamantane
1. Reaction of DHA v/ith Oxygen - Preparation of
Polyperoxyadamantane
A solution of adamantane (0.033 g) and DHA (0.367 g) in n-heptane (50.0 ml) v/as prepared in a 100 ml single necked round bottom flask. Oxygen (25 ml/min) v/as bubbled through this solution for 15 hrs.
The supernatant liquid was separated from the
floculent white precipitate by suction filtration through a sintered glass funnel of medium coarseness. By using the Carbowax column (80°C/6 min 32 •C//m:Ln a»20OC), this supernatant liquid v/as shown to contain only one major compound and many minor compounds. This major compound v/as apparently formed by the thermal decomposition of the soluble fraction of the peroxypolymer in the input manifold of the glpc. This major compound v/as found to be super- posable with authentic 1,3-dihydroxyadamantane*, 90 min, using the above Carbowax column at 200°C, 68 ml/min. No assymmetry or broadening of the major compound glpc trace
Authentic 1,3-dihydroxyadamantane was prepared from 1,3-dibromoadamantane by a method Stetter and Wulf9 used to prepare 1-hydroxyadamantane from 1-bromoadamantane. A poor yield of 1,3-dihydroxyadamantane was obtained. Recrystallization several times chloroform gave an analytically pure sample of 1,3-dihydroxyadamantane. - 130 -
compared with the authentic compound trace was noted.
This thermal decomposition also was the source of many
of the minor glpc traces. By comparison with an authentic
solution an estimate was made of 1,3-dihydroxyadamantane
(0.045 g, 10.4%) in the supernatant liquid (0.211 g, 46%).
The fluffy white solid (0.211 g, 46%) was triturated o in benzene, suction filtered and dried in vacuo at 50 C overnight to give an analytical sample, ep (explosion o point) 146 C. The polymer was not soluble in any of the
common organic solvents. The infrared spectrum (nujol mull) showed at: ill 3.X
3400 (m), 1755 (shoulder), 1720 (s), 1360 (s), 1320 (s),
1280 (s), 1240 (w), 1150 (w), 1115 (s), 1097 (shoulder),
1040 (w), 995 (s), 940 (m), 895 (m), 835 (w), 800 (w), and 775 era"1 (w).
c Anal. Calcd. for 10Hlif02: C, 72.26; H, 8.49.
Found: C, 72.55; H, 8.28.79a
a) Reduction of the peroxypolymer
The reaction was carried out in a dry single necked
100 ml round bottomed flask fitted with an ether condenser and drying tube. The peroxypolymer (0.052 g) was treated with a suspension of lithium aluminum hydride (1.0 g) in - 131 -
dry refluxing ether (60.0 ml) for 45 hr. Water (1.0 ml)
then 15% sodium hydroxide (1.0 ml) followed again by water (3»1 ml) was added dropwise to stop the reaction.
The granular precipitate of inorganic salts was suction
filtered from the supernatant liquid. Tne ether layer was extracted with water (15 ml), dried over anhydrous
sodium sulfate, and filtered. The solvent was removed by
rotary evaporation to give a crystalline white solid
(0.029 g). Analytical glpc using the Carbowax column at o
200 C, 68 ml per min, snowed one major compound, 9.0
min,;and many very minor ones. The identical retention
time of authentic 1,3-dihydroxyadamantane and the major
reduction product as well as the observed analytical glpc
trace enhancement on this same column resulting from
enrichment of the product solution with authentic dihydroxy
compound identified this product. Two recrystallizations
from chloroform yielded fine wnite needle-like crystals
(0.021 g) whose infrared and nmr spectra were identical
with the spectra of the authentic 1,3-dihydroxyadamantane.
2. Halogenation of DHA
o a) Bromination of DHA in n-Heptane at -75 0
A rapidly stirred solution of DHA (0.260 g) in n- o heptane (10.0 ml) at -75 0 under an inert atmosphere was - 132 -
titrated with bromine (0.668 g). The resulting floculent pale-yellow precipitate was collected in a sintered glass
Buchner funnel, cooled by passing n-heptane (5 nil) at o
-75 0 through the funnel, followed by a few ml of liquid air.
During the filtration, the funnel was cooled by cold air generated by passing air through liquid air. Passage of warm air through the pale yellow fluffy precipitate caused a colour change from yellow to orange. Furtner passage of air left a white solid (0.527, 91.8%) identified as 1,3-dibromoadamantane by glpc trace superposition and infrared and nmr spectral comparison with spectra of an authentic sample.
Analysis of the filtrate by analytical glpc (after removal of excess bromine with solid potassium carbonate) disclosed the presence of more 1,3-dibromoadamantane
(0.042 g, 7.3%; total yield; 99%).
b) Bromination of DHA in Diethyl Ether at -75°C
i) Decomposition of the intermediate in ether
A rapidly swirled ether solution (25.0 ml) containing
DHA (0.167 g) at -75°C was titrated with bromine (0.775 g).
The resulting floculent lemon-yellow precipitate was o resuspended twice with ether (50 ml) at -75 0, settled by - 133 -
centrifugation, and the supernatant liquid pipetted off
to remove the excess bromine.
The solid was suspended in ether (250 ml) and potassium o carbonate (4 g) at -75 0 was added before allowing the stirred suspension to reach room temperature.
