Studies in Multicyclic Chemistry
This thesis is submitted in fulfillment of the requirements for the degree of Doctor of Philosophy
by Djamal Sholeh Al Djaidi
Supervisor Professor Roger Bishop
School of Chemistry The University of New South Wales
Sydney, Australia December, 2006 PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet
Surname or Family name: AL DJAIDI
First name: DJAMAL Other name/s: SHOLEH
Abbreviation for degree as given in the University calendar: PhD
School: CHEMISTRY Faculty: SCIENCE
Title: STUDIES IN MULTICYCLIC CHEMISTRY
Abstract 350 words maximum: (PLEASE TYPE)
* A series of investigations has been carried out on multicyclic organic systems. The Ritter Reaction was used to obtain bridged imines containing an azacyclohexene functionality. The crystal structure of the benzene inclusion compound of one of these was determined, and also that of another spontaneously oxidised example. The reactivity of these bridged imines was then investigated using mercaptoacetic acid, and also dimethyl acetylenedicarboxylate (DMAD). The three bridged imines studied were found to react with DMAD in totally different ways and produced most unusual products whose structures were proved using X-ray crystallography. Mechanistic explanations are provided for the formation of these novel and totally unexpected products.
* 6-Methylidene-3,3,7,7-tetramethylbicyclo[3.3.1]nonan-2-one was reacted with acetonitrile and sulfuric acid to deliberately combine molecular rearrangement with Ritter Reaction chemistry. Five different products were obtained and the pathway of formation of these products was uncovered. The structures of three of these rearranged substances were confirmed by X-ray methods.
* The rare tricyclo[5.3.1.1 3,9]dodecane ring system is known to contain severe skeletal distortions due to the nature of its skeleton. These properties were investigated by means of X-ray determinations at two temperatures. It was found that although the bond lengths were little affected, several of the bond angles were highly anomalous. These had angles far from the ideal tetrahedral value and, in some cases, were close to planar (120 degrees). The molecular motion of the skeleton was also investigated using variable temperature NMR measurements and energy values for the twisting motion involved were determined.
* Schroeter and Vossen's Red Salt, first discovered in 1910, was investigated in detail by NMR and X-ray spectroscopy. The detailed structure of this most unusual compound was determined for the first time.
* The Red Salt is based on the bicyclo[3.3.0]octane ring system and can be converted into several synthetically useful derivatives, including a tetraester and the 3,7-diketone. The former was shown to exist completely in the enolised tautomeric form (like Meerwein's Ester), and the latter was used as a synthetic entry for making diquinoline substituted analogues of interest in host-guest chemistry.
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Studies in Multicyclic Chemistry
DECLARATION
The research presented in this thesis was undertaken in the School of Chemistry at the University of New South Wales, Sydney, Australia under the supervision of Professor Roger Bishop. The work presented in this thesis is, to the best of my knowledge and belief, original. This thesis has not been submitted in part or whole for a degree at any other university. Full acknowledgment has been made where the work of others has been cited or used.
Djamal Sholeh Al Djaidi, BSc Pharm, FDA Dip. December, 2006
ii Studies in Multicyclic Chemistry
Table of Contents
Chapter 1 Introduction 1
1.1 The Ritter Reaction 1 1.1.1 The Classical Ritter Reaction 1 1.1.2 Intramolecular Ritter Reactions 6 1.1.3 Bridged Ritter Reaction Products 9 1.1.4 Inclusion Compounds Formed by Ritter Reaction Products 15 1.2 Addition of DMAD to Bridged Ritter Reaction Products 16 1.3 Ritter Rearrangement Reactions 21 1.4 Tricyclo[5.3.1.13,9]dodecane System Chemistry 30 1.5 Schroeter and Vossen’s Red Salt 35 1.6 Bicyclo[3.3.0]octane-based Diquinolines 38 1.6.1 Inclusion Behaviour of the Dibromo Host 94 43 1.6.2 Inclusion Behaviour of the Dichloro Derivative 97 50 1.6.3 Inclusion Behaviour of the Tetrabromide 95 54 1.6.4 Inclusion Chemistry of the Hexabromide 96 58 1.7 Aims of the Project 64
Chapter 2 Results and Discussion 66
2 Chemistry of Multicyclic Ritter Reactions 66 2.1 The Structure of a Ritter Reaction Product-Benzene Inclusion Compound 66 2.2 The Structure of an Oxidised Ritter Reaction Product 74
Chapter 3 Results and Discussion 80
3 Reaction of Bridged-Ritter Products 80
3.1 Reaction of the Bridged Imines with Mercaptoacetic Acid 80
iii Studies in Multicyclic Chemistry
3.2 Reaction of the Bridged Imines with Dimethyl Acetylenedicarboxylate (DMAD) 83 3.2.1 Reaction of Imine 36a with DMAD 83 3.2.1.1 Mechanism for the Formation of 110 and 112 88
3.2.1.2 Structure of the Inclusion Compound (112).(benzene)0.5 90 3.2.2 Reaction of Imine 100 with DMAD 97 3.2.2.1 Mechanism for Formation of 111 97 3.2.2.2 X-ray Structure of the Orthoester 111 99 3.2.3 Reaction of Imine 101 with DMAD 104 3.2.3.1 Mechanism for Formation of 115 105 3.2.3.2 X-ray Structure of the Lactam 115 106
Chapter 4 Results and Discussion 111 4 A Sequence of Novel Ritter Rearrangement
Reactions 111
4.1 Rearrangement of the Unsaturated Ketone 120 111 4.2 3,3,6,6,7-Pentamethylbicyclo[3.3.1]non-7-en-2-one 121 115 4.3 4,4,7,8,8-Pentamethylbicyclo[3.3.1]non-6-en-3-one 122 116 4.4 {7-Anti-hydroxy-3,4,4,8,8-pentamethylbicyclo[3.2.2]non-2-en-1- yl}acetamide monohydrate 123 118 4.5 {3,4,4,8,8-Pentamethyl-2-oxatricyclo[3.3.1.13,7]dec-1- yl}acetamide 124 125 4.6 {4,4,8,8-Tetramethyltricyclo[3.3.1.13,7]decane-1,3- diyl}bis(acetamide) 125 130
Chapter 5 Results and Discussion 137 3,9 5 Tricyclo[5.3.1.1 ]dodecane System Chemistry 137
5.1 Synthetic Studies 137
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5.2 X-ray Studies on Tricyclo[5.3.1.13,9]dodecane Derivatives 139 5.2.1 Crystal Structure of the Bis(pyrazolone) 135 139 5.2.2 Crystal structures of compound 83 at 90K and 300K 142 5.3 NMR Studies 149 5.3.1 Tricyclo[5.3.1.13,9]dodecane System Chemistry 149 5.3.2 Dynamic NMR Analysis of Compound 83 161
Chapter 6 Results and Discussion 165
6 The Structure of Schroeter and Vossen’s Red Salt 165
Chapter 7 Results and Discussion 175
7 Further Bicyclo[3.3.0]octane-based Diquinolines 175 7.1 The Stucture of the Tetraester 90 175 7.2 Diquinoline-substituted Bicyclo[3.3.0]octanes 181
Chapter 8 Experimental 185
Chapter 9 References 225
Published Material Related to this Thesis vi
v Studies in Multicyclic Chemistry
Published Material Related to this Thesis
1. Ritter Reactions. X. Structure of a New Multicyclic Amide—Benzene Inclusion Compound D. Djaidi, R. Bishop, D.C. Craig and M.L. Scudder Journal of Inclusion Phenomena and Molecular Recognition in Chemistry, 1995, 20, 363.
(36a).(benzene) ZIPYIG
2. Ritter Reactions. Part 11. The Diverse Reactivity of 5,10-(Azenometheno)-5H- dibenzo[a,d]cyclohepten-11-yl Amides with Dimethyl Acetylenedicarboxylate D. Djaidi, R. Bishop, D.C. Craig and M.L. Scudder Journal of The Chemical Society, Perkin Transactions 1, 1996, 1859.
101 TITKAI (112).(benzene)0.5 TITJIP 111 TITJUB 115 TITJOV
3. Ritter Reactions. XIII. Reactivity of Schiff Bases with Dimethyl Acetylenedicarboxylate and Mercaptoacetic Acid Q. Lin, D. Djaidi, R. Bishop, D.C. Craig and M.L. Scudder Australian Journal of Chemistry, 1998, 51, 799.
4. Ritter Reactions. Part 14. Rearrangement of 3,3,7,7-Tetramethyl-6- methylidenebicyclo[3.3.1]nonan-2-one D. Djaidi, I.S.H. Leung, R. Bishop, D.C. Craig and M.L. Scudder Journal of The Chemical Society, Perkin Transactions 1, 2000, 2037.
(123).(H2O) MAYVOX 124 MAYVUD 125 MAYWAK
5. Schroeter and Vossen’s Red Salt Revealed D. Djaidi, R. Bishop, D.C. Craig and M.L. Scudder New Journal of Chemistry, 2002, 26, 614.
(89a).(methanol)2 XIZRED
Crystallographic data for the X-ray structures listed above were deposited with the Cambridge Crystallographic Data Centre at the time of publication. Copies can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail: [email protected]], or by consulting the Refcodes cited above in the Cambridge Structural Database.
vi Studies in Multicyclic Chemistry
Acknowledgements.
Praise to Allah and may peace and blessing be on His beloved Messengers. I would like to thank, firstly, my parents for their dedicated support, encouragement and guidance. To my wife Nikmah, for her unlimited support; also to all my children Juaid, Rayhana, Muhammad, Raefa and Khansa.
The many people who contributed assistance to this thesis and the various steps along the way. The crystallographers Mr. Don Craig, Dr. Marcia Scudder, and Prof. Ogawa for all your support and data which underpins a significant portion of this thesis. Dr. Jim Hook, Mrs. Hilda Stender and Dr. Graham Ball for your help in obtaining the NMR data, Dr. Phung Pham for elemental analysis, Dr. Joe Brophy for the mass spectral data, and Dr. Nick Roberts for assistance with crystallization.
The Bishop group: Wei Min Yue, Paul Ahn, Chris Marjo, Qing Hong Lin, Solhe Alshahateet, A.N. Rahman, Vi Nguyen, Jason Ashmore, and Felicia Maharaj. Also the other postgraduate students of the School of Chemistry.
The Lecturers in the Organic Chemistry Department and all the General Staff of the School, particularly Dr. Naresh Kumar and Mrs. Thanh Vo Ngoc.
This work was carried as a part-time research student at UNSW while employed by Abbott Australasia Pty. Ltd. I wish to thank all the Abbott Staff, especially those working in the R & D and QA Departments.
Very special thanks to my supervisor Professor Roger Bishop. It is very difficult to find words to describe his contribution, dedication, enthusiasm and help from the day one until this thesis was completed. Once again Roger, many…many thanks for your support, academically, scientifically, and psychologically.
Finally, hopefully this research will give a continuous benefit to all, particularly to myself.
vii Studies in Multicyclic Chemistry Chapter 1
Chapter 1 Introduction
1.1 The Ritter Reaction
1.1.1 The Classical Ritter Reaction
In 1948, John Ritter published two papers describing reactions that are now known as the Ritter Reaction1,2. Later work has demonstrated that this is a remarkably widespread process that has mechanistic links to several other named reactions. In its widest form, the Ritter Reaction describes the formation of a carbenium ion, its subsequent nucleophilic trapping by a nitrile nitrogen atom, and the further events that lead to isolable products. Despite this versatility, the Ritter Reaction remains much less familiar to many chemists than other named reactions.
A number of review articles are available describing the Ritter Reaction3-10. Probably the most useful surveys are those by Krimen and Cota in Organic Reactions9 and by
Bishop10.
In its simplest form, the Ritter Reaction involves reaction of an organic substrate with strong acid in the presence of a nitrile, followed by subsequent aqueous work up to yield an amide product in a one-flask process, for example the conversion of t- butanol 1 into N-t-butylacetamide 2:
1 Studies in Multicyclic Chemistry Chapter 1
i. H2SO 4,CH3CN CH 3 CH 3 CH 3 ii. H2O 3COHCH 3C CH 3CNH-CO-CHCH 3
CH 3 CH 3 CH 3 1 2
The mechanism of the process is illustrated in Scheme 1. In the first step, reaction of the substrate with acid yields a carbenium ion intermediate 3. This is trapped by the nitrile to produce a resonance-stabilised nitrilium ion 4, which is converted into the corresponding imidate 5. The latter is then hydrolysed to the final amide product 6.
R-OH + H2SO 4 RHSO4 ROSO3H 3
CH 3CN R R-N N 4 HSO4
O R H2O R N N OSO H 3 H 5 6
Sch eme 1
The Ritter Reaction is much more versatile than it initially appears. A wide range of substrates and a variety of different acids can give rise to carbenium ions and, indeed, the latter can be obtained by many non-acidic methods. Any procedure that leads to a carbenium ion is appropriate for use in a Ritter Reaction. Furthermore, the
2 Studies in Multicyclic Chemistry Chapter 1
nitrilium ion intermediate can frequently participate in intramolecular cyclisations of various types. This allows entry into a wide variety of heterocyclic systems, and may exclude amide formation entirely.
The majority of nitrile containing compounds will undergo Ritter Reaction with carbenium ions. Aliphatic nitriles, aromatic nitriles, and hydrogen cyanide all work extremely well. Other nitrile containing reagents such as cyanogen, cyanamide and dicyandiamide react with varied effectiveness. Provided that the other functional groups present are unreactive to the acidic conditions, multi-functionalised molecules incorporating a nitrile group are usually efficient reagents. This includes cyanohydrins, where the presence of the hydroxy group still allows a significant amount of Ritter product to form. Some representative examples include the Ritter Reactions of cyanohydrin 711, allene 812, dinitrile 911, and the acetylenic nitrile 1013.
0 OH i. H2SO 4,AcOH,0 C OH NH-But ii. H2O But-O H CN 40 % 7 O
3 Studies in Multicyclic Chemistry Chapter 1
O
R CN i. H2SO4,AcOH R1 1 ii. H O C 2 . t But-OH . NH-Bu 60 % R2 R2 8
0 O CN i. H2SO4,AcOH,45 C t ii. H O Bu -OH 2 NH-But t NC 88 % Bu -HN 9 O
i. H2SO4,AcOH Cl ii. H2O O Cl CN CN 70 % H 10
Hydrogen cyanide can be used directly, or generated from cyanide ion which is experimentally easier and safer. This is a particularly useful nitrile to use because the
N-alkylformamide 11 product can be hydrolysed rather easily to yield the N- alkylamine 122. This can sometimes be a surprisingly difficult process to carry out for some of the other N-alkylamides. An important recent development has been the application of trimethylsilyl cyanide as the hydrogen cyanide source14.