The inorganic solids were removed by filtration and the filtrate concentrated by rotary evaporation. The resultant brown oil was diluted (25.0 ml) with oenzene. o
Qualitative glpc using the usual Carbowax column at 200 C,
51.5 ml/min, indicated the presence of 1,3-dibromoadamantane
(0.113 g, 28.7%), 7.0 min, and another product (0.24 g,
67.8%), 5.5 min assayed by comparison of this product with a standard 1,3-dibromoadamantane solution.
The major product, l-bromo-3-ethoxyadamantane, was isolated by column chromatography of the reaction mixture on V/oelm grade I neutral alumina (15 g). 1,3-Dibromoaaamantane (0.109 g) was eluted with cyclohexane (250 ml). The major product (0.077 was eluted with 9:1 cyclohexane:benzene (80 ml) and then 1:1 cyclohexane:benzene (200 ml) eluted more major product
(0.048 g). Flushing the column with chloroform (100 ml) gave a brown oil (0.050 g) consisting mainly of the major product.
The infrared spectrum of the neat compound showed the following Vmax: 2940 (s), 1480 (w), 1388 (w), 1360 (w), - 134 -
1340 (m), 1320 (m), 1295 (m), 1280 (w), shoulder, 1233 (w),
1158 (w), 1113 (s), 1090 (s), 1050 (m), 964 (s), 940 (w),
972 (m), 824 (s), 788 (w), and 738 cm"1 (m).
The nmr spectrum (chloroform-d) gave the following resonances: 3.47 quartet, J = 7.0 Hz, 2 protons of the ethoxyl methylene; 2.29, unsymmetrical doublet, 8 protons of the C-5 and 7 bridgehead and C-3,9 and 10 methylenes;
1.27, unsymmetrical doublet, 6 protons of the C-4,6 and 8 methylenes; and 1.148 > triplet, J = 7.0 Hz, 3 protons of the etnoxy methyl.
The nmr spectrum (benzene) gave the following resonances: 3.19, quartet, J = 7.0 Hz, 2 protons of the ethoxyl methylene; 2.29, singlet, 2 protons of the C-2 methylene; 2.03, unsymmetrical doublet, 4 protons of the
C-9 and 10 methylenes; 1.79, unresolved multiplet, 2 protons of the C-5 and 7 bridgeheads; 1.47, unsymmetrical doublet, 4 protons of the C-4 and 8 methylenes; 1.17, unresolved multiplet, 2 protons of the C-6 methylene; and 1.0b6, triplet, J = 7.0 Hz, 3 protons of the ethoxy methyl.
In the mass spectrum of the compound (molecular weight, 258, 260) no parent peak was seen: m-45 were the first peaks observed.
Anal. Calcd. for C^H-^OBr: C, 55.7; H, 7.34; Br, 30.9.
Found: C, 55.50; H, 7.21; Br, 30.79. - 135 -
a) Conversion of l-bromo~3-cthoxyadamantane to
1,3-dibromoadainantane
To l-bromo-3-ethoxyadamantane (O.298 g) in benzene
(0.2 ml) contained in-a 10 ml round bottomed flask a solution of kS% hydrogen bromide in concentrated sulfuric acid (10.0 ml) was added and the reaction v/as heated on a steam bath (5.75 hr) v/ith occasional sv/irling and allowed to stand at room temperature overnight. Sodium bicarbonate was added until the.acid was neutralized. The remaining salts and organic reaction products v/ere dissolved in water (15 nil) and benzene (15 ml). The phases v/ere separate and the water layer was back-extracted with benzene (5 ml).
The pooled benzene solution was dried over anhydrous sodium sulfate, suction filtered and diluted (25.00 ml) with benzene. Comparison of this solution with one containing authentic 1,3-dibromoadamantane gave the yield of the conversion of l-bromo-3-ethoxyadamantane to 1,3-dibromo• adamantane (0.253 g| 74.8/o) after correcting for the 1,3- dibromoadamantane (0.013 g) in the l-bromo-3-ethoxyadamantan preparation.
The identity of the reaction product, 7.3 min, v/as
established in the following manner. First, using the 0
Carbowax column at 200 C, 45 ml per min, the reaction product was enriched with authentic 1,3-dibromoadamantane
and enhancement of the reaction product peak was observed.
Second, the crude reaction product (0.287 g) was isolated - 136 -
by rotary evaporation and recrystallized once from n- hexane. The infrared spectrum of the crystals was identical to the infrared spectrum of authentic 1,3-dibromoadamantane.
b) Characterization of the lemon-yellow
precipitate, (l-bromoadamant-3-yl) diethyl oxonium
tribromide
The lemon-yellow precipitate was prepared under nitrogen from 1,3-dehydroadamantane (0.157 g) in ether o (25.0 ml) at -75 0 by the addition of bromine. The excess bromine was removed by resuspending the finely dispersed o solid in ether at -75 0, centrifuging, and pouring off the supernatant liquid, until the final supernatant liquid was colorless. The precipitate was dried by evaporating the o residual ether under vacuum at -75 C The precipitate was suspended in carbontetrachloride (50 ml) and allowed to dissolve while reaching room temperature. The solution was diluted (100.0 ml) and compared spectrophotometrically at 415 mjj (optical density in a 0.2 cm quartz cell, 0.43 units) with authentic solution of bromine in carbon• tetrachloride (0.211 g/100.0 ml; optical density in a 0.2 cm quartz cell, 0.54 units). Care was taken to maintain dark conditions, e.g. volumetric flasks were wrapped in aluminum foil and manipulations were performed in darkened rooms. By this method it was shown that molecular bromine
(0.169 g, 90.5%) was released from the trialkyi oxonium compound by its thermal decomposition. - 137 -
The microanalysis of the intermediate itself was not successful. These variable results were obtained due to decomposition before analysis could be carried out. The isolated precipitate was found to be soluble in moderately polar solvents such as acetone, nitromethane ana acetonitrile.
The compound could oe reprecipitated from these solutions o by addition of dietnyl ether at -75 C Low temperature o nmr (acetone-dg) under a nitrogen atmosphere at -65 C showed the following resonances: 5.19, quartet, J = 7.0
Hz, 4 protons of the oxonium ether methylenes; 3*37, quartet, methylene of the trace of ether solvent; 3.07, singlet, 2 protons of the C-2 methylene; 2.59, singlet,
6 protons of the C-9 and 10 methylenes and C-5 and 7 bridgeheads; 2.36, singlet, 4 protons of the C-4 and 10 methylenes; 2.15, quintet, trace of acetone in solvent;
1.71, complex triplet, 8 protons of the oxonium ether methyls and C-6 methylene; and 1.10 S, triplet, methyl of the trace of ether solvent.
By raising the temperature slowly the spectrum of the o intermediate compound was shown to change rapidly at -25 C
(over 10 min). At -35 C very little change was.observed.
ii) Decomposition of the intermediate in 95%
ethanol
A rapidly swirled ether solution (250 ml) of DHA
(0.165 g) at -75-0 under nitrogen was titrated with bromine - Ijo -
(0.58 g). The supernatant liquid was removed and the o precipitate was washed twice with ether (50 ml) at -75 C.<
The residual ether was removed by evaporation in vacuo at o
-75 0. The lemon-yellow solid was suspended, stirred in
95% ethanol (950 ml) containing anhydrous powdered potassium carbonate (4 g), and allowed to reach room temperature overnight. This mixture was filtered then reduced to an oil by rotary evaporation. The residue v/as taken up in chloroform, washed v/ith water and the organic layer dried over anhydrous sodium sulfate filtered and the liquid evaporated. The residue was diluted with benzene (25.0 ml).
Analytical glpc showed that an excellent yield of 1-bromo-
3-ethoxyadamantane (0.298 g, 93.0%) had been obtained.
Analytic glpc revealed more 1,3-dibromoadamantane (0.056,
1.5%) and l-bromo-3-ethoxyadamantane (0.0072 g, 2.2%) in the pooled ether v/ashings.
iii) Decomposition of the intermediate in acetone-
sodium iodide solution
A rapidly swirled ether solution (25.0 ml) of DHA o (0.134 g) at -75 0 was titrated with bromine (0.445 g).
The lemon-yellow precipitate was v/ashed three times with o ether at -75 0, and the supernatant liquid v/as removed. The residual ether was removed by high vacuum pumping (8 hr) at o o -75 0. Acetone (25 ml) at the same temperature (-75 0) was used to dissolve the dry solid. This acetone solution - 139 -
was added rapidly to a solution of acetone (200 ml) at o
-75 0 containing sodium iodide (1.0 g). An immediate change (3 min) from yellow to a deep wine color resulted.
The crystals of iodine settled out completely (0.5 hr).
The supernatant liquid was decanted and stirred (16 hr) v/ith anhydrous sodium sulfite (5 g) to remove the free iodine. The solvent was removed by rotary evaporation and the residue partitioned betv/een water-benzene. The organic layer was dried and concentrated (25.0 ml). Quantitative glpc of this solution, indicated that only l-bromo-3- ethoxyadamantane (0.277 g, 100%) was present in a quanti• tative amount. No other compound was visible in the glpc o trace using the Carbowax column (80°C/6 min 32 C/min ^ o
200 C). The identity of the reaction product v/as confirmed by superimposition of authentic l-bromo-3-ethoxyadamantane on two different analytical glpc columns*, as well as by its infrared spectrum which v/as identical v/ith that of analytically pure l-bromo-3-ethoxyadamantane.
iv) Decomposition of the intermediate in
acetone-sodium cyanide solution
The complex was prepared by titrating DHA (0.134 g) o dissolved in ether (25.0 ml) at -75 0 under a nitrogen
* o The Carbowax column at 200 C and Phenoxysilicone grease column at 170€C were used. - 140 -
atmosphere witn bromine (0.560 g). The precipitate was washed and dried as described in the previous experiment. o
The solution of the complex in acetone (25 ml) at -75 C was added to a suspension of sodium cyanide (0.34 g) in acetone (200 ml) and stirred at -75°C The solution became colorless (4 hr). The solvent was removed by rotary evaporation and the residue partitioned between water and benzene. The organic layer was dried and concentrated
(25.0 ml). Qualitative glpc* indicated only l-bromo-3- ethoxyadamantane (0.271 g) was present. The identity of the reaction product was confirmed by peak enhancement studies** with analytically pure l-bromo-3-ethoxyadamantane.
Furthermore, the infrared spectrum of the reaction product and that of analytically pure l-bromo-3-ethoxyadamantane were found to be the same. No glpc trace which might indicate the presence of l-bromo-3-cyanoadamantane was observed.
v) Decomposition of the intermediate in acetone
solutions o
Bromination of DHA in diethyl ether at -75 C under nitrogen was performed. The yellow precipitate was isolated
* The Carbowax column v/as used with the usual temperature program. ** o The above column at 200 C and the Phenoxysilicone grease column at 170 C were used. - 141 -
o at -75 C by swirling, settling the precipitate by centri- fugation and then pipetting off the supernatant liquid and adding more cold ether until the final supernatant liquid was colorless. The residual solvent was removed by o evaporation at -30 C under high vacuum. The lemon-yellow solid was dissolved in acetone (50 ml) at -75° 0 and then diluted with acetone solutions (to 250 ml) at the same temperature containing various solvent additives
(TABLE IV), before being allowed to reach room temperature.