NaOH,H2O H 0 t H SO 5h,100 C Bu -O H Na CN 2 4 t t Bu N C Bu NH2 H O 87 % 11 overall 12
Many functional groups can be persuaded to yield a carbenium ion under strongly acidic conditions. The most commonly used, and most generally effective ones, are
4 Studies in Multicyclic Chemistry Chapter 1
alkenes and alcohols. However, alkyl halides, dienes, aldehydes, alkanes, carboxylic acids, esters, epoxides, ketones, oximes, glycols and others, have also been used.
Examples employing alkene 1315, oxime 1416,17,ester1518,andN-methylolamide
1619,20 groups are shown as representative cases.
i. H2SO4 ii. H2O CN 81 % O HN C 13
NOH polyphosphoric acid (PPA) H O t But+ +CH -CN Bu N C But 3 14
0 O i. H2SO4,50 C O ii. H2O Ph3COC H MeCN Ph3CN 100 % H 15
O O
i. H2SO4,AcOH ii. H2O N N O OH CN HN C 89 % O O 16
Carbenium ions for use in Ritter Reactions can also be produced by other means.
+ 10 These include reagents such as nitrosonium hexafluorophosphate NO PF6 , boron
21 22 23 trifluoride etherate BF3.Et2O ,AlCl3 , SnCl4 in appropriate cases. Less obvious
5 Studies in Multicyclic Chemistry Chapter 1
techniques such as oxidation of carbon radicals10, UV light10, electrophilic attack10, electrochemistry10, and microwaves24, also can work effectively.
Most types of strong acid have been used to produce carbenium ions in the Ritter
Reaction, and the optimum reagent varies according to the particular case. Typical reaction times are 1-24 hours and typical temperatures 20-50 °C. In cases where conditions have been carefully compared, it is usually found that 85-90 % sulfuric acid is the most effective reagent15,25-27. The presence of a small amount of water appears to be beneficial. Its function may be to increase the solvent polarity which is known to polarise the nitrile group and increase its nucleophilicity28. Co-solvents such as acetic anhydride, glacial acetic acid or nitrobenzene are sometimes added for the same reason. However, significant amounts of side-products result in some cases.
In others, such dilution prevents reaction from taking place. Zeolites have found some favour as catalysts in recent work29,30. The Krimen and Cota review9 presents a comprehensive survey of Ritter Reactions reported up till 1966, and also lists representative experimental procedures.
1.1.2 Intramolecular Ritter Reactions
In 1952, Ritter and Murphy reported examples of reactions that should be regarded as variants of the original process but which yield heterocyclic products31.Avery large number of such reactions is now known. Meyers and Sircar8 have reviewed the means by which nitriles can become involved in such ring closure reactions. These occur by two different intramolecular pathways (Scheme 2).
6 Studies in Multicyclic Chemistry Chapter 1
R X N R N + R N X R N X Y Y Y Y X
17
Y Y- N N X NH NH
X X X 18 X = Schematic electrophilic group; Y = schematic nucleophilic group
Scheme 2
The more common mechanism involves a bimolecular reaction that produces an acyclic nitrilium ion. This reacts with a nucleophilic species within the same molecule to yield heterocyclic products of type 17. In contrast, the less common reaction is a unimolecular process. Intramolecular reaction affords a cyclic nitrilium ion which reacts with an external nucleophile to yield products of type 18. A typical example of the latter process is shown by the reaction of nitrile 1932.
7 Studies in Multicyclic Chemistry Chapter 1
Ph PPA, 135 0C Ph N NN CN 19 H2O 90 % overall
Ph
HN NH
O
Representative examples of the former process are the cyclisations of 2033, 2134and methyleugenol 2231 with the appropriate nitrile reagent.
R N Cl Sn Cl 4 R-CN 8-17 % S
20 S
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R N N R Cl AlCl3 Ph CN 3 N
21 Ph
CN MeO i. H2SO 4 MeO ii. H2O 53 % N MeO OMe MeO
22 OMe
OMe
OMe
1.1.3 Bridged Ritter Reaction Products
A less common variant of the bimolecular cyclisation reaction involves formation of bridged Ritter Reaction products. The mechanism just described always produces fused heterocyclic products. Many of these include an imine functionality as part of their structure. In 1978, the reaction of cis-carveol with acetonitrile and BF3·Et2O was reported21. This was a rather complex process in which several products resulted. These included a small quantity (9 %) of an azabicyclo[3.3.1]nonane derivative. Several such reactions, in much better yields, are now recorded. In all cases the nitrilium ion undergoes reaction with an internal alkene group to produce a
9 Studies in Multicyclic Chemistry Chapter 1
1-azacyclohexene ring and a new carbenium ion. This then undergoes conventional
Ritter Reaction to produce an amide. The latter process is frequently stereospecific, since Ritter Reaction has to take place from the least hindered side of the carbenium ion p orbital.
Marschoff reported in 1984 that the reaction of (R)-(+)-limonene 23 and (IS)-(-)-ß- pinene 24 with acetonitrile yield opposite enantiomers of the bicyclic amide 2535.
These terpenoid reactions have since been followed up in greater detail36,37.
H N ClO4
HClO4,MeCN 28 %
AcHN 23 (-)-(25)
H N ClO4
HClO4,MeCN 46 %
AcHN 24 (+)-(25)
Shortly afterwards, Bishop discovered that the bicyclic diene 26 underwent a related reaction producing the heterocyclic derivative 27 in good yield38.
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N i. H2SO 4,MeCN ii. H2O 63 %
AcHN
26 27
The structure of 27 was originally deduced from spectroscopic data, then later confirmed by means of X-ray determination39. At the same time, an analogous product was obtained by means of reacting diene 26 with benzonitrile. However, when 26 was reacted with benzyl cyanide reagents, then an unexpected process was observed.
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26
X CH2-CN
a) X= H b) X= Br c) X= Cl
H C H H3C O 3 N 2 N C X C X
CH3 X C CO NH CH3 XCC ONH H H2 2
28 29
a) 33 % b) 35 % c) 32%
It was anticipated, by comparison with the first two examples, that the product would have structure 28. Mass spectrometry showed, however, that the molecular weight was 14 units too high for this product, and the oxidized structure 29 was proposed.
Three benzyl cyanide reagents were used and similar results were recorded in each case.
Two oxidants, concentrated sulfuric acid and molecular oxygen were present during this reaction. It was considered most likely that the initial product 28 underwent autoxidation to yield 29 under the experimental conditions. The site of observed
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oxidation would be expected to be extremely reactive, since this methylene group is both benzylic and adjacent to the imine functionality. A rather similar case of autoxidation has been reported for a derivative of tetrahydrobenz[f]indole40.
A further example of the bridged Ritter Reaction was reported by Reamer et alia who found that the alcohol derivative 30 was converted efficiently into the bridged imine 31 under Ritter Reaction conditions41. In this case, there was some uncertainty as to the direction of addition of the bridged imine group, but isomer 31 was favoured.
NHCOR
i. H2SO 4,RCN ii. H2O R N N a) R= Me, 56 % N b) R= Ph, 71 % OH
30 31
This group also investigated the behaviour of 5-methyl-5H-dibenzo[a,d]cyclohepten-
5-ol 32 under Ritter Reaction conditions. Use of acetonitrile afforded at 97 % yield of a dimeric acetamide product whose remarkable structure 33 was confirmed by X- ray crystallography42.
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Me-OC-HC
i. H2SO 4,CH3-CN ii. H2O
97 % Me
33
H3C OH i. H2SO 4,Ph-CN ii. H O Ph 32 2 NHCOPh 97 % N
CH3
34
In contrast, reaction of 32 with benzonitrile once again yielded the bridged structure
34. Surprised by these findings, Pich et al.43 re-investigated these reactions. It was found that compound 33 was indeed produced, and none of the bridged Ritter
Reaction product could be observed when acetonitrile was used as the reagent.
However, using benzonitrile, the dimeric product analogous to 33 was produced in
86 % yield. The spectra recorded were quite different for those reported for compound 34, so it appears that either product may be obtained by variation of the reaction conditions. Once again there was some doubt as to which way round the nitrile had added in the formation of 34. The structure of the isomer drawn was supported by 1H NMR Overhauser measurements42.
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When Pich43 examined the reactivity of the four 5H-dibenzo[a,d]cyclohepten-5-ol derivatives 35 a-d, only the bridged Ritter products 36 a-d were observed in each case. The yields were in the range of 52-64 %.
NHCOCH H3C 3 R1 R1 i. H2SO 4,CH 3CN ii. H2O N
R2 OH R2 a) R1=H, R2=H 35 36 b) R1=H, R2=Ph c) R1=CH3,R2=H d)R1=CH3,R2=CH3
Furthermore, the X-ray crystal structure of product 36b was obtained, and fully confirmed this structural assignment. Given the great similarity of all the spectral data across this series of compounds, it is reasonable to assume that all of these bridged Ritter products are of the same isomeric type.
1.1.4 Inclusion Compounds Formed by Ritter Reaction Products
There are almost no examples of Ritter Reaction products being isolated as inclusion compounds. The bridged product 27 was, however, isolated as its monohydrate. Pich found that both of the classical Ritter Reaction products 37 and 38 could be crystallized as host:guest = 1:2 adducts from dioxane. These compounds were
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unstable and their crystals rapidly became opaque due to loss of the guest molecules at room temperature.
NH-CO-CH3 NH-CO-CH3
37 38
44 Despite this difficulty, the crystal structure of (37).(dioxane)2 was able to be solved .
1.2 Addition of DMAD to Bridged Ritter Reaction Products
It is known that the imine functional group often can react with dimethyl acetylenedicarboxylate (DMAD) to produce unusual structures45-50. Such reactions are complicated by the observation that the corresponding enamine tautomer can also participate in such reactions, and that sometimes more than one equivalent of DMAD can add to the substrate. In short, this is an interesting area of chemistry which allows little prediction of what might occur. For example, Nair51 reported that 6,7- dimethoxy-1-methyl-3,4-dihydroisoquinoline 39 gave the lactam 40 when treated with DMAD in methanol. However, when the reaction was carried out in anhydrous diethyl ether, the alternative product 41 was obtained through addition of two equivalents of DMAD. These reactions were proposed to proceed via the enamine and imine structures, respectively.
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H3CO H3CO
N methanol NH H3CO H3CO
39 CH3 CH2 R-C C-R R= CH3O2C-
H3CO H3CO
NH N H3CO H3CO R R
R R
H3CO
N O H3CO
40 R
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R CCR H3CO H3CO (R=CH 3O 2C-) N anhydrous ether N R H3CO H3CO CH H3C 3 C 39 41 R R R
In light of this work, the Bishop group52 carried out a reaction of their imine 27 with
DMAD in refluxing chloroform and obtained a 48 % yield of an orange solid that was originally formulated as structure 42 by analogy with the earlier report.
O CO2CH3
H3C H3C N CH3 N DMAD
48 %
CH3 CH3
H3C-OC-HN H3C-OC-HN 27 42
Unfortunately, crystalline samples of 42 grown from a variety of solvents were all found to suffer from twinning disorder that precluded X-ray structure determination.
Subsequent work in this area showed that little prediction of product structure was possible by analogy, so later the structure of the orange product was re-investigated using a combination of advanced NMR techniques53. These experiments revealed that the true structure was 43.
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CO 2CH3 CO 2CH3 O H H CO 2CH 3
H3C H3C N NCH2
CH3 CH3
H3C-OC-HN H3C-OC-HN 43 44
CO 2CH3 H CO 2CH3
H3C N CO 2CH3
CH2
CO 2CH3
CH3
H3C-OC-HN 45
To complicate things further, the reaction of 27 with DMAD was also found to initially yield the adduct 44 which was then readily converted into the product 43.
Furthermore, the 1:2 adduct 45 was also isolated, and its structure was determined by single crystal X-ray crystallography54.
Similar studies also showed that the true structure of 40 was really 46. This structure was subsequently confirmed by X-ray determination54.
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H3CO CO 2CH 3 N H 3CO H
46 O
In contrast, the bridged imine 4739 reacted with DMAD to produce 37 % of the yellow compound 48. During this process, the azaadamantane ring system of the starting material had been broken open52.
CO 2CH3 H CO 2CH 3 H C H C HN 3 N 3 DMAD
37 %
CH3 CH3
H3C-OC-HN C6H5-O C-H N 47 48
Finally, the bridged imine 29a reacted with DMAD to give a 64 % yield of the white solid 49. The structures of both 48 and 49 were determined by X-ray crystallography52.
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CO CH H3CO 2C 2 3
H C H C 3 N 3 N C O O DMAD 64 % CH3 CH3
H3C-OC-HN H3C-OC-HN
29a 49
It is apparent from the reactions just described that the area of imine reactions with
DMAD is a complex and fascinating one. The three bridged imines studied by the
Bishop group varied little in their molecular structure, yet reacted in totally different ways. Determination of the true structure in each case was no simple matter, and this was carried out using single crystal X-ray determinations whenever possible. The original papers propose possible mechanisms for all these unusual reactions, but it is true to say that prediction of further behaviour is fraught with difficulties.
1.3 Ritter Rearrangement Reactions
As discussed earlier (Section 1.1), the Ritter Reaction commences by means of formation of a carbenium ion, and then continues through reaction with a nitrile group. It is well known that carbenium ions are prone to rearrangement reactions.
Several carbenium ions may be in equilibrium and their relative amounts depend on their G°F values. Generally speaking, isomeric carbenium ions have the relative
21 Studies in Multicyclic Chemistry Chapter 1
energies: primary > secondary > tertiary. Hence in Ritter Reactions, it is always wise to consider the possibility of rearrangement processes being involved.
This phenomenon was studied in detail by Christol, and one of his best examples is showninScheme355. Five isomeric alcohol compounds (50-54) were reacted with acid and HCN, and their Ritter Reaction products subjected to hydrolysis. All five reaction mixtures contained substantial quantities of 1,2-dimethylcyclohexylamine
55, because all five reagents can react to generate the common carbenium ion 56.
CH OH 3 CH CH3 CH 3 CH OH
CH3 51 50 NH OH CH3 2 - HCN CH C CH3 3 H2O CH3 CH3 CH3 52 56 55
OH CH3
CH3 CH3
OH CH3 53 54
Scheme 3
As would be expected, tertiary carbenium ions usually react without rearrangement56, whereas secondary carbenium ions are prone to doing so28, as illustrated in the reactions in Scheme 4.