Using the Silicone elastomer column* at 170°C, 45.4 ml per min, the major product, 4.6 min, was shown to be sufficiently separated from its co-product to determine
TABLthe yieldE IV. s Substitutioby comparisonn owitf h(3-Bromo-l-adamantanyl authentic solutions.) diethyl oxonium tribromide in Solvent Mixtures Additives % Yield of Productsa l-bromo-3- l-bromo-3- l-acetoxy-3- ethoxy- hydroxy- bromo- adamantane adamantane adamantane
b — 1) 2% H20 22.3 54.7
2) C — 10% H20 27.1 53.1 3) 0.7% H0Acb 33.1 43.8 0
c 4) 25% H0Ac 33.4 6.1d 6.3
e 5) 0.4% H2S0^ 32.8 61.2 a by analytical glpc of product solutions, b with complex from 0.1698 g DHA. c with complex from 0.171 g DHA. d decomposes under basic conditions of the workup, e with complex from 0.157 g DHA.
The major product was observed to decompose on base washed columns. On the Phenoxysilicone grease acid washed column, the retention times of the ethoxy and the hydroxy compounds were identical. - 142 -
c) Bromination of DHA in Acetone
A solution of ca, 5% aqueous acetone (150 ml) contain• ing DHA (0,128 g) was titrated with bromine under a nitrogen atmosphere. The orange colour due to excess bromine quickly faded (5 min). Analytic glpc* indicated only one reaction product. The reaction product was concentrated by rotary evaporation, redissolved in chloroform (40 ml), washed with 10% sodium bicarbonate dried over anhydrous sodium sulphate and filtered. Rotary evaporation gave dark red- brown oil contaminated crystalline materials (0.320 g).
A blank run showed this viscous oil to result from a reaction between bromine and acetone.
By fractional recrystallization from cyclohexane: benzene -1:9 and once from benzene, the major product of the oxonium ion decompositions in acetone, was isolated o as a white chunky crystalline compound, mp 157-158 C. o
This compound sublimed readily at 70 C under a pressure of
1.0 mm of Hg.
The infrared spectrum (nujol mull) showed 1/... at: nicix 3300 (s), 1338 (m), 1315 (m), 1285 (m), 1205 (w), 1138 (w),
1102 (s), 1090 (w), 1075 (s), 1022 (w), 948 (s), 933 (w),
910 (s), 803 (s), 772 (m), 728 (s), and 665 cm""1 (s).
* The Carbowax and the Silicone elastomer columns were
used with the following temperature programs: 0_ (80°C/6 min ?£°C7fTli-rW000C) and (90°C/6 min 20 C/min^, 275 C) respectively. - 143 -
The nmr spectrum (benzene) showed the following resonances: 2.17, singlet, 2 protons of tne C-2 methylene;
1.98, unsymmetrical doublet, 4 protons of the C-8 and 10 methylenes; 1.68, broad unresolved multiplet, 2 protons of the C-5 and / bridgeheads; 1.35, unsymmetrical doublet,
4 protons of the C-4 and 8 methylenes; 1.19, singlet, 1 proton of the hydroxyl - disappeared in the presence of deuterium oxide; and 1.08 , triplet - partly obscured,
2 protons of the C-6 methylene. For the nmr spectrum in acetone-dg the following resonances were observed: 2.22, broad doublet, 7 protons of the C-2,9 and 10 methylenes and hydroxyl; 2.05, broad multiplet of the C-5 and 7 bridgeheads - obscured by solvent, 2 protons; and 1.67 & , broad multiplet, 6 protons of the C-4 and 10 methylenes and tne C-6 methylene.
The mass spectrum showed parent peaks with m/e+ at
230, 232, identical with the values calculated for C-^H^^-OBr.
Anal. Calcd. for O^H^Br: C, 52.00; H, b.48; Br, 34.60.
Found: C, 52.00; H, 6.6; Br, 34.90.
i) Ring opening of l-bromo-5-hydroxyadamantane
to the "enone" (3-keto-7-methylene Bicyclo
,5. ,3.1 nonane)
The compound, 3-keto-7-metnylene bicyclo [£,3,-^J nonane, had resulted from case catalyzed ring opening of
1,3-disubstituted adamantane compounds v/ith labile hydrogens - 144 -
on one of these substituents. The compound, l-bromo-3- hydroxyadamantane, formed from the addition of water during the bromination of DHA would satisfy this criterion; thus base catalyzed treatment of this compound was undertaken to further prove the structure of the compound which spectroscopic evidence indicated to be l-bromo-3-hydroxy- adamantane.
An ether solution (10.0 ml) containing l-bromo-3- hydroxyadamantane (0.110 g) was stirred (4.5 hr) with aqueous sodium hydroxide (0.5 ml; 0.093*0; then more of the same base (0.1 ml, IN) was added and the reaction continued to completion (1 hr). The progress of the reaction was followed using the Phenoxysilicone grease column at 180°C, 47.6 ml/min, to note the disappearance of l-bromo-3-hydroxyadamantane, 6.1 min, and the appearance of 3-keto-7-methylene bicyclo |^«5.lj nonane, 2.2 min. The ether was removed by rotary evaporation and the oily residue was diluted with benzene (10.00 ml). o
Analytic glpc using the Carbowax column at 160 C indicated that the (0.0716 g, 100%) enone v/as present in the reaction product solution. The identity of the reaction product v/as verified by superimposition v/ith authentic
"enone"* on 2 different glpc columns**.
The minor product formed in the presence of 25% HoAc * This compound v/as kindly donated by Dr. V/. B. Scott. ** The columns used are the ones mentioned above at the given temperatures and flov/rates. was identified by superimposition with authentic l-acetoxy-
3-bromoadamantane* on 2 different glpc columns**.
ii) Acetylation of l-bromo-3-hydroxyadamantane
The authentic l-acetoxy-3-bromoadamantane was prepared by acetylation of l-bromo-3-hydroxyadamantane (0.130 g) in acetic anhydride (1 ml) catalyzed by 1 drop (ca. 0.05 ml) of concentrated sulfuric acid. The reaction mixture was poured into ice water and excess 10% sodium bicarbonate solution was added. Column chromatography of the neutral reaction product (0.136 g) was performed on grade I Woelm neutral alumina (15 g). A central fraction on the peak eluted with equal parts of chloroform ether yielded an oil (0.075 g) which was shown to consist of only one compound; 9.2 and 11.9 min by analytical glpc using the Silicone elastomer column at
170°C, 45.6 ml/min or the Phenylsiloxane grease column at o _
170 C, 48.O ml/min, respectively. .
The infrared spectrum showed at: 1745 (s) saturated carbonyl stretching, 1345 (w), 1320 (w), 1230
(s), 1160 (w), 1100 (w), 1062 (s), 1020 (w), 1010 (w),
967 (s), 940 (m), 872 (w), 824 (s), 790 (m), 748 (w),
739 (m), and 694 cm"1 (m).
* ** Refer to experiment 2.c)ii). The following columns were used: The Phenoxysilicone grease at 170°C, 47.7 ml per min, and the Carbowax at 200°C, 52 ml/min. The nmr spectrum (benzene) showed the following resonances: 2.74, singlet, 2 protons of the C-2 methylene;
1.98, sharp complex multiplet, 8 protons of the C-4,8,9 and
10 methylenes; 1.70, partly obscured broad multiplet, 2 protons of the C-5 and 7 bridgeheads; I.64, sharp singlet,
3 protons of the acetyl; and 1.15 & , broad multiplet, 2 protons of the C-6 methylene.
o
d) Iodination of DHA at -75 0 - Preparation of
l-etnoxy-3-iodoadamantane
A solution of iodine (0.867 g) in ether (5.0 ml) v/as used to titrate DHA (0.171 g) in ether (25.0 ml) at -75°C under a nitrogen atmosphere. Analogous to the bromination of DHA, a dark rust colored precipitate formed. Due to its low solubility in ether, the excess iodine was not removed prior to evaporation of the residual ether under o high vacuum (10 hr) at -75 0. The dry residue was dissolved in acetone (250 ml) containing suspended sodium 0 cyanide (0.50 g) and was stirred at -75 0 until the solution became colorless (24 hr). The floculent white precipitate of inorganic salts was removed by vacuum filtration and carefully flushed down the sink with generous amounts of water. The solvent in the supernatant solution was removed by rotary evaporation, and the residues were partitioned - 147 -
between water (10 ml) and chloroform (20 ml). The organic layer was dried over granular anhydrous sodium sulfate and reduced to an oil once more after filtering out the drying agent. The oil was diluted (25.0 ml) with benzene.
The yield of l-ethoxy-3-iodoadamantane (0.395 g>
74«3%)j 7.0 min, and 1,3-di-iodoadamantane, 19.3 min, (2%), was determined by comparing this prepared solution with a benzene solution of authentic 1,3-dibromoadamantane*, o 7.0 min, using the Carbowax column at 200 C, 52 ml/min. o
The Phenoxysilicone grease column at 170 C, 51.3 ml/min, also was used to detect l-ethoxy-3-iodoadamantane, 7.9 min.
The major product could be isolated by column chromatography of the reaction product on Woelm grade I neutral alumina (20.0 g). The first fraction with cyclo• hexane (100 ml) gave only a very small amount (ca. 0.005 g) of the 1,3-di-iodoadamantane by-product. The major product
(0.051 g) was obtained with cyclohexane-benzene (4:1) after removing traces of solvent in vacuo. (Further decreasing amounts of l-ethoxy.-3-iodoadamantane were obtained with increasingly polar solvents). This sample
Due to differences in degrees of ionization in the hydrogen flame, a conversion ratio of 1.45 was established by comparing benzene solutions of the authentic compounds. - 148 - of major product was isolated and sublimed to give o analytically pure white crystals, mp 35-37 C, distillation o point (uncorrected) 115 C at 1.0 mm of Hg.
The infrared spectrum of the unsublimed oil showed the following V'. 2950 (s), 1450 (m), 1390 (w), 1360 (w),
1340 (m), 1320 (m), 1290 (w), 1275 (m), 1265 (m), 1233 (w),
1155 (w), 1110 (s), 1088 (s), 1048 (m), 958 (s), 937 (m),
870 (m), 815 (m), 785 (w), and 731 cm"1 (m).