22 Studies in Multicyclic Chemistry Chapter 1
Me O i. H2SO 4,AcOH O O Et + ii. H2O OH NC Me N N Bu 86 % Et N Bu H
NHAc
+ MeCN
OH
Sch eme 4
Kinetic control can also influence the outcome of the Ritter Reaction57 (Scheme 5). If the alcohol 57 is mixed first with the nitrile and acetic acid, and the sulfuric acid is added last, then the product 58 dominates (kinetic control)58. However, if 57 is first mixed with the acid, and the nitrile added, then the compound 59 dominates
(thermodynamic control)59. In other reactions, the use of lower temperature and/or less acidic conditions can result in greater selectivity and control over the products60,61, but the overall yield sometimes is decreased as a result.
23 Studies in Multicyclic Chemistry Chapter 1
O H OH i. H2SO 4,AcOH,RCN NR ii. H2O Ph Ph Ph 57 58
H N R Ph Ph O 59
Sch eme 5
The interplay of such factors is well illustrated by the behaviour of 1- hydroxymethyladamantane 60 and 3-homoadamantanol 61 reportedbySasaki62
(Scheme 6 and Table 1).
OH
60 i. H2SO4, MeCN ii. H2O NHAc NHAc
62 63
OH
61 Scheme 6
24 Studies in Multicyclic Chemistry Chapter 1
Table 1 Correlation of reaction conditions for alcohols 60 and 61 with the resulting kinetic 62 and thermodynamic 63 amide products62.
Reagent (s) Condition Total yield of Relative yield (%) Temperature (°C) Time (h) amides (%) 62 63 60 15 1 20 66 34 60 15 24 42 10 90 60 50 1 40 2.9 97.1 60 50 24 92 0.2 99.8 61 15 24 93 16.5 83.5 61 50 24 98 10 90
60,AlCl3 15 24 23 92 8
60,AlCl3 15 96 42 17 83
61,AlCl3 15 24 72 31 69
61,BF-Et2O1524 76 397
The Ritter Reaction can also be combined with transannular cyclisation processes.
These can allow elegant preparations of appropriate ring compounds to be made in one-flask reactions. For example, 3,7-bis(methylidene)bicyclo[3.3.1]nonane 64 was converted directly into the acetamidoadamantane 65 in 75 % yield (Scheme 7)63.
Similarly, the keto olefin 66 produced the adamantane derivative 67.
25 Studies in Multicyclic Chemistry Chapter 1
CH2 CH i. H2SO 4,CH3CN 2 ii. H2O
CH 2 CH3
64
NH-CO-CH3
75 %
CH3 CH3 65
O OH i. H2SO 4,CH3CN ii. H2O
CH2 CH 2
66
OH OH
57 %
NH-CO-CH3 67 Sch eme 7
26 Studies in Multicyclic Chemistry Chapter 1
This combination of Ritter Reaction with transannular cyclisation is a very neat means of preparing appropriate cyclic systems. Therefore the basic concept reported by Stetter has been used by the Bishop group on a number of occasions. Thus, 1,5- bis(methylidene)cyclooctane 68 affords a 69 % yield of 1-acetamido-5- methylbicyclo[3.3.1]nonane 69 on its reaction with sulfuric acid and acetonitrile in acetic acid solution64 (Scheme 8).
i. H SO ,CH CO H, CH CN CH2 2 4 3 2 3 ii. H2O
69 % H3C
H2C NH-CO-CH3 68 69 Scheme 8
Similar behaviour is shown by the benzobicyclo[3.3.2]decane derivatives 70 and 7164
(Scheme 9) and (Scheme 10).
a) i. H2SO 4,CH3CO 2H,CH3CN ii. H2O
b) i. H2SO 4,CH3CO 2H, 4-Cl-C6H5-CN H3CNH-CO-R CH CH2 2 ii. H2O 70
a. R= CH3 87 % b. R= Cl-C6H5 88% Sch eme 9
27 Studies in Multicyclic Chemistry Chapter 1
i. H2SO 4,CH3CN ii. H2O 60 % HO NH-CO-CH3 O CH2
71 72 Sch eme 10
Thus, 71 reacts in the Stetter manner to yield the hydroxyamide 72 in 60 % yield.
However, the resulting hydroxy functional group is reactive under Ritter conditions.
Therefore 72 can also be converted into 67 % of the bis(amide) 73 (as its hydrate) in a one-flask reaction (Scheme 11).
i. H2SO 4,CH3CN ii. H2O 67 % HO NH-CO-CH3 H3C-OC-HN NH-CO-CH3
72 73 Sch eme 11
Hence, the keto olefin 71 may be converted into a hydroxyamide 74, a symmetrical bis(amide) 75, or an asymmetric bis(amide) 76 depending on the reaction conditions chosen (Scheme 12).
28 Studies in Multicyclic Chemistry Chapter 1
i. H2SO 4,C6H5CN ii. H2O 71 +
C H -O C-H N 6 5 NH-CO-C6H5 HO NH-CO-C6H5 75 74 2% 74 % i. H2SO 4,C6H5CN ii. H2O
i. H2SO 4,CH3CN ii. H2O
H3C-OC-HN NH-CO-C6H5
76 73 %
Sch eme 12
These examples indicate that the Ritter Reaction can be combined with deliberate rearrangement process, or deliberate transannular reactions, to produce interesting structures in simple one-flask reactions. The relief of steric strain can also influence the outcome of these processes65.
29 Studies in Multicyclic Chemistry Chapter 1
1.4 Tricyclo[5.3.1.13,9]dodecane System Chemistry
The tricyclo[5.3.1.13,9]dodecane 77 molecule contains an unusual alicyclic skeleton that so far has been scarcely investigated in adequate detail. It is a 1,1- bishomoadamantane system that would be expected to show unusual properties.
1 3 7 5
77 78
Parker et al.66 have shown that the C1 and C5 bridgehead positions of bicyclo[3.3.3]undecane (manxane) 78 are highly reactive and that the hydrocarbon rapidly forms hydroperoxides at these sites on standing in air. Force field calculations indicated that processes involving sp3 to sp2 rehybridisation at C1 and
C5 were exothermic by about 28 kJ mol-1 due to release of angle strain. Hence, processes leading to the bridgehead radical, cation, or alkene will be enhanced.
Experimental results showed that 1-chloromanxane was about 104 times more reactive than tert-butyl chloride in carbocation forming solvolyses under similar conditions.
These authors also predicted that the C3 and C7 bridgehead positions of tricyclo[5.3.1.13,9]dodecane 77 would also be considerably flattened, since this ring system can be regarded as a methano-bridged analogue of bicyclo[3.3.3]undecane.
30 Studies in Multicyclic Chemistry Chapter 1
Relief of angle strain due to rehybridisation at one of these positions was calculated to be about 18 kJ mol-1, and therefore this would make 77 much more reactive in comparison with related alicyclic systems such as adamantane. Facile removal of the bridgehead hydrogen atom to generate carbocation or radical intermediates would be expected. Similarly, formation of bridgehead alkene derivatives (anti-Bredt olefins) is likely67. The formation of a bridgehead inside pyramidalised hydrogen structure even has been considered as a possibility68.
These differences are also reflected in the difficulty of its synthesis, because the ring system is significantly strained at the C3 and C7 bridgehead sites. Preparative methods involving formation of the necessary eight-membered rings utilising cyclisation methods are frequently difficult to achieve in satisfactory yield. However, preparations of 1,5-diaza- and 1,5-diphospha-maxanes have been very successful69,70.
Several synthetic approaches to the tricyclo[5.3.1.13,9]dodecane ring system have been reported in the literature, but most are not entirely satisfactory:
(i) Silver(I)-assisted hydrolysis of the dichlorocarbene adduct of
homoadamant-4-ene yields a mixture of products, including 5-
chlorotricyclo[5.3.1.13,9]dodec-5-en-4-ol in 30 %71.
(ii) Homoadamantan-4-one is readily formed through ring expansion of
adamantanone. Subsequent Tiffeneau-Demjanov ring expansion affords
tricyclo[5.3.1.13,9]dodecan-4-one in 15 % yield. Several other 4-
substituted derivatives, and also the parent hydrocarbon, were prepared
31 Studies in Multicyclic Chemistry Chapter 1
from this material. However, attempted ring expansion of 3-
tosyloxymethylhomoadamantane failed72.
(iii) Tricyclo[5.3.1.13,9]dodecan-4-one has also been used to prepare several
bridgehead enolate derivatives, and also the bridgehead alkene itself73.
These successes confirm the expectation that bridgehead sp2 carbon
hybridization is favourable in this ring system.
(iv) Alternatively, the bicyclic ester 79 may be reacted with sodium hydride
in 1,2-dimethoxyethane, and then heated with 1,3-dibropropane. This
process yields 3,7-bis(methoxycarbonyl)tricyclo[5.3.1.13,9]dodecane-2,8-
dione 80 in 26 % yield (Scheme 13)74. Unfortunately, most of the
alkylation takes place on the more exposed exo-faces of the
bicyclo[3.3.1]nonane ring system, so this yield cannot be improved
further. Furthermore, this reaction is capricious and isolation of pure
product is difficult. Despite those problems, Bishop has used this
approach to prepare a helical tubuland diol host 81 based on this ring
system and has studied the inclusion properties of this compound75,76.
HO i. NaH O OH O ii. Br-(CH2)3-B r
H3CO 2C CO 2CH3 26 % H3CO 2C CO 2CH3
79 80 Sch eme 13
Recently, a much more satisfactory synthetic route has been devised by Bishop and
Yue77. Replacement of the 1,3-dibromopropane by 3-chloro-2-chloromethylprop-1-
32 Studies in Multicyclic Chemistry Chapter 1
ene 82 was found to result in a much cleaner cyclisation reaction to 83 in 75 % yield
(Scheme 14). This observation has some precedent in the work of Schulze69 and
Bell78, who found the diiodo analogue of 82 to be a good reagent for 8-membered ring formation in certain systems.
H3C CH 3 HO OH
81
10
O 1 9 Cl Cl O HO NaH 2 OH 12 11 8 75 % 3 7 H COOC 3 COOCH3 4 6 H COOC CH2 5 3 COOCH3 79 82 83 CH2
Sch eme 14
The discovery of this cyclisation procedure has made available the first efficient synthetic route to the tricyclo[5.3.1.13,9]dodecane system. This has been exploited by
Bishop and Yue in a series of preparations77.
Prior to my work, several crystal structures of diol 81 inclusion compounds had been determined and published75,76. In addition, X-ray structures of diols 84, 85 and 86 have been reported77. All of these structure determinations indicated severe distortion
33 Studies in Multicyclic Chemistry Chapter 1
of the tricyclic skeleton, particularly in the vicinity of the C3 and C7 bridgehead sites.
H C HO 3 H3C CH 3 CH3 OH HO HO OH OH H3C CH 3
CH2 CH3 CH3
84 85 86
The tricyclo[5.3.1.13,9]dodecane system also showed unusual effects in its solution
NMR spectra. Typically, the majority of decoupled carbon signals appeared as sharp singlets, but the remaining signals were considerably broadened and of low intensity.
This characteristic could even be used as a qualitative measure of the presence of tricyclo[5.3.1.13,9]dodecane compounds in a number of synthetic reactions77.For
13 example, at 355 K in d6-DMSO, the broadband decoupled C NMR spectrum of compound 83 showed 10 sharp singlets as would be expected for this symmetric molecule in solution. At 300 K, however, only 6 of these carbons gave a sharp singlet signal. Two appeared as broad peaks at 58.8 (C) and 45.4 (CH2), and the final two as very broad and extremely weak peaks at 211.1 (C=O) and 38.6 (CH2).
These signals correspond to C3/C7, C4/C6, C2/C8 and C11/C12, respectively.
There are three aspects of tricyclo[5.3.1.13,9]dodecane of especial relevance to this thesis.
(i) Is it possible to utilize the expected unusual reactivity of the C3 and C7
bridgehead positions for preparing new derivatives?
34 Studies in Multicyclic Chemistry Chapter 1
(ii) Are the anomalous bond length and angle values recorded in the X-ray
crystal structures of the tricyclo[5.3.1.13,9]dodecane system meaningful?
(iii) Can the unusual 13C NMR spectral data of the tricyclo[5.3.1.13,9]dodecane
system be explained?
1.5 Schroeter and Vossen’s Red Salt
In 1910, Vossen reported work on condensation reactions involving chloral and dimethyl malonate in his Inauguraldissertation at the University of Bonn79. Included in this work was a description of an unexpected red organic compound. This material, which proved to have the molecular formula C16H15O10Na, later became known as Schroeter and Vossen’s Red Salt.
The first journal description of this compound was published by his supervisor,
Schroeter, in 192280. This account contained no preparative details for the Red Salt, and provided little supporting evidence for its proposed structure. However,
Schroeter described it is being a sodium salt formed from 2,4,6,8- tetracarbomethoxybicyclo[3.3.0]oct-1-ene-3,7-dione 87. Despite the lack of experimental data, this conclusion showed much chemical insight and later proved to be correct.
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CO 2-CH 3 CO 2-CH 3
O O
CO 2-CH 3 CO 2-CH 3 87
Wanzlick (1953)81, and Yates and Bhat (1954)82 reported further work on the Red
Salt, and showed beyond any doubt that Schroeter’s conclusions had been correct. In addition, Yates and Bhat used infrared and visible spectroscopy to show that the Red
Salt structure was the conjugated enolate salt 88. More accurately, 88 is only one resonance contributing form of the structure. Therefore, its structure might be better represented as 89, when electron delocalisation is considered.
CO2-CH3 CO2-CH3 CO2-CH3 CO2-CH3
O O O O Na Na
CO2-CH3 CO2-CH3 CO2-CH3 CO2-CH3 88
36 Studies in Multicyclic Chemistry Chapter 1
Na H3CO OCH3
O C CO
8 2 1
O O 7 5 3 6 4
R H 1 R2 R3 R4
89
The Red Salt has found use as a synthetic intermediate in the preparation of several bicyclo[3.3.0]octane compounds. This work has included attempts to prepare pentalene derivatives by Paul and Wendel83, Boekelheide84, and Yates85. The Red
Salt does provide a convenient route to valuable compounds such as the tetraester 90 and bicyclo[3.3.0]octane-3,7-dione 91. However, it has not been widely employed for such work. No preparative details for the Red Salt were published in the primary literature until the work of the Yates group in 1960. Furthermore, a simpler synthetic route to 90 and 91 is available using glyoxal and dimethyl 1,3-acetone dicarboxylate86. The red tetraethyl ester analogue of 89 and also its orange-red potassium and yellow-green copper salts have been described by Tanaka87.
CO2-CH3 CO2-CH3
O O O O
CO2-CH3 CO2-CH3 90 91
37 Studies in Multicyclic Chemistry Chapter 1
Our interest in the Red Salt was spurred by the report that preparation of 89 from methanol actually yielded a methanol solvate compound. There were also several features of the Red Salt structure which could not be uncovered through use of just
IR and visible spectroscopy, but which would become apparent through use of more modern analytical methods. The outcome of our investigation is presented in Chapter
6.