The nmr spectrum (benzene) showed the following resonances: 3.17, quartet, J = 7.0 Hz, 2 protons of
the ethoxy methylene; 2.57, singlet, 2 protons of the
C-2 methylene; 2.25, unsymmetrical doublet, 4 protons of
the C-4 and 8 methylenes; 1.54, singlet with a shoulder,
6 protons of the C-5 and 7 bridgeheads and C-9 and 10 methylenes; 1.35, partly obscured unresolved multiplet,
2 protons of the C-6 methylene; and 1.05 £ , triplet J = 7.0
Hz, 3 protons of the ethoxy methyl.
Anal. Calcd. for C16HlgI: C, 47.00; H, 6.21; I, 41.57.
Founds C, 47.29; H, 6.33; I, 41.31.
3. Reaction of DHA with Acids
a) Acid Catalyzed Hydration of DHA - Preparation
of 1-Hydroxyadamantane
A solution of adamantane (0.070 g) and DHA (0.580 g)
in freshly opened tetrahydrofuran was prepared in a 50 ml
three-necked round bottomed flask which was cleared of - V-i-9 -
oxygen. Sulfuric acid (3.5 ml, 8.35 M) was added to
the stirred solution.
The reaction was followed (35 min) by analytical glpc o using the Carbowax column at 80 C, until the 1,3-dehydro- adamantane peak was no longer evident. Using the same column with the temperature program, the glpc trace showed only one major and one minor product. The aqueous phase was saturated with potassium carbonate (7.5 g) and separated from the organic phase. The aqueous phase was back extracted twice with tetrahydrofuran (ca. 5 ml). The pooled organic solution was dried, filtered and diluted in a volumetric flask (50.0 ml).
Analytical glpc using the above Carbowax column at o
160 C showed the following results. First, superposition of the major product with authentic 1-hydroxyadamantane established the products identity. Second, comparison of the reaction solution with an authentic solution of 1- hydroxyadamantane indicated the acid catalyzed hydration reaction proceeded in high yield (90 +_ 5%).
b) Reaction with Acetic Acid - Preparation of
1-Ace toxyadaman tane
An n-octane solution (10.0 ml) containing DHA (0.096 g) was treated with glacial acetic acid (ca. 50 mg). Within - 150 -
10 min the DHA had reacted to give one compound. The identity of this compound was established by comparison . with authentic 1-acetoxyadamantane prepared by sulphuric acid catalyzed addition of 1-hydroxyadamantane to acetic anhydride.
c) Reaction with Para-nitrobenzoic Acid -
Preparation of l-Adamantanyl para-nitrobenzoate
An ether solution (25.0 ml) containing DHA (0.141 g) was stirred (6 hr) with para-nitrobenzoic acid (0.300 g) under nitrogen. The ether solvent was replaced with benzene and the insoluble acid was filtered off. The clear solu• tion was extracted twice with 1% sodium bicarbonate (20 ml), dried over sodium sulfate and separated from the drying agent by vacuum filtration. This solution was diluted (25.0 with benzene and compared to an authentic solution of 1- adamantyl para-nitrobenzoate, 7.2 min, using the Phenoxy- o silicone grease column at 275 0, 37.5 ml per min*.
The infrared spectrum (nujol mull) showed the follow• ing \ax: 1715 (s), 1605 (w), 1515 (m), 1340 (m), 1270
(m), 1105 (m), 1050 (m), 1015 (w), 965 (w), 895 (w), 878
(w), 845 (m), 785 (w) and 718 cm"1 (s).
The nmr spectrum (CCl^rCDCl^ - 2:1)** showed the * This compound was prepared by W. B. Scott. ** This compound was insufficiently soluble in CC1,. - 151 -
following resonances: 9.20, complex multiplet, 4 protons
of the aromatic ring; 2.29, sharp singlet, 9 protons of the
C-2,9 and 10 and C-3,5 and 7 bridgeheads; and 1.78 5,
broad singlet, 6 protons of the C-4,6 and 8 methylenes.
The mass spectrum showed a parent peak with m/e+ at
301, calculated for C-^H-^O^N, 301.
Anal. Calcd. for C^H^O^N: C, 67.75; H, 6.32; N, 4.65.
Found: C, 67.62; H, 6.41; N, 4.63.
4. Reaction of DHA with Mercuric Acetate -
Preparation of 1-Hydroxyadamantane
A solution of mercuric acetate (1.35 g) in water
(4.3 ml) was added to a solution of adamantane and DHA
(0.58 g, 1:12.5) in tetrahydrofuran (4.3 ml). After 2.5 minutes the precipitation of free mercury was observed.
Quickly, sodium hydroxide (4.3 ml, 3N) and sodium borohydride (4.3 ml, IN) were added successively to reduce the organomercurical products. The mixture was stirred
(5 min) before sodium chloride was added to salt out the water. The organic layer was drawn off and the aqueous layer washed 4 times with ether (5 ml). The combined organic layers were dried over sodium sulfate. Rotary evaporation after filtering out the drying agent followed by drying in vacuo (15 min) gave a white oil (U./Ul g).
This oil was diluted with methanol (to 50.0 ml) and - 152 -
compared to an authentic sample of 1-nydroxyadamantane 0 using the Carbowax column at I6u C. The major product
1-hydroxyadamantane (0.291 g, 47.7%), together with an unknown by-product (ca. 18%) and 1,3-dihydroxyadaman-cane
(ca. 9%) accounted for 75% of the starting material. Both hydroxy compounds were identified by superposition with authentic materials using the above Carbowax column at o o 160 C for the single hydroxy compound and at 200 C for the double hydroxy compound. The major product also was isolated by column chromatography on Woelm grade III neutral alumina. Elution with 2% methanol in chloroform
(25 ml) gave 1-hydroxyadamantane (0.310 g). Further elution with this solvent mixture (75 ml) yielded a mix• ture (0.075 g) containing some adamantanol but primarily adamantane-l,3-diol. A flush of the column with 10% methanol gave a mixture (0.068 g) of at least five compounds.