1.6 Bicyclo[3.3.0]octane-based Diquinolines
Synthetic organic chemistry has traditionally been concerned with the breaking and making of covalent bonds between atoms. In recent years, there has been an increasing awareness that the non-covalent bonding between molecules is not only of huge importance, but is becoming accessible to measurement and interpretation. This important new field is called supramolecular chemistry88. It can be defined as ‘the designed chemistry of the intermolecular bond’89. This concept allows us to make new substances and aggregates by controlling the intermolecular associations present90,91. It is necessary to discover what intermolecular attractions exist, understand how they operate between molecules, and learn to control their self- assembly behaviour. Early contributions to supramolecular chemistry were made by
Pedersen92,Lehn93,andCram94, all of whom were awarded the Nobel Prize for
Chemistry in 1987.
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Inclusion compounds are an excellent means of learning about the action of intermolecular attractive forces between dissimilar molecules. They are substances where one component (the host) encloses a second component (the guest) without conventional bonding being present95,96. Generally speaking, there are two classes of inclusion compounds. Materials such as cyclodextrins, crown ethers and cryptands are familiar examples of the first group. All of these hosts have some form of permanent receptor structure that is complementary to the guest species, allowing efficient host-guest complexation. The second group of compounds is the clathrates or lattice inclusion compounds. Here, a combination of many hosts and guests generates a stable structure in the solid state containing two or more different types of molecules. The behaviour of these molecules is more difficult to predict, and the design of new hosts is still somewhat of a black art97.
In recent work, the Bishop group has designed a general type of molecular structure that can be used in the deliberate synthesis of new lattice inclusion hosts98. This concept is illustrated in Figure 1.
39 Studies in Multicyclic Chemistry Chapter 1
ALICYCLIC CENTRAL LINKER GROUP
EXO- EXO- BROMINE BROMINE ATOM ATOM
PLANAR AROMATIC WINGS
Figure 1 A general modular design for the synthesis of new inclusion hosts.
Each host molecule incorporates three structural parts, all of which have a specific function, and all of which are necessary for its action. Most of these hosts can be synthesised from readily available starting materials in only two steps. In the first of these the two planar aromatic wings are joined to an alicyclic diketone which provides the central linker group. The alicyclic linker also allows twisting and/or folding of the host molecule to accommodate different sizes and shapes of guest molecules. The aromatic wings allow the possibility of host-host and host-guest aromatic edge-face (EF) and offset face-face (OFF) interactions99-102. The two sensor groups are added in the second synthetic reaction. In this work, these are simply bromine atoms. The presence of these sensor groups reduces the possibilities for OFF interactions in the crystal, and provides contact points for host-guest attractions such
40 Studies in Multicyclic Chemistry Chapter 1
as halogen---halogen103,104, halogen---N105-108, halogen---H__Ar109, and halogen---
110,111 interactions.
The resulting host has C2 symmetry which, statistically, has been found to be a desirable property for inclusion behaviour to occur. Either racemic or homochiral hosts can be obtained, through use of the appropriate alicyclic diketone reagent. In simple terms, the molecule carrying sensor groups packs less efficiently in the solid than the parent compound where hydrogen replaces bromine (Figure 1). This encourages the inclusion of guest molecules to yield a lower energy solid state structure.
Alternatively, sensor groups may be placed on the aromatic wings either instead of, or in addition to, the benzylic sites shown in Figure 1. These also can yield effective host molecules This molecular design is also modular in nature. Aromatic wings, alicyclic linker groups, and sensor groups can be switched around at will. This has allowed the synthesis of a considerable number of new lattice inclusion hosts in a short time.
Here, I shall only describe those systems utilising bicyclo[3.3.0]octane-2,6-dione 92 as the reagent for constructing the central linker group. This work was carried by
Rahman, who prepared the dibromo-, tetrabromo-, and hexabromo-hosts illustrated in Scheme 15. In addition to these, he also studied the dichloro derivative 97,which was synthesised in a manner related to that of its parent analogue 94.
41 Studies in Multicyclic Chemistry Chapter 1
CHO H Aq. NaOH MeOH H O N O 75 % NH2 H N H 92 93
Br2,H2SO4 78 % NBS, CCl4 Ag2SO4 51 %
Br Br H Br H N N
N N Br H H 94 Br 95 Br 85 % NBS, CCl4
Br Br H Br N
N Br H Br Br 96
Scheme 15
Br Cl H N
N H Cl 97 Br
Scheme 15 summarises the synthetic chemistry used to obtain the various diquinoline compounds 93-96. In the first step, one equivalent of bicyclo[3.3.0]octane-2,6-dione was condensed with two equivalents of 2-aminobenzaldehyde by means of
Friedländer condensation112,113. The resulting diquinoline 93 does not contain sensor groups, can pack effectively by itself, and shows no host properties. If reacted with
42 Studies in Multicyclic Chemistry Chapter 1
N-bromosuccinimide (NBS) then the product 94 is obtained in 78 %. This process is both regio- and stereo-selective. All four alicyclic sites are benzylic but the only significant reaction occurs at the two equivalent positions shown. This is due to the radical-like nature of the transition state in the endothermic NBS hydrogen abstraction step. The reactive site involves a p-orbital that overlaps much more efficiently with the aromatic ring than that of the alternative reaction site. Therefore the two competing pathways are very different in energy. Since the molecular skeleton is V-shaped, the bromination occurs much more efficiently on the exo-face of the radical p-orbital, than on the crowded endo-face114.
Alternatively, the aromatic rings of 93 can be brominated to obtain the tetrabromide
95, in 51 % yield. This reaction used the methodology devised by de la Mare115,116, and uses molecular bromine, silver sulfate and concentrated sulfuric acid. Benzylic bromination using NBS affords the hexabromide 96 in 85 % yield. All three brominated products 94-96 act as lattice inclusion hosts. The dichloro compound 97 is made in a similar manner to compound 94, except that 2-amino-5- chlorobenzaldehyde is employed in the Friedländer condensation step.
1.6.1 Inclusion Behaviour of the Dibromo Host 94
The dibromide 94 forms inclusion compounds with wide range of guest molecules
(methylchloroform, trifluoromethylbenzene, toluene, dioxane, ethyl acetate, 1,1,2,2- tetrachloroethane, chloroform, 1,2-dichlorofluoroethane, acetone, and allyl
43 Studies in Multicyclic Chemistry Chapter 1
cyanide/acetonitrile)117,118. All of these materials have closely related crystal structures. Two molecules of 94 surround one molecule of the guest compound to form a molecular pen. The aromatic wings act like fences and enclose the host within
(Figure 2). The pens can vary their dimensions and geometries slightly to accommodate guests of differing size and shape. These molecular pens pack together by means of aryl offset face-face (OFF) interactions99-102to generate layers of pens.
The layers of pens stack on top of each other to generate the overall crystal structure.
Figure 2
Side view of one molecular pen in the crystal structure of (94)2.(CCl3-CH3). The host fences are indicated in framework representation, and the guest molecule using space-filling representation.
44 Studies in Multicyclic Chemistry Chapter 1
In cases such as the dioxane compound, (94)2.(dioxane), the adjacent layers (Figure
3) stack directly above each other. This results in the guest molecules occupying molecular tubes (Figure 4). Alternatively, the layers may be offset, as in the methylchloroform compound, and then the guests are present within cage-like structures (Figure 5). In both cases, the layers associate by means of a network of
__ 119-122 dimeric C H---N interactions . The arrangement in (94)2.(dioxane) is shown in
Figure 6 as a representative example.
45 Studies in Multicyclic Chemistry Chapter 1
Figure 3 117 One layer of molecular pens in the crystal structure of (94)2.(dioxane) .
46 Studies in Multicyclic Chemistry Chapter 1
Figure 4 Stacking of molecular pens directly on top of each other to generate the crystal 117 structure of (94)2.(dioxane) .
47 Studies in Multicyclic Chemistry Chapter 1
Figure 5 Offset stacking of layers of molecular pens to generate the crystal structure of 117 (94)2.(CCl3-CH3) .
48 Studies in Multicyclic Chemistry Chapter 1
Figure 6 The structure of C__H---N interactions operating between layers of molecular pens in 117 solid (94)2.(dioxane) .
This series of compounds provides a good illustration of how host conformational changes are related to accommodation of different guests. We define the fold-angle
49 Studies in Multicyclic Chemistry Chapter 1
O H N
N H O
98
as the angle present between the three mid-bond points marked on the example of molecular structure 98. For host 94, these range from 95.7 to 104.8 °. However, this angle opens up to the considerably greater value of 141.4 ° in the crystal structure of the bis(N-oxide) 98, because its packing mode requires an edge-edge arrangement.
This illustrates the conformational flexibility available to host molecules of the general structure illustrated in Figure 1.
1.6.2 Inclusion Behaviour of the Dichloro Derivative 97
The dichloro compound 97 was obtained by Friedländer reaction of bicyclo[3.3.0]octane-2,6-dione and 5-chloro-2-aminobenzaldehyde, followed by
NBS bromination. Although its molecular structure only differs by replacing two hydrogens by chlorines, its supramolecular chemistry is completely changed.
Crystallisation from trifluoromethylbenzene or acetone yields solvent-free crystalline material (the apohost), something that could not be achieved in the case of 94.The apohost has an exceedingly complex and interesting crystal structure123. Its lattice
50 Studies in Multicyclic Chemistry Chapter 1
arises from multiple interlocking of two sets of parallel molecular grids. Each grid connector site is a centrosymmetric tetrameric assembly involving weak intermolecular forces, quite unlike the metal co-ordination sites usually involved in generating grid structures124.
Only two inclusion compounds could be obtained from 97. The ethyl acetate compound has a molecular pen structure which is superficially similar to those observed for 94. It differs principally in having a very different inter-layer packing.
This involves C__H---N interactions that are dissimilar to those of 94125.
The second inclusion compound, containing benzene, forms a staircase structure125 similar to those found for the tetrabrominated host 99, which has a bicyclo[3.3.1]nonane core126-128.
Br Br N
N
Br Br 99
In the staircase structure, two molecules of the host with opposite chirality associate face-face by means of a pi-halogen dimer (PHD) interaction128-130.Thisisa centrosymmetric motif where the endo-faces of two host molecules interact by an
51 Studies in Multicyclic Chemistry Chapter 1
OFF interaction. Rather than the two ends of the wings participating in EF interactions, the two molecules are mutually rotated, such that a halogen atom of the molecule becomes placed directly over the centres of two pyridine rings of the second molecule (Figure 7).
OFF
Figure 7 A typical PHD interaction showing the interfacial OFF and the four Br… interactions (dashed lines).
The PHD units then stack on top of each other, utilising OFF interactions, to generate each staircase (Figure 8). These staircases pack parallel to each other, with guest molecules occupying interstitial sites (Figure 9).
52 Studies in Multicyclic Chemistry Chapter 1
Figure 8
Two side views of the host molecular staircase present in solid (97)2.(benzene). Symbolism used: centre of symmetry (*) and twofold axis (ellipse or arrow, respectively). All hydrogen atoms are omitted125.
53 Studies in Multicyclic Chemistry Chapter 1
b
a
Figure 9
Top view of the parallel molecular staircases present in solid (97)2.(benzene). The guest molecules (purple carbon atoms) occupy interstitial sites125.
1.6.3 Inclusion Behaviour of the Tetrabromide 95
The tetrabromide derivative 95 proved to be an efficient lattice inclusion host for a number of guest molecules131. Three distinct classes of inclusion structure were obtained, but all of these involved the PHD motif. The allyl cyanide inclusion compound formed a staircase structure in a similar manner to the case just described.
A quite different layer structure was obtained when the aromatic compounds chlorobenzene, toluene, or benzene/water were included. These compounds
54 Studies in Multicyclic Chemistry Chapter 1
contained three independent host molecules (A-C) and their enantiomers (A*-C*).
Both A*-B and A-B* PHD units are present, these being the only non- centrosymmetric PHD motifs so far recorded131. The C and C* molecules participate in OFF interaction with the PHD units, rather than forming PHD units themselves.
The guest molecules occupy positions between the layers. The case of
(95)3.(chlobenzene)2 is shown in Figure 10.
55 Studies in Multicyclic Chemistry Chapter 1
Figure 10
The crystal structure of (95)3.(chlorobenzene)2 projected on the ab plane. Opposite enantiomers of the host molecules are coloured light or dark green. Host molecules associate into A*-B PHD units that are linked to C molecules by OFF interactions (and the anantiomorphous arrangement in neighbouring layers). Crystallographically independent chlorobenzene molecules lie below (purple), or above (dark blue), the host layer illustrated131.
The haloalkanes methylchloroform and carbon tetrachloride from a third type of structure involving host 95. Once again, this is a layer arrangement, but the guests are trapped within channels of rectangular cross-section between these layers (Figure
56 Studies in Multicyclic Chemistry Chapter 1
11). Within each layer, neighbouring PHD units are linked by only edge-edge C__H--
-N dimer motifs (Figure 12)120.
Figure 11 Zig-zag layers of host molecules 95 in the crystal structure (95).(methylchloroform). The guest molecules (only one disorder component shown) occupy channels of rectangular cross-section running along c131.
57 Studies in Multicyclic Chemistry Chapter 1
*
*
*
Figure 12 Host molecules within a layer of (95).(methylchloroform), showing the inversion centres (*) within the PHD units, and the edge-edge C__H---N dimer interaction. Opposite enantiomers are coloured light and dark green131.
1.6.4 Inclusion Chemistry of the Hexabromide 96
The hexabromide compound 96 showed quite different inclusion compound properties once more132. Only small aromatic hydrocarbons were included.
Furthermore, analysis of the various crystal structures provided a convincing explanation for this remarkable selectivity. The crystal structure of the apohost revealed that the molecules pack into parallel layers with an extremely high density
58 Studies in Multicyclic Chemistry Chapter 1
of bromine atoms between each layer (Figure 13). Within a layer the molecules are arranged as parallel chains through use of OFF and EF interactions, but there are no recognizable favoured interactions between these individual chains (Figure 14).
Figure 13 Crystal structure of the apohost 96 projected on the ab plane. Layers of molecules lie parallel to each other in the bc plane. The high density of bromine interaction between the layers is very apparent132.
59 Studies in Multicyclic Chemistry Chapter 1
Figure 14 An individual layer of molecules in the crystal structure of apohost 96. Chains of molecules, associated by means of OFF and EF interactions, run along b. There are only dispersion forces operating between these chains132.