The major product was further identified as 1-hydroxy• adamantane by its infrared spectrum which was identical to the infrared spectrum of the authentic compound (Aldrich laboratories).
5. Reaction of DHA witn Methanol - Preparation of
1-Methoxyadamantane
A freshly prepared mixture of adamantane (0.138 g) and DHA (0.602 g) was dissolved in dry methanol (10 ml) and ether (20 ml). Boron trifluoride etherate (0.25 ml) - 153 -
was added to this stirred solution which was protected by an inert atmosphere. The completion of the reaction
(2 min) was indicated by analytical glpc of the reaction o solution using the Carbowax column at 80 C. Water (0.2 ml)
•was added to react with the borontrifluoride. After this simple workup, the organic solution was dried over sodium sulfate, filtered and diluted (50.0 ml) with methanol.
The yield of 1-methoxyadamantane (0.794 g) was determined by comparison with the authentic compound using the above o
Carbowax column at 160 C. Only one other compound v/as observed in the methanol addition reaction, but its yield v/as very small.
Authentic methoxyadamantane was prepared from 1- hydroxyadamantane (0.608 g) by reflux (24 days) v/ith methyl iodide (40 ml) in a suspension of sodium hydride
(10.8 g) and ether (75 ml). (The reaction was followed by glpc using the Carbowax column). Addition of methanol
(15 ml) decomposed the sodium hydride. The reaction mixture was partitioned between water (70 ml) and chloro• form (100 ml) in a simple workup. The organic layer was dried over sodium sulfate, the drying agent filtered out, and the solvent removed by rotary evaporation to give a yellow oil (0.613 g). Distillation at 95-100°C - 1.4 mm of mercury gave a colorless analytically pure sample of
1-methoxyadamantane (4.6 g, 69%). - 154 -
The infrared spectrum of the neat oil showed the
following 2900 (s), 2680 (w), 1450 (m), 1350
(m), 1300 (m), 1285 (w), 1203 (w), 1180 (m), 1115 (w),
1085 (s), 1050 (m), 985 (w), 973 (w), 937 (v/), 897 (m),
818 (w), 777 (w), and 715 cm"1 (w).
The nmr spectrum (carbontetrachloride) showed the
following resonances: 3*12, singlet, 3 protons of the methoxyl; 2,11 broad singlet, 3 protons of the C-3,5 and
7 bridgeheads; and 1,67 S , sharp multiplet, 12 protons of the total methylenes. The nmr spectrum (benzene) showed the following resonances: 3.12, singlet, 3 protons of the methoxyl; 2.00, singlet, 3 protons of the C-3,5 and 7 bridgeheads; 1.83, multiplet, 6 protons of the adjacent C-2,9 and 10 methylenes; and 1.77 S , multiplet,
6 protons of the C-4,6 and 8 methylenes.
The mass spectrum showed a parent peak at m/e+
C H 166 (calculated for 11 130, 166).
Anal. Calcd. for C^H^O: C, 79.50; H, 10.84.
Found: C, 79.56; H, 10.94.
6. The Catalytic Hydrogenation of DHA - Preparation
of Adamantane
a) in n-heptane
A suspension of Adam's catalyst (0.120 g) in dry n-heptane (10.0 ml) was saturated with hydrogen (21.5 ml) - 155 -
by rapid stirring in a 50 ml Erlenmeyer flask, modified with a serum cap stoppered side arm. A solution of adamantane (0.023 g) and DHA (0.216 g) in dry n-heptane
(10.0 ml) was injected into the hydrogenation flask. The uptake of the hydrogen gas (41.5 ml, corrected) proceeded
for 30 min at which time a second aliquot (ca, 0.20 ml) was withdrawn. The analytical glpc trace using the
Carbowax column at 80°C, 52 ml/min, indicated the total absence of DHA, 6.0 min; one major peak (79.5%) at
5.5 min; and an overlapping group of peaks (16.9%) at
3-4 min.
The major peak was identified as adamantane by analytical glpc trace superimposition with an authentic sample as well as by infrared spectroscopy. The infrared spectrum of the reaction product recrystallized six times from ethanol v/as identical with the infrared spectrum of authentic adamantane.
b) in Ethanol
Adam's catalyst (0.04 g) was suspended in Ethanol
(10 ml) under an atmosphere of hydrogen at room temperature.
When the uptake of hydrogen ceased, an ethanol solution
(25.0 ml) of adamantane (0.32 g) and DHA (0.32 g) v/as added. The rapid uptake of hydrogen (38.9 ml, corrected) ceased again after 38 min. Analytic glpc using the o Carbov/ax column at 80 C, 54 ml/min showed a modest - 156 -
conversion of DHA into adamantane (ca. 50%) when compared to an authentic adamantane solution. , An alteration also v/as noted in the composition of the by-product traces,
3-4 min, but the areas of these traces did not account for the decreased yield of adamantane; however, glpc at o .
200 C indicated another compound (ca. 31 i 5%, by integration of the ethoxy methylene group nmr trace in the crude reaction product) v/as formed whose trace was superposable with the only observed compound resulting from the reaction of DHA v/ith neat ethanol.