When o-xylene, p-xylene or toluene are included, these guest molecules occupy sites within the layers and between parallel chains, linking the latter together with additional OFF and EF interactions. At the same time there is marked reduction in the number of Br---Br interactions operating between the layers (Figures 15 and 16).
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Figure 15 Edge-on view of the molecular layers in solid (96).(o-xylene). The guest molecules are coloured purple, and only one disorder component is shown. Note the reduced density of bromine atoms between the layers in this structure132.
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Figure 16 Part of a molecular layer in (96).(o-xylene) showing how the o-xylene guest molecules associate efficiently with the chain host molecules to produce a strengthened layer structure132.
The host:guest stoichiometry changes from 1:1 to 2:3 when benzene is included, and the relative packing energy become even more favourable. This occurs by the packing motifs within each chain changing from an OFF and two EF interactions,
62 Studies in Multicyclic Chemistry Chapter 1
into one PHD unit created by the two host molecules mutually rotating slightly. A space is thereby created which can accommodate a second crystallographically independent benzene molecule. This positions itself between the host layers at the expense of further Br---Br interactions. Since all these intermolecular forces are very weak, it is probably the directional properties of the aromatic interactions that are the driving force for this series of changes (Figure 17).
Figure 17
Layers of the host molecule 96 viewed edge-on in solid (96)3.(benzene)2. Two crystallographically independent benzene molecules are present. The ones within the layers (purple) stabilise these layer structures, while those between the layers (yellow) replace further Br---Br interactions132.
63 Studies in Multicyclic Chemistry Chapter 1
1.7 Aims of the Project
The chemistry in sections 1.1–1.3 has described how the Ritter Reaction and related processes can be used in synthesis. In the following Chapters 2 - 4 these concepts will be developed into novel approaches to multicyclic systems containing nitrogen atoms. The aim is to carry out preliminary chemistry in establishing new and unusual routes to such compounds, rather than targetting any specific structure. It should be noted that the structures of some products obtained have parallels with known bioactive molecules such as those illustrated in Figure 18.
H C 3 O N
N Cl - C6H5 CH (CH2)2-N(CH3)2 Diazepam Amitriptyline (sedative) (antidepressant)
Cl N N (CH2)3-N(CH3)2 (CH2)3-N(CH3)2 Imipramine Clomipramine (antidepressant) (antidepressant)
Figure 18 Structures of some multicyclic sedative and antidepressant drugs.
Other examples, notably the DMAD adducts and Ritter rearrangement products
(described in Chapters 3 & 4) have multicyclic structures akin to non-natural
64 Studies in Multicyclic Chemistry Chapter 1
alkaloids but are obtained by means of very short and unexpected methods. One such molecule from earlier work in the group has been found to exhibit anti-cancer properties.
Chapters 4 & 5 deal with the chemistry of carbocyclic systems bearing bridgehead nitrogen atoms. The short preparations of such compounds are aimed towards future development of new anti-viral bridgehead agents133 related to those shown in Figure
19.
NH2 NH2 CH CH3
Amantadine Rimantadine
NH-CO-CH2-O-CH2-CH2-N(CH3)2
Tromantadine
Figure 19 Structures of some anti-viral bridgehead amines.
Finally, Chapters 6 & 7 investigate two rather different areas of chemistry involving bicyclo[3.3.0]octane chemistry; one old and one very new.
65 Studies in Multicyclic Chemistry Chapter 2
Chapter 2 Results and Discussion
2 Chemistry of Multicyclic Ritter Reactions
Previous research in our group had led to convenient synthetic routes to several unusual multicyclic products whose formation involved both the bridging and the standard Ritter reactions. These compounds contained an imine group present in the form of a 1-azacyclohexene ring, in addition to the more common amide functional group. The further chemistry of compounds of this type was the starting point for my research.
2.1 The Structure of a Ritter Reaction Product-Benzene Inclusion Compound
Earlier work by Pich43 had shown that 5H-dibenzo[a,d]cyclohepten-5-ol
(dibenzosuberenol) 35a underwent Ritter reaction with acetonitrile and sulfuric acid to yield either the standard Ritter reaction product 37 or the bridged Ritter reaction compound 36a, depending on the conditions used (Scheme 16).
CH 3CN
H2SO 4 mild conditions 78% 35a OH 37 NHCOCH3 vigorous conditions 64% CH3CN H3COCHN CH3 H2SO 4 C N
36a Sch eme 16
66 Studies in Multicyclic Chemistry Chapter 2
The acetamide 37 was found to give a 1:2 host-guest product when crystallised from dioxane44. On repeating the above preparative work, it was found that the bridged product 36a yielded a previously unknown benzene inclusion compound. Pich43 had previously carried out the X-ray structure of the closely-related bridged amide 36b43.
H3COCHN CH 3
C N
C6H5 36b
The latter important result confirmed beyond doubt the structure of this family of bridged amide products. However, no signs of guest inclusion were encountered while working on this compound and other close analogues.
Crystallisation of compound 36a from benzene yielded unstable crystals that rapidly became opaque due to loss of included solvent. The crystal used for X-ray analysis was therefore coated in glue to reduce the rate of crystal decay. This compound had the structure (36a).(C6H6) and crystallised in space group Cc. Table 2 lists numerical details of the solution and refinement of the crystal structure.
67 Studies in Multicyclic Chemistry Chapter 2
Table 2 Numerical details of the solution and refinement of the structure (36a) (benzene)
Compound number 36a (benzene)
Formula, formula mass (C19H18N2O).(C6H6), 368.5 Space group Cc /Å 10.694(5) b/Å 22.843(5) c/Å 9.901(4) /º 124.02(2) V/Å 2005(1) Temp./°C 21(1) Z 4 -3 Dcalc/g cm 1.22 Radiation, / Cu K , 1.5418 μ/cm¯ 5.48 Crystal dimension/mm ~0.4 X 0.1 X 0.1 Scan mode /2
2 max/º 120 Scan angle 0.6 + 0.15 tan Largest peak in final diff. map/e ů 0.21 No. of intensity measurements 1621 Criterion for observed reflection I/ (I) > 3 No. of independent obsd. reflections 1111 No. of reflections (m) and variable (n) in final refinement 1111, 218 m m R = | F|/ |F0| 0.054
m 2 μ 2 Rw =[ | F| / |F0| ] 0.066 s =[m | F|2/(m–n) 2.33 Crystal decay 1 to 0.82
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Figure 20 shows the molecular structure of the host 36a, emphasising the configuration of the bridging imine group and the acetamide substituent. These findings are completely consistent with expectation from the earlier work, and confirm the earlier structure assignment43.
Figure 20 Molecular structure of the bridged Ritter reaction product 36a emphasising the stereochemistry of the amide group and imine bridge. Colour code: C= green, H= light blue, N= dark blue and O= red. This colour code will be used throughout this thesis, unless otherwise stated.
69 Studies in Multicyclic Chemistry Chapter 2
Figure 21 __ Cell diagram for (36a).(C6H6) showing the N H---O=C hydrogen bonding along c as dashed lines. The carbon atoms of the benzene guest molecules are coloured pink. Opposite enantiomers of 36a are coloured dark or light green. This symbolism will be used throughout the thesis, unless otherwise stated.
Molecules of 36a have a V-shape with one aromatic wing bearing the amide functionality. Chains of 36a associate by means of N__H---O=C hydrogen bonds along c (Figure 21). Due to this molecular asymmetry, the host molecules are oriented alternatively left, right, left, right etc. with respect to the c direction. Adjacent molecules also have the opposite chirality. However, these enantiomers along each side of the hydrogen bonded chain are at different heights with respect to the a direction. Hence, the aromatic wings closest to the amide group can interact by means of aromatic offset face-face (OFF) interactions. This can be seen more clearly in Figure 22 where the stack of benzo groups down c is apparent. The shortest distance between these aromatic rings is 3.05 Å, which is short for an OFF interaction.
70 Studies in Multicyclic Chemistry Chapter 2
In Figure 22, the hydrogen bonded chains appear as parallel stacks along the c direction. The columns of OFF interactions are located at the centre of each stack.
Figure 22
Cell diagram of (36a).(C6H6) viewed as a projection on the ab plane. The hydrogen bonded chains of 36a appear as stacks parallel to c.
The other benzo ring of each molecule of 36a interleaves with others of the same type in adjacent stacks. Each edge of a hydrogen-bond stack involves only one enantiomer of 36a, and this interleaves with immediate neighbours of opposite chirality. Benzene guest molecules associate with the host benzo groups more distant from the amide functionality by means of aromatic edge-face (EF) interactions (Figure 23). One host hydrogen atom of the benzo ring is positioned almost equidistantly from all six carbon atoms of the guest (2.88, 2.89, 2.98, 3.00, 3.10 and 3.10 Å).
71 Studies in Multicyclic Chemistry Chapter 2
Figure 23 The aromatic edge-face (EF) interaction present between a host molecule 36a and a guest benzene molecule. The hydrogen atom is positioned almost equidistantly from the carbon atoms of the guest.
This association of host and guest molecules produces distinct zones within the crystal structure. Chains of the host molecules lie in the ac plane around b =0andb =0.5, with the guests in between at b =0.25andb = 0.75 (Figure 21). The benzene molecules form the zig-zag arrangement illustrated in Figure 24. These guest molecules are tilted with respect to each other (interplanar angle 40.1°) and poor EF
72 Studies in Multicyclic Chemistry Chapter 2 interactions are present. (The ideal EF interaction has an interplanar angle of 90°).
The Ar_H--C contacts present between neighbouring guests are 2.72, 2.85, 2.95, 2.96 and 3.02 Å. It appears that this guest-guest interaction is of least importance compared to the host-host and host-guest interactions present in the (36a).(C6H6) structure (Figure 24).
Figure 24 The zig-zag arrangement of benzene guest molecules in the inclusion compound _ (36a).(C6H6) showing the Ar H---C distances.
73 Studies in Multicyclic Chemistry Chapter 2
2.2 The Structure of an Oxidised Ritter Reaction Product
As discussed in the introduction (Section 1.1.3), Bong and Ung39 found that the use of benzyl cyanides in the Ritter reaction led to unexpected oxidation products 29a-c being formed. Thus, the diene 26 underwent the bridging Ritter reaction but did not yield the expected product 28. Instead, material assigned the structure 29 was isolated.
This appeared to have resulted from oxidation of 28. Two potential oxidation agents, concentrated H2SO4 and O2, were present under the Ritter reaction conditions used.
One, or perhaps both, of these had oxidised the allylic-benzylic CH2 group of 28 into the fully conjugated C=O of 29.
Due to the strongly acidic conditions used in the Ritter reaction, care should always be taken regarding the assignment of product structures. Confirmation by means of X- ray single crystal analysis is a prudent experiment to carry out where this is possible.
To pursue this question further, dibenzosuberenol 35a was subjected to the bridging
Ritter reaction using sulfuric acid and both benzonitrile and benzyl cyanide (Scheme
17). The reaction with benzonitrile proceeded as expected and produced the bridged adduct 100 in 39 % yield. However, the benzyl cyanide reaction again yielded an unexpected product.
74 Studies in Multicyclic Chemistry Chapter 2
Ph-OCHN Ph
C N Ph-CN H SO 2 4 100
Ph-H2COCHN CO-Ph OH Ph-CH2CN 35a H2SO 4 C N
101 Sch eme 17
The new material 101 was obtained in 30 % yield after chromatography of the crude
+ products. This had a microanalysis of C31H24N2O2 and a mass ion M = 456. These results demonstrated that 101 was an oxidised Ritter reaction product, analogous to
39 1 those observed by Bong and Ung .The H NMR spectrum only showed one CH2 unit, which was observed as an AB system due to the magnetic inequivalence of the two protons of the benzylamide side chain. Similarly, only one CH2 group was indicated by 13C NMR data. Furthermore, there were three quaternary C signals at high chemical shift ( = 170.0, 170.2 and 191.2), and these are compatible with the carbon atoms of the two carbonyl and one imine functionalities. All this information supports a structure similar to 101 where one benzyl group has been oxidised to a benzo group. Additional supports comes the mass spectrum where a peak at m/z = 351
_ was observed. This corresponds to the loss of a C6H5 CO fragment.
75 Studies in Multicyclic Chemistry Chapter 2
Although structure 101 appeared to be the most probable one, the recorded data does not rule out alternative isomeric structures, such as 102 formed by a rearrangement reaction.
C6H5-H 2COCHN C6H5
O C N C
102
For these reasons, the structure of the oxidation product was determined by X-ray methods. This material crystallised in space group P21/c and did have the proposed structure 101. Numerical details of the solution and refinement are given in Table 3.
The molecular structure of compound 101 itself is shown in Figure 25.
Figure 25 Molecular structure of the imine 101 determined by X-ray crystallography. The benzylamido, benzoyl, and bridged imine portions of the molecule are clearly visible in this view.
76 Studies in Multicyclic Chemistry Chapter 2
Table 3 Numerical details of the solution and refinement of the structure 101.
Compound number 101 Formula, formula mass C31H24N2O2, 456.5 Crystal description {100} {010} {12-1} (0-2-1) (021) (0-21)
Space group P21/c /Å 10.160(2) b/Å 24.829(2) c/Å 9.983(1) /º 90 /º 105.082(7) /º 90 V/Å 2431.7(5) Z 4 Dcalc/g cm-3 1.25 μ/cm¯ 5.83 Crystal dimension/mm 0.16 x 0.18 x 0.28
2 max/º 140 Scan angle 0.6 + 0.15 tan Max., min. transmission coefficients 0.92, 0.85 Rint for (no.) multiple measurements 0.016 (366) Largest peak in final diff. map/e ů 0.20 No. of intensity measurements 4993 No. of independent obsd. reflections 3115 No. of reflections (m) and variable (n) in final refinement 3115, 316 m m R = | F|/ |F0| 0.044 m 2 m 2 Rw =[ | F| / |F0| ] 0.059 s =[μ | F|2/(m–n) 2.02 Crystal decay None
77 Studies in Multicyclic Chemistry Chapter 2
This determination of structure 101 confirmed our earlier ideas regarding the formation of oxidised Ritter products in the bicyclo[3.3.1]nonane system, and almost certainly demonstrates that the structures 29a-c have been correctly assigned.
The molecules of 101 assemble into _N_H--O=C (amide) hydrogen bonded chains along the c direction as shown in Figure 26. Adjacent molecules in each chain have opposite handedness. In common with structure (36a).(C6H6), the benzo groups closest to the amide functionality are positioned nearer the centre of the hydrogen bonded chain, and the remaining benzo groups are orientated left, right, left, right, etc. along the c direction. The molecules of 101 within each chain are additionally linked by Ar_H---O=C (benzoyl) weak hydrogen bonds, and aromatic EF (phenyl) Ar_H---
(benzo) interactions.
Figure 26 Crystal structure of 101 projected onto the ac plane. The molecules are assembled into chains of alternating enantiomers by means of N_H---O=C hydrogen bonds (black dashed lines). The EF interactions are indicated by arrows, and Ar_H---O=C interactions by the red dashed lines.
78 Studies in Multicyclic Chemistry Chapter 2
Figure 27 Crystal structure of 101 projected on the ab plane. The hydrogen bond chains of molecules run in parallel along the c direction, and associate through EF interactions (black arrows).
In addition, the structure is stabilised by EF interactions between neighbouring chains
(Figure 27). One of these is (benzo) Ar_H--- (phenyl) and the other (benzo) Ar_H---
(benzo). Repetition of these interactions roughly along the b direction holds the neighbouring parallel chains together.
79 Studies in Multicyclic Chemistry Chapter 3
Chapter 3 Results and Discussion
3 Reactions of Bridged-Ritter Products
Work carried out earlier in the Bishop group, and described in Section 1.1.3, has made available a series of bridged-Ritter reaction products. These are available with a variety of substituents, but all contain a bridged imine functionality in the form of a 1- azacyclohexene part structure. Some unusual chemistry was expected for such compounds, and this is the subject of Chapter 3.
3.1 Reaction of the Bridged Imines with Mercaptoacetic Acid
It is well known that the imine functional group is reactive and can lead to unusual and interesting chemical products. For example, Nair134 demonstrated that the methyl- substituted imines 103 and 104 reacted with mercaptoacetic acid 105 to produce the thiazolidin-4-one derivatives 106 and 107 in 50–55 % yield (Scheme 18). This represents a simple synthetic route to compounds that have been shown to exhibit a wide range of biological properties135-138.
R R
+ HS-CH2-CO2H N N R 105 R O
H3C CH3 S
103, R = H 106, R = H 104, R = CH3O 107, R = CH3O Scheme 18
80 Studies in Multicyclic Chemistry Chapter 3
First, the reaction of the dimethoxy compound 104 was repeated to ensure that appropriate reaction conditions were established. Then the behaviour of our imines
27, 36a and 36b was investigated. We were surprised to find that imine 36a reacted as anticipated, but that the compounds 27 and 36b were unreactive.
H C H COCHN 3 CH 3 R N 3 CH3 C N N
H3C-OC-HN CH3 R CH3 H NH-CO-CH3 27 36a, R = H 36b, R = Ph
Mercaptoacetic acid 105 and imine 36a produced a single product. This solid had a sharp melting point of 284–286 °C, the expected microanalysis figures for
+ 13 C21H20N2O2S, the expected M value of 364, and a clean C NMR spectrum containing only 21 peaks. These data were compatible with a 54 % yield of a single isomer of a thiazolidin-4-one adduct.
H H O O N N H3C
S S
H CH 3 H
NH-CO-CH3 NH-CO-CH3
108 109
Two isomers, 108 or 109, are possible. Although the stereochemistry at the ring methyl group was not clear, we believe that the product obtained is 108. Addition of
81 Studies in Multicyclic Chemistry Chapter 3 mercaptoacetic acid to the face of the imine group opposite to the acetamide functionality is likely to be strongly favoured on steric grounds. This would lead to the product 108 where the methyl and acetamide groups are syn.
Both of the imines 27 and 36b failed to react with mercaptoacetic acid, even after one week refluxing in benzene. No indication of thiazolidin-4-one products was seen, and the starting material was recovered unchanged. There seem to be two possible explanations for this behaviour. First, most imines previously reacted with mercaptoacetic acid had their C=N group conjugated with an aromatic system (see, for example, 103 and 104). In contrast, our methyl imines are non-conjugated materials.
A more probable explanation, however, is provided by steric crowding effects. The imine nitrogen atom in 27 occupies a neopentyl site, and that in imine 36b is attached to a closely-related triphenylmethane group. Both types are well-known to be subject to reduced reactivity due to severe crowding. In contrast, imine 36a with only a diphenylmethane substituent, is much more open to attack by incoming reagents.
In the next section 3.2, the reactions of our imines with dimethylacetylene dicarboxylate (DMAD) are described. As will be shown, these compounds were generally found to be highly reactive with DMAD. The one exception was imine 36b which did not react under any of varied experimental conditions we tried. This observation tends to support the steric crowding arguments outlined above.
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3.2 Reaction of the Bridged Imines with Dimethyl Acethylenedicarboxylate
(DMAD)
In light of the earlier results described in Section 1.2, the reactivity of the three cyclic imines 36a, 100 and 101, with dimethyl acetylenedicarboxylate (DMAD) was of considerable interest. The most reasonable expectation was that 36a would react in thesamemanneras27, 100 as 47,and101 as 29a. However, to be certain of identifying the products unambiguously, it was planned to obtain X-ray crystal structures whenever possible. This proved to be a very wise decision.
3.2.1 Reaction of Imine 36a with DMAD
The imine 36a was dissolved in chloroform and refluxed with DMAD overnight.
Evaporation of solvent yielded a red-brown coloured viscous material. This crude product was dissolved in boiling benzene, filtered, and the filtrate stored at room temperature. After 3 days the yellow precipitate that had been formed was filtered off and found to be a pure substance (44 %). The same compound was obtained in lower yield (40 %) if benzene replaced the chloroform solvent.
The reaction product had molecular mass of 432, and gave microanalysis figures for
C25H24N2O5. These data indicated that one equivalent of DMAD has added to 36a.
1 This was supported by the presence of two –OCH3 groups in the H NMR spectrum (
13 = 3.59 and 3.74) and a =CH-CO2CH3 signal at = 99.9 in the C NMR spectrum.
Other NMR data indicated that the basic ring system of the starting material remained intact, but also revealed the presence of a =CH2 group ( = 5.95 and 97.2). This
83 Studies in Multicyclic Chemistry Chapter 3 suggested the presence of an enamine structure since the carbon atom to nitrogen in
6-membered ring enamines is recorded in the range = 94–100139.
These observations all indicate that the product is structure 110. Additional support is provided by the previous isolation of stable conjugated enamine structures by Huisgen et al.140, and our own isolation (see Section 3.3) of compound 111 from the reaction of DMAD with imine 100.
H3COCHN H3CO 2C H CH2 C C C N CO CH N 2 3
H3CO2C C CH2 C H NH-CO-CH3 CO 2CH3 H 110
CO2CH3 C H
C OCH3 N C
O OCH3 C6H5
HNHCOC6H5 111
When 36a and DMAD were refluxed overnight in methanol, then the reaction worked up in the same manner, a different product 112 was obtained in 35 % yield after
84 Studies in Multicyclic Chemistry Chapter 3
recrystallisation from benzene. This substance contained four –OCH3 groups ( =
3.56, 3.59, 3.69 and 3.73) in its 1H NMR spectrum, which indicated a 1:2 reaction of
36a with DMAD. The mass ion m/z = 574 confirmed that the two DMAD molecules had added to 36a.
The melting point of 112 was indistinct over 212-240 °C (decomposition, accompanied by colour change yellow to orange), but the 13C NMR spectrum showed clearly that this substance was one pure compound, plus a guest benzene signal at
=128.6. Incorporation of benzene guest molecules was further supported by the microanalysis figures for (C31H30N2O9).(C6H6)0.5.
Once again, the NMR data suggested that the basic ring structure of the starting material was intact, and also revealed the presence of a =CH group ( = 92.9). The
=CH-CO2-CH3 functionality, observed in the earlier product 110, was now absent.
However, the aliphatic region of the 13C NMR spectrum contained two quaternary carbon atoms at = 62.5 and 74.1, suggesting that some sort of cyclisation process had occurred. The identity of product 112 was finally determined by single crystal X- ray crystallography.
H3CO 2C CO 2CH3 N
CO CH CO 2CH3 2 3 H NHCOCH3
112
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The structure of 112 is shown with all atoms present (Figure 28), and in simplified form (Figure 29). Addition of the DMAD has taken place with concurrent cyclisation to produce a most unusual structure containing fused cyclobutane and dihydropyrrole rings. As suspected, the core skeleton of the starting material is still present. The additional view shown in Figure 30 illustrates an intramolecular N_H---O=C hydrogen bond present between one of the ester carbonyl groups and the amine NH group.
Figure 28 Molecular structure of the tetraester 112 determined by X-ray crystallography, showing the fused cyclobutane and dihydropyrrole rings.
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Figure 29 The molecular structure of tetraester 112 in simplified form, where each ester group has been replaced by a yellow sphere for clarity.
Figure 30 The molecular structure of tetraester 112 showing the intramolecular N__H---O=C hydrogen bonding.
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3.2.1.1 Mechanism for the Formation of 110 and 112
This work yielded two DMAD addition products with 36a, a 1:1 compound formed in aprotic solvents and a 2:1 compound formed in the protic solvent, methanol. Possible mechanisms for the formation of these products involve proton transfer (more efficient under protic conditions), with compound 110 almost certainly being an intermediate in the formation of 112. A possible mechanism for formation of the two products is shown in Scheme 19 below.
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H3CO 2C H3CO 2C C C + C N C N: CO 2CH3
CO 2CH3 CH 3 CH 3
HNHCOCH3 36a H+transfer
H3CO 2C H
C C H3CO 2C H + C N CO CH C 2 3 N CO 2CH3 - CO CH C C 2 3 CH C CO CH CH2 2 3 C H CO 2CH 3 HNHCOCH 3 CO 2CH 3 110 -H +
H CO C H CO C 3 2 H 3 2 H C C C - C CO 2CH 3 N CO CH N 2 3 H+ - C CO CH C C 2 3 C C C CO 2CH 3 H H + CO 2CH 3 H CO 2CH 3
H3CO 2C CO 2CH 3 N
CO CH CO 2CH 3 2 3 H NHCOCH 3 Sch eme 19 112
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The imine nitrogen atom attacks the first molecule of DMAD, and then proton transfer yields the 1:1 adduct 110. This is where the reaction stops in aprotic solvents.
In methanol, however, a second DMAD molecule then is added through attack by the enamine =CH2 group. The cyclisation of the two DMAD-derived groups is somewhat more problematic. Closure, as shown, to give a seven-membered ring intermediate bring the two units sufficiently close for the second cyclisation to occur. Stepwise addition of electron rich and electron poor alkenes to give cyclobutane rings can proceed either through radical141 or ionic142 mechanisms. The geometrical requirements of intramolecular ring formation require the second DMAD-derived group to react as a cisoid-carbanion. Since the first such group has a transoid- geometry, the cyclisation process results in formation of the cyclobutane structure with three cis-carbomethoxy groups. It is also possible, however, that both cyclisation processes could occur in just one combined step.
3.2.1.2 Structure of the Inclusion Compound (112).(benzene)0.5
Crystallisation of 112 from benzene resulted in the unexpected formation of the lattice inclusion compound (112).(benzene)0.5 in the monoclinic space group C2/c.
Numerical details of the solution and refinement of this structure are presented in
Table 4. The packing diagram of crystalline (112).(benzene)0.5 is illustrated in Figure
31. The molecules of 112 are present as parallel undulating chains along the a direction. Each chain is homochiral, and its neighbours have the opposite handness.
Molecules of benzene guest are aligned along the c direction.
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Figure 31
Cell diagram of (112).(benzene)0.5 projected onto the ac plane. The benzene guest molecules (purple C) are aligned along c. Sinusoidal homochiral chains of 112 are present along the a direction.
Table 4 Numerical details of the solution and refinement of the structure 112 (benzene)0.5.
Compound number 112 (benzene)0.5
Formula, formula mass (C31H24N2O9).(C6H6)0.5, 613.6 Crystal description (0-10) (-11-1) (31-1) (111) (-311) {100} {001} Space group C2/c /Å 39.832(2) b/Å 11.0716(3) c/Å 14.879(7) /º 90 /º 109.646(2) /º 90 V/Å3 6179.7(5) Z 8 -3 Dcalc/g cm 1.32
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μ/cm¯ 7.57 Crystal dimension/mm 0.51 x 0.35 x 0.22 2 max/º 140 Scan angle 0.5 + 0.15 tan Max., min. transmission coefficients 0.90, 0.81
Rint for (no.) multiple measurements 0.014 (366) Largest peak in final diff. map/e Å-3 0.39 No. of intensity measurements 6430 No. of independent obsd. reflections 4163 No. of reflections (m) and variable (n) in final refinement 4163, 406 m m R = | F|/ |F0| 0.049 m 2 m 2 Rw =[ | F| / |F0| ] 0.068 s =[m| F|2/(m–n) 2.44 Crystal decay None
Four neighbouring host molecules associate around the benzene guest which occupies a cage-like cavity. In the resulting structure, there is a centre of symmetry at the centre of the benzene molecule, and hence the four 112 molecules comprise two symmetry-related pairs (Figure 32).
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Figure 32 The centrosymmetric cage-like structure formed by the host molecules. The carbon atoms of the benzene guest molecules are coloured pink.
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Figure 33 _ _ Association of one molecule each of 112 and benzene, showing the O CH2 H--- interactions as red arrows.
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Figure 34 __ __ The O CH2 H--- (benzo) interactions present between host molecules in 112.C6H6.
There are four recognisable host-guest interactions that are helping to stabilise the observed inclusion compound. The first of these is a standard aromatic edge-face (EF) contact, between a benzene Ar-H and the face of a host benzo group, with the shortest
C---C distance being 3.7 Å (Figure 32).
The second type of interaction is less well-known, and involves association between two different neighbouring methyl groups of one host molecule with the -cloud of the benzene (C---C 3.5 and 3.6 Å) (Figure 33). This interaction will be encouraged by the methyl groups in this case being –OCH3, which gives the hydrogen atoms a slight
+ charge. Methyl---aromatic ring contacts are fairly common. A Cambridge
Structural Database (CSD)143 search for methyl---benzene associations under 3.6 Å
95 Studies in Multicyclic Chemistry Chapter 3 revealed 88 examples144. In some of these, the inter-carbon distance was as short as
3.2 Å.
__ __ The third interaction (Figure 34) shows related O CH2 H--- interaction present between the ester groups of 112 and both benzo groups of a neighouring host molecule.
Figure 35 The face-face ester CO-O--- interaction present between the host and guest
molecules in 112.C6H6. The host is truncated to show just the one specific carboxmethoxy group.
The fourth interaction is even less well-known. Here, there is a face-face interaction between the benzene ring and one of the host ester groups (Figure 35). The closest C--
-C distance is 3.7 Å, and the angle between the normals to the plane of the benzene and ester groups is 20.7°. The CSD contains 155 examples of methyl ester groups within 4.0 Å of aryl groups144. In many cases, the ester and aromatic groups are near
96 Studies in Multicyclic Chemistry Chapter 3 to coplanarity, with 109 examples having an angle between the normals to the planes of under 20°.