7. The Reaction of DHA with Benzene Catalyzed by
Aluminum Chloride - Preparation of 1-Phenyladamantane
Aluminum chloride (2.0 g) v/as added to an anhydrous, oxygen-free benzene solution (310 ml) containing adamantane
(0.177 g) and DHA (0.693 g) which was stirred rapidly o under a nitrogen atmosphere at 60 C. The Carbov/ax column o at 80 C, showed no DHA was evident in the analytic glpc trace (10 min). Water (15 ml) was added rapidly causing the solvent to reflux in the condenser. The reaction mixture was v/ashed v/ith water (50 ml), 5% sodium bicarbonate
(30 ml) and once more with water (50 ml). After drying over sodium sulfate and filtering out the drying agent, the solution was concentrated. This benzene solution - 157 -
(50.0 ml) was compared to a solution of authentic 1- phenyladamantane to determine the yield (0.437 g, 39.8%) in the Lewis acid catalyzed phenylation of DHA. This comparison was performed using the Silicone elastomer o o column at 180 C. By using this column at 180 C and the
Carbowax column at 200°C, the reaction product v/as further identified by observing an enhancement of the phenylation reaction product trace on each of these columns, after enrichment with authentic 1-phenyladamantane.
Authentic 1-phenyladamantane v/as prepared from 1- bromoadamantane (4.0 g) by tne action of aluminum cnloride
(268 g) in benzene (120 ml) at 0°C. The reaction mixture was allowed to reach room temperature (2 hr) before v/ater (20 ml) was added (over 5 min). The reaction mixture was partitioned between water (50 ml) before being dried over anhydrous sodium sulfate. The drying agent was filtered out and the solvent removed by rotary evaporation to give a red-brown semicrystalline oil
(3.9 g). Recrystallization twice from methanol and o sublimation at 60 C (25 mm mercury) yielded (1.46 g,
38%) yellow crystals. Eight more recrystallizations yielded flaky white crystals (0.6y g) with mp (sealed tube) 79-81°C (reported, 82°C).128
The nmr spectrum (chloroform-d) showed the following resonances: 7.26, multiplet, 5 protons of the aromatic - 158 -
ring; 2.06, broad singlet, 3 protons of the C-3,5 and 7
bridgeheads; 1.93, sharp singlet, 6 protons of the C-2,
9 and 10 methylenes; and 1.77 & , sharp closely spaced
multiplet, 6 protons of the C-Zf,6 and 8 methylenes.
The mass spectrum showed an m/e+ at 212 which v/as
identical v/ith that calculated for C]_6^20*
Anal. Calcd. for Cl6H20: C, 90.52; H, 9.48.
Found: C, 90.32; H, 9.53.
8. The Pyrolysis of DHA
a) In the solid phase
A 5 ml Kimble "break seal" ampule containing adamantane (0.141 g) and DHA (0.556 g) was sea'led under high vacuum. The ampule v/as immersed in an oil bath o overnight at 145 C. Volatile materials (0.106 g) were allowed to sublime into the tip of the ampule for 8 hours and eliminated upon opening the ampule. The non• volatile insoluble white solid (0.565 g, 98.5%) coating the walls was carefully removed. Differential scanning calorimetry under an inert atmosphere, indicated this solid possessed no distinct melting point, but a fraction o o of it did sublime at temperatures greater than 450 C (ca. 500 C), o o
In air, it turned yellow at 450 C, over 125 0 higher than for the polyadamantane compound prepared by Wurtz coupling of 3,3l-dibromobiadamantane.x-7X
The polymer was insoluble in all common solvents. - 159 -
Tne infrared spectrum (nujol mull) showed the
following V' : 2770 (rn), 1365 (s), 1300 (s), 1100 (s),
1060 (w), 1035 (s), and 825 cm"1 (w).
Anal. Calcd. for ^1Q\L- C, 89.49; H, 10.51.
Found: C, 89.30; H, 10.90.
b) In solution
A solution of DHA (0.287 g) and an internal standard,
orthoxylene (0.1445 g)> in dry deoxygenated n-octane
(25.00 ml) was prepared in an oxygen-free nitrogen filled
dry box. An aliquot (5.00 ml) of this solution was
withdrawn and diluted (to 50.00 ml) for other experiments.
A series of 1 ml Kimble colour-seal vials with severely
constricted necks were half-filled with the above
solution using a syringe with a fine long (8-in) needle
and immediately stoppered well with nmr tube serum caps.
The stoppered vials were removed and sealed in a very
small hot oxygen-natural gas flame. A series of samples were immersed in a silicone oil bath thermostatically o
controlled at 195.3 i 0.2 C for varying periods of
time. - 160 -
Each vial was opened and assayed for DHA using the
Carbowax column at 80°C. The trace weight of DHA was normalized v/ith respect to an internal standard. The rate -5 -1 constant, k = 4.315 x 10 sec , was determined from the slope of the graph of the log trace values versus time of exposure after conversion to natural logarithms. The half life, t^ = 4.45 hr, was calculated from the following equations.
From the graph: slope = 2.30-k 3
11 = In 2 2 k sec-1
TABLE V. Normalized 1,3-Dehydroadamantane Trace Weights for Samples after Various Times at 195°C
t (min) weight of the trace (g) log (wt) + 2
0 0.120 1.0792 10 0.112 1.0492 25 0.104 1.0170 40 0.101 1.0043 60 0.093 0.9685 80 0.094 0.9731 100 0.089 0.9494 120 0.081 0.9085 150 0.079 0.8976 180 0.071 0.8513 270 0.056 0.7483 390 0.0425 0.6284 - 161 -
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