3.2.2 Reaction of Imine 100 with DMAD
The imine 100 was refluxed overnight with DMAD in benzene. Evaporation of the solvent gave a viscous brown crude product, which was dissolved in methanol and allowed to stand for one week. Filtration gave a 14 % yield of a clean product 111 with a molecular mass of 588 and formula C36H32N2O6. This corresponds to addition of one DMAD plus one equivalent of methanol. 1H NMR spectroscopy indicated the presence of three CH3O groups ( = 2.34, 2.96 and 3.82). Two of these signals, however, are at too low a chemical shift value for a carbomethoxy group. A =CH group at = 6.64 was also present. Other NMR signals indicated that the basic ring structure of the starting material was intact in 111. The structure of this product was proved to be the orthoester 111 by means of single crystal X-ray determination.
3.2.2.1 Mechanism for Formation of 111
The formation of 111 can be explained relatively easily (Scheme 20). Initially there is attack by the imine nitrogen atom on a molecule of DMAD, followed by protonation, in a similar manner to formation of 110. A molecule of methanol attacks one of the ester groups, whose carbonyl oxygen carries out a Michael addition to the iminium salt group. Finally, loss of a proton affords the observed orthoester product 111
(Scheme 20).
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CO2CH3 H CO C 3 2 C C H C N: CO2CH3 + C HOCH3 H+ N C OCH C6H5 3 O C6H5 H NHCOC6H5 H NHCOC6H5
100
-H+
CO2CH3 C H
C OCH3 N C
O OCH3 C6H5
HNHCOC6H5 111 Scheme 20
Some precedent for this type of reaction is available in the literature145. 1-Phenyl-6,7- dimethoxy-3,4-dihydroisoquinoline 113 yielded the lactone 114 on treatment with
DMAD in methanol (Scheme 21). Hypothetical conversion of the lactone carbonyl group into its dimethoxyacetal would give an orthoester product analogous to our compound 111.
The explanation given was that water from the solvent added to the imine group of
113, and that this was followed by unexplained addition, cyclisation and dehydration steps.
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However, our work has indicated that bridged imines are not especially reactive with water. Compound 27, for example, forms a stable hydrate. An alternative explanation would be a pathway similar to Scheme 21, with the cyclisation being initiated by water instead of methanol. Elimination of methanol would then produce the observed compound 114.
H3CO H3CO H2O N NH H3CO H3CO C6H5 OH C6H5 113
DMAD H2O DMAD
H3CO -MeOH H3CO
N N H3CO H3CO CH-CO2CH3 CH-CO2CH3 C6H5 O C6H5 O HO OCH3 O 114
Scheme 21
3.2.2.2 X-ray structure of the Orthoester 111
Crystallisation of 111 from methanol afforded material suitable for X-ray analysis
(Figure 36). This substance crystallised in the monoclinic space group P21/c.
Numerical details of the solution and refinement of this structure are presented in
Table 5.
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Figure 36 Molecular structure of the orthoester 111 determined by X-ray crystallography.
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Table 5 Numerical details of the solution and refinement of the structure 111
Compound number 111
Formula, formula mass C36H32N2O6, 588.7 Crystal description {012} {001} {10-3} (110) (-1-10)
Space group P21/c /Å 11.8119(9) b/Å 9.6624(4) c/Å 25.832(2) /º 90 /º 90.211(4) /º 90 V/Å3 2948.2(4) Z 4 -3 Dcalc/g cm 1.33 μ/cm¯ 6.97 Crystal dimension/mm 0.30 x 0.30 x 0.12
2 max/º 120 Scan angle 0.5 + 0.15 tan Max., min. transmission coefficients 0.93, 0.79
Rint for (no.) multiple measurements 0.007 (106) Largest peak in final diff. map/e Å-3 0.35 No. of intensity measurements 4786 No. of independent obsd. reflections 3322 No. of reflections (m) and variable (n) in final refinement 3322, 397 m m R= | F|/ |F0| 0.045 m 2 m 2 Rw =[ | F| / |F0| ] 0.062 s=[m| F|2/(m – n) 2.28 Crystal decay None .
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Figure 37 Part of the structure of a double EF chain of molecules of 111. Only the EF chain on the top surface is shown. There is a second chain along the undersurface. The aromatic EF interaction are indicated by the arrows.
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Figure 38 Cell diagram of 111 projected onto the ac plane. No N__H---O=C hydrogen bonding is present in this solid. Instead, the molecules are arranged into double EF chains along b. These are highlighted by the ellipses in this diagram, and shown in more detail in Figure 37.
Molecules of 111 pack together as shown in Figure 37 without any N__H---O=C hydrogen bonding being present. In this crystal structure the phenyl substituent is positioned close to the amide nitrogen atom and blocks off approach by the amide O=C of a second molecule. The phenyl group is flanked on its other face by a methoxy group (Figure 37). So, instead, the molecules assemble as double aromatic EF chains along the b direction. These are highlighted by the ellipses marked on the Figure 38. These double chains involve the same enantiomer. The construction of part of one chain is shown in detail in Figure 39.
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Figure 39 The pendant phenyl group of 111 interacts with the amide group by means of an ______N H--- interaction, and with one of the ring methoxy groups by an O CH2 H--- interaction. This aromatic substituent shields the amide group, and prevents it from forming the usual N__H---O=C hydrogen bonded chain motif.
3.2.3 Reaction of Imine 101 with DMAD
Unlike the earlier examples, the imine 101 only reacted with DMAD under forcing reaction conditions. Following two weeks refluxing with DMAD in chloroform, a brown viscous material was obtained. This was boiled with methanol and a 10 % yield of pure product 115 was obtained on standing. This substance had a molecular mass of 598, and the molecular formula C37H30N2O6, which indicated addition of one equivalent of DMAD to 101. Unfortunately, this product was so insoluble that 1Hand
13C NMR data could not be obtained. However, its structure was demonstrated to be
104 Studies in Multicyclic Chemistry Chapter 3 the unsaturated lactam 115, where the original ring skeleton had been partially broken open, by means of X-ray crystallography (Figure 40).
3.2.3.1 Mechanism for Formation of 115
The mechanistic pathway generating 115 is unclear, but a possible explanation is shown in Scheme 22. Once again, the imine nitrogen atom attacks a molecule of
DMAD. We suggest that the carbanion intermediate carries out a nucleophilic attack on the carbonyl of the benzo group. This could lead to formation of an epoxide intermediate 116 through addition to the iminium group. Finally, proton transfer, accompanied by carbon ring opening and epoxide ring opening, leads to the observed structure 115 (Scheme 22).
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H CO C H CO C 3 2 3 2 C C C CO CH N: CO2CH3 + _ 2 3 N C
COC6H5 C C6H5 O H NHCOCH2C6H5 H
101 C6H5H2COCHN
H3CO2C H+ H3CO2C C CO CH CO CH 2 3 C 2 3 N + C N C C O C H C H C6H5 6 5 H _ O NHCOCH2C6H5 C6H5H2COCHN 116 H+transfer
H3CO2C H C N CO CH C 2 3
O C C6H5
NHCOCH2C6H5 115
Scheme 22
3.2.3.2 X-ray Structure of the Lactam 115
– Compound 115 crystallised from methanol in the triclinic space group P1. Numerical details of the solution and refinement of this structure are presented in Table 6.
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Table 6 Numerical details of the solution and refinement of the structure 115 Compound number 115
Formula, formula mass C37H30N2O6, 598.7 Crystal description {100} {010} {001} – Space group P1 /Å 10.586(1) b/Å 11.527(2) c/Å 14.003(2) /º 100.964(7) /º 105.907(6) /º 101.899(7) V/Å 1551.7(3) Z 2 -3 Dcalc/g cm 1.28 μ/cm¯ 6.73 Crystal dimension/mm 0.20 x 0.04 x 0.09
2 max/º 120 Scan angle 0.5 + 0.15 tan Max., min. transmision coefficients 0.97, 0.91
Rint for (no.) multiple measurements - Largest peak in final diff. map/e ů 0.40 No. of intensity measurements 4595 No. of independent obsd. reflections 2404 No. of reflections (m) and variable (n) in final refinement 2404, 401 m m R= | F|/ |F0| 0.055 m 2 m 2 Rw =[ | F| / |F0| ] 0.068 s=[m| F|2/(m – n) 2.10 Crystal decay 1 to 0.95
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Figure 40 Molecular structure of the lactam 115 determined by X-ray crystallography.
Figure 41 Cell diagram of solid 115 projected onto the bc plane.
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The unit cell arrangement in solid 115 is shown in Figure 41. Opposite enantiomers of the lactam 115 pack as a centrosymmetric dimer (Figure 42). This is held together by
N_H---O=C (lactam carbonyl) hydrogen bonds, and aromatic (benzo) Ar_H---
(benzo) EF interactions.
Figure 42 The centrosymmetric dimer of molecules present in the crystal structure of 115. This unit associates by means of N_H---O=C hydrogen bonds (dashed lines), and Ar_H--- EF interactions (arrows).
There is also interaction between molecules of 115 of the same handedness. An ester methoxy group of one molecule interacts with the -systems of both benzo groups as indicated in Figure 43.
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Figure 43 Interaction between the ester methoxy--- group and the phenyl rings. Homochiral molecules of 115 interact by the methoxy group of the ester adjacent to the phenyl group interacting with the -systems of both benzo groups of the second molecule (arrows). A third interaction of the same type involves a methoxy group of a third molecule (not shown) and the upper benzo group of the right-hand side molecule in this Figure.
Conclusions
The work described in this chapter has confirmed that the reaction of imines with
DMAD is a very interesting area of chemistry. Addition products are always obtained, but the products vary considerably in their complexity. Very little prediction is currently possible in this area. In light of the unusual and unexpected nature of the products encountered, it is wise to employ X-ray crystallography in studies of this type.
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Chapter 4 Results and Discussion
4 A Sequence of Novel Ritter Rearrangement Reactions
4.1 Rearrangement of the Unsaturated Ketone 120
As discussed in the Introduction (Section 1.1), the Ritter reaction involves the intermediacy of a carbenium ion. In such reactions, therefore, the possibility of potential molecular rearrangements must always be considered. This chapter describes deliberate attempts to combine Ritter reaction and molecular rearrangement as a novel means of synthesis.
Previous work in our research group showed that combination of rearrangement and
Ritter reaction could give good yields of unusual products in a one-flask reaction
(Section 1.3). In particularly, it was demonstrated the tetramethylated diene 117 could be converted either into its rearranged isomer 118, or into the adamantyl acetamide derivative 119, in high yields (Scheme 23). It was also shown that the new diene 118 was an intermediate on the route to formation of 119146.
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CH CH3 3 H3C H2C CH3 75 % H3C
CH 2 CH3 H3C CH3 H3C CH3 118 117 84 % 70 % CH3 H3C
H3C NHCOCH3
CH H3C 3 119
Scheme 23
Summary of the Ritter rearrangement reactions of diene 117, using 98 % sulfuric acid in acetonitrile, and subsequent aqueous work-up.
The proposed sequence of mechanistic steps involved in the isomerisation of diene
117 to 118 and further conversion of 118 into the acetamido adamantane product,
119 is illustrated in Scheme 24.
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CH3 CH CH 3 3 2HC H C CH H2C CH3 CH 2 3 + 3 CH3 +H migration
CH2 CH3 + + CH3 H3C CH3 H C H C CH 3 CH3 3 3 117 -H+
CH3 CH3 CH3
H3C H3C 2HC repeat steps CH3 +H+ 1-3 above H C H C 3 -H+ 3
CH3 CH3 CH3 H3C CH3 H3C CH3 H3C CH3 118 118 +H+ +H+ -H+ CH2 H3C + H2C H3C cyclisation H3C H3C H3C CH3 CH H C 2 3 + H C CH CH3 3 3 H3C CH3
H3C CH3 i. CH3CN ii. H2SO4 CH3 CO-CH3 C + NH H C N H3C H2O 3 H C H3C 3 CH CH3 3 H CCH H3CCH3 3 3 119
Scheme 24
Schematic sequence for the rearrangement of 117 to 118, and finally to the Ritter reaction product 119.
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In light of these interesting results it was decided to also investigate the behaviour of the unsaturated keto olefin 120 under similar Ritter reaction conditions. The chemistry of 120 proved to be more complex, and evidence for the formation of five products 121-125 was obtained. However, variation of the exact reaction conditions permitted most of these to be obtained cleanly in good yields in one-flask reactions.
These results are summarised in Scheme 25. Some of these products clearly involve complex molecular changes, so whenever possible these products were characterised unambiguously by X-ray structure determination. The formation of these individual products is now examined case by case.
7CH3 CH CH3 H C 3 H2C CH3 H3C 3 H C H3C H C 3 3 O O CH3 3 O H3C CH3 H3C CH3 121 122 120
CH3 H3C O H3C NHCOCH3
CH H3C 3 124
CH H3C 3 H3C H3C NHCOCH3
CH3 H3C NHCOCH3 H OH CH3 NHCOCH3 CH 125 H3C 3 123 Scheme 25
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Structures of the products 121–125 obtained when the unsaturated keto olefin 120 was reacted with sulfuric acid and acetonitrile under Ritter reaction conditions.
4.2 3,3,6,6,7-Pentamethylbicyclo[3.3.1]non-7-en-2-one 121
Reaction of 120 with sulfuric acid and acetonitrile at room temperature for 15 minutes gave a colourless liquid in 76 % yield. This material was isomeric with the starting material 120, as indicated by its mass ion (m/z 206) and its correct microanalysis for C14H22O. Infrared and NMR spectral data showed this compound
-1 13 still contained a non-conjugated carbonyl group: vmax 1715 cm , CNMR = 216.2.
-1 13 However, its alkene group was now trisubstituted: vmax: 850 cm , CNMR =
145.0 (C), and 120.4 (CH). Other NMR data, 1H = 1.65 (3H) and 5.27 (1H), clearly
13 supported the partial structure –CH=C(CH3). Also from the C NMR spectrum it was noted that only two aliphatic CH2 peaks ( = 40.8 and 27.1) were now present, whereas the starting compound contained three. This information indicated that this rearrangement product had the structure 121.
This structural assignment is also supported by the earlier work showing that diene
117 was readily rearranged into its isomer 118, which involved the same type of molecular changes (Section 4.1). The bicyclo[3.3.1]nonane ring system prefers, when possible, to adopt the twin chair confirmation147,148.
This is prevented in both 117 and 120 by the presence of the endo-C3 and endo-C7 methyl groups. Hence, the driving force for these rearrangements is relief of
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transannular steric crowding, concomitant with the conversion of the alkene group from di- to tri-substitution. The proposed mechanistic steps for the conversion of 120 into 121 are shown in Scheme 26.
CH3 H C 3 CH3 H2C CH3 H3C
+H H3C O CH3 O H3C CH3
120 CH3 migration
CH 3 CH3 H3C H3C -H H3C H3C H C H3C 3 CH CH3 3
O O 121
Sch eme 26
Proposed steps involved in the isomerisation of 120 into 121.
4.3 4,4,7,8,8-Pentamethylbicyclo[3.3.1]non-6-en-3-one 122
Using slightly more severe conditions, the reaction of 120 gave a yellowish oil.
While the major product was still 121, a second unsaturated non-conjugated ketone was now also present. From 13C NMR spectroscopy these were present in the ratio
3:1. The new compound could not be separated, but its 13C NMR spectrum contained
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signals at = 218.3 (C), 123.6 (C), 121.0 (CH), plus other peaks. This material is believed to be 4,4,7,8,8-pentamethylbicyclo[3.3.1]non-6-ene-3-one, 122. In light of the unambiguous identity of the products 124 and 125, the structure of compound
122 is believed to be the most reasonable intermediate product on mechanistic grounds (Scheme 27).
CH3 CH3 H3C H3C + H3C H H3C H3C H3C CH3 CH3
O O H 121 CH3 migration
CH3 H3C CH3 H3C H3C H3C H3C H3C OH O H3C H3C H
CH3 migration
CH3 CH3 H C H3C 3 H -H+ H C H3C O 3 O
CH H3C CH3 H3C 3 122 Sch eme 27
Possible mechanistic pathway for the conversion of 121 into 122.
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4.4 {7-Anti-hydroxy-3,4,4,8,8-pentamethylbicyclo[3.2.2]non-2-en-1-yl}
acetamide monohydrate 123
Compound 123 was obtained from keto olefin 120 under different experimental conditions. Trituration of the crude product using a small amount of diethyl ether, followed by filtration, allowed the removal of a small amount of the bis(acetamide) product 125. Concentration of the filtrate gave a 12 % yield of a solid product. The mass spectrum revealed a molecular weight of 265, corresponding to the formal addition of acetamide. However, the microanalysis figures indicated a formula of
C16H29NO3, which suggested the presence of an additional molecule of water.
The acetamido group CH3-CO-NH- was clearly indicated by the following spectral
-1 1 13 data: vmax: 1640 cm , HNMR =2.03(CH3CO) and 5.68 (NH), CNMR =
170.9 (CONH). Also the partial structure of –CH=C(CH3) could be identified from
1HNMR = 5.34 (1H, q) and 13CNMR = 141.3 (C) and 131.2 (CH). Additionally, four methyl groups attached to quaternary sp3 carbons were seen at = 29.1, 27.8,
27.7 and 26.5 and two aliphatic CH2 peaks were also seen at = 38.9 and 31.3. There also seemed to be a secondary alcohol group present (1HNMR = 4.68, 13CNMR
= 69.8). At this stage it was not at all clear what the exact structure of 123 was.
Fortunately, recrystallisation from aqueous ethanol, followed by X-ray single crystal determination revealed this new compound as being the monohydrate of {7-anti- hydroxy-3,4,4,8,8-pentamethylbicyclo[3,2,2]non-2-en-1-yl} acetamide 123.
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Numerical details of the solution and refinement of this structure are shown in Table
7.
The molecular structure of 123 is illustrated in Figure 44.This clearly shows the bicyclo[3.2.2]nonane skeleton of this rearrangement product, the stereochemistry of its secondary alcohol group, and that this is where the water molecule is attached by hydrogen bonding.
Figure 44 Molecular structure of the monohydrate of the product 123. The intramolecular __ O H---OH2 hydrogen bond is indicated by the dashed line.
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Table 7 Numerical details of the solution and refinement of the structure 123.
Compound number (123).(H2O)
Formula, formula mass (C16H27NO2).(H2O), 283.4
Space group P21/c /Å 17.444(6) b/Å 7.241(1) c/Å 13.329(5) /º 111.55(1) V/Å 1565.9(8) Temp./°C 21(1) Z 4 μ/mm¯1 0.616 No. of intensity measurements 2962
Rmerge 0.023 No. of independent observed reflections 1935 No. of reflections (m) and variable (n) in final refinement 182
m m R = | F|/ |F0| 0.042
m 2 m 2 Rw =[ | F| / |F0| ] 0.061 s =[åm| F|2/(m–n) 1.50
The structure 123 is very surprising on number of grounds. First, bicyclo[3.3.1]nonane derivatives (which have their skeleton comprised of two conjoined cyclohexane rings) are normally lower in energy than their corresponding
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bicyclo[3.2.2]nonane isomers. Secondly, this product also contains alkene and secondary alcohol groups, both of which are potentially active in Ritter reactions.
Thirdly, only one alcohol isomer (that with the hydroxy group anti- to the largest ring bridge) was isolated. Furthermore, the Ritter reaction product 123 was always obtained as the monohydrate compound.
The crystal structure of 123.(H2O) comprises a stack of sandwich-like layers. Each layer contains two sheets of 123 molecules with their hydrocarbon groups creating the two outer layer faces. Hence, only weak hydrophobic dispersion forces operate between adjacent layers. At the same time, the amide and hydroxy groups of both sheets of 123 molecules face inwards to the centre of the sandwich-like layer, hydrogen bonding to water molecules, and creating a hydrophilic filling in the middle of the sandwich. These distinct regions are clearly visible in Figure 45. The enantiomers of 123 alternate along each hydrogen bonded sheet.
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Figure 45
Section through two sandwich-like layers of the molecular structure 123.(H2O). This shows the hydrophobic outer surfaces, and the hydrophilic hydrogen bonded interiors.
Each water molecule in the structure 123.(H2O) participates in two donor and two acceptor hydrogen bonds (Figure 46). Water hydrogens are donated to the amide carbonyl oxygen of one, and to the hydroxy group oxygen of a second, 123 molecule.
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Hydrogens are accepted from the amide N-H of a third (translationally related to the second), and the hydroxyl O-H of a fourth molecule, of 123. A two-dimensional sheet of intermolecular hydrogen bonding is thereby established in the centre of each layer (Figure 46).
Figure 46 The intermolecular hydrogen bonding arrangement of 123 monohydrate. Each water molecule is hydrogen bonded to four different molecules of the acetamide 123, thus giving rise to a two-dimensional hydrogen bonded arrangement. Hydrogen bonds are indicated by the dashed lines.
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A possible reaction pathway for the conversion of 120 into 123 can be seen in the
Scheme 28 below.
CH3 CH3 H3C H2C CH3 H3C H3C CH3 O O 120 121 H3C CH3 H
CH3 CH3 H3C H3C
H3C H3C
CH3 CH3
H CH3 H + CH3 O+ :OH 127 H 126
CH3 CH3 H3C H3C
H3C H3C
CH3CN
H2O CH3 CH3 + H OH CH3 H OH CH3 NHCOCH3 128 123 Scheme 28
Proposed reaction pathway for the conversion of the starting material 120 into the acetamido product 123.
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The proposed reaction pathway to 123 is outlined in Scheme 28. It is believed that protonation of the carbonyl of 121 is followed by a 1,2-alkyl group shift producing
126. The secondary carbenium ion of the latter is trapped as the protonated epoxide
127, ring opening of which affords the tertiary carbenium ion 128. This pathway explains the formation of the bicyclo[3.2.2]nonane ring system, and also the stereochemistry of the secondary alcohol group. Reaction of 128 with acetonitrile, then leads to formation of ultimate Ritter reaction product 123.
It was demonstrated that compound 123 is not an intermediate on the way to the products 124 and 125. Its use as a potential starting material for these compounds produced none of either compound 124 or 125. Probably all reactions prior to the amide formation are reversible, thus probably all intermediates as far as 128 could potentially re-access the main reaction pathway shown in Scheme 28.
4.5 {3,4,4,8,8-Pentamethyl-2-oxatricyclo[3.3.1.13,7]dec-1-yl}acetamide 124
Reaction of 120 using the conditions of Experiment 8.3.7 gave a 38 % yield of a new compound. Its molecular mass was 265, and microanalysis gave a formula of
C16H27NO2, which corresponds to the formal addition of acetamide to the structure
120. The IR and NMR data revealed an absence of alkene and ketone carbonyl groups, but confirmed the presence of an acetamido group (CH3-CO-NH-). This was
-1 1 indicated by the IR (vmax: 1650 cm )andNMRdata[H =1.95(CH3CO) and 5.53
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(NH), 13C = 168.8 (CONH)]. There were also five methyls on sp3 quaternary carbons (13CNMR = 24.14, 24.06, 23.8, 22.7 and 22.5). The 13C NMR spectrum contained two quaternary carbons at = 87.7 and 78.2, the values of which suggested a adjacent oxygen atom. Once again, the structure of the product 124 was proved unambiguously using X-ray methods (Figure 47).
Figure 47 Molecular structure of the Ritter rearrangement product 124.
The numerical details of the solution and refinement of the structure 124 are presented in Table 8. The molecules of 124 pack as parallel homochiral stacks along the c direction (Figure 48). Figure 49 shows two of these stacks (involving opposite enantiomers) and their propagation along c by means of inter-stack M---O=C hydrogen bonding.
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Figure 48
Cell diagram of crystalline 124 projected onto the ab plane. The molecules are arranged as parallel homochiral stacks along the c direction.
Figure 49
Two parallel stacks of molecules of 124, running along the c direction, showing the inter-stack N__H__O=C hydrogen bonding chain. 127 Studies in Multicyclic Chemistry Chapter 4
Table 8 Numerical details of the solution and refinement of the structure 124.
Compound number 124
Formula, formula mass (C16H27NO2), 265.4 Formula mass 265.4
Space group P21/c /Å 13.730(5) b/Å 11.477(4) c/Å 9.621(4) /º 96.43(2) V/Å 1507(1) Temp./°C 21(1) Z 4 μ/mm¯1 0.562 No. of intensity measurements 2227
Rmerge 0.013 No. of independent observed reflections 1083 No. of reflections (m) and variable (n) in final refinement 174
m m R = | F|/ |F0| 0.065
m 2 m 2 Rw =[ | F| / |F0| ] 0.104 s =[m| F|2/(m – n) 1.81
Formation of the acetylated hemi-aminal 124 is easily understood, if the unsaturated ketone 122 (discussed earlier) is an intermediate (Scheme 25). Protonation of its alkene group, followed by internal trapping of the tertiary carbenium ion by the carbonyl group oxygen, would produce an 2-oxa-1-adamantyl ion, 129. Addition of
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acetonitrile in the Ritter reaction then would lead directly to the formation of compound 124 (Scheme 29).
CH3 CH 3 CH3 H3C H2C CH3 H3C + H C H H C 3 3 H C 3 O O CH3 CH O H3C 3 H3C CH3 121 122 120 H+
CH H C 3 CH 3 H C 3 O 3 H3C H3C O
H C CH3 3 H3C CH3 129 CH3CN H2O
CH3 H3C O H3C
NHCOCH3
CH H3C 3 124 Sch eme 29
Proposed schematic pathway for the formation of compound 124.
The product 124 could be reacted under Ritter reactions to produce material identical with product 125 (Experiment 8.3.7). This demonstrated that the hemi-aminal
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derivative 124 is a genuine intermediate in the reaction pathway shown in the
Scheme 29.
4.6 {4,4,8,8-Tetramethyltricyclo[3.3.1.13,7]decane-1,3-diyl}bis(acetamide) 125
Reaction of the starting material 120 with acetonitrile and concentrated sulfuric acid
(Section 8.3.8) gave the bis(acetamide) product 125 in 77 % yield, and 48 % if the compound 124 wasused(Section8.3.8).
The mass spectrum and combustion analysis data indicated the compound 125 has molecular weight of 306 and formula C18H30N2O2, which corresponded to formal addition of two acetamide, and loss of one water molecules. Its 13CNMRdata spectrum showed only ten signals, which indicated C2 symmetry. The presence of the acetamido group (CH3CO-NH-) was clearly seen from the IR and NMR data : vmax:
-1 1 13 1635 cm , HNMR =1.90(CH3CO) and 5.12 (NH), CNMR = 169.8 (CONH).
13 In addition, the C NMR spectrum indicated three CH2 groups ( = 34.1, 30.2 and
27.3), another three peaks aliphatic CH3 ( = 24.9, 23.3 and 22.7), and only one CH
( = 41.3). These data indicated that the structure of this product is the 1,3- bis(acetamido)adamantine derivative 125. This assignment was confirmed by X-ray crystallography (Figure 50).
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Figure 50 Molecular structure of the compound 125 determined by X-ray crystallography.
The crystal structure of 125 has distinct similarities with the crystal structure of the hemi-aminal 124. It consists of parallel homochiral stacks of molecules running along the c direction (Figure 51). Pairs of enantiomer stacks are linked by means of double N__H---O=C hydrogen bonded chains. One of these sub-structures is highlighted by an ellipse in the Figure 51. This double hydrogen bonded chain between two stacks is illustrated in Figure 52.
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Figure 51 Projection of the cell diagram of 125 on the ab plane. The molecules are assembled into parallel homochiral stacks along c. Stacks of opposite handedness (one marked by an ellipse) are hydrogen bonded together.
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Figure 52 Two enantiomeric stacks of molecules of 125 showing the double N__H—O=C hydrogen bonded chains running along the c direction.
The numerical details of the solution and refinement of the structure 125 are presented in Table 9.
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Table 9 Numerical details of the solution and refinement of the structure 125.
Compound number 125
Formula, formula mass (C18H30N2O2), 306.5 Space group C2/c /Å 16.222(7) b/Å 11.362(3) c/Å 9.661(4) /º 113.08(2) V/Å 1638(1) Temp./°C 21(1) Z 4 μ/mm¯1 0.599 No. of intensity measurements 1548
Rmerge 0.022 No. of independent observed reflections 1154 No. of reflections (m) and variable (n) in final refinement 101
m m R = | F|/ |F0| 0.042
m 2 m 2 Rw =[ | F| / |F0| ] 0.061 s =[m| F|2/(m – n) 2.04
The formation of 125 can be envisaged by protonation of the ether oxygen of 124, followed by ring opening of either C-O bond to produce alternative bicyclo[3.3.1]nonane structures with a carbenium ion and hydroxyl group at C3 and
C7, or the reverse.
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CH CH3 CH H C 3 H C 3 3 H2C CH3 3 H C H C 3 3 H C 3 O CH O 3 CH O H3C 3 H3C CH3 120 121 122
CH3 H3C H CH + H C 3 O H 3 H3C O H 3C NHCOCH3 NHCOCH 3
H C CH3 3 CH H 3C 3 124 CH H C 3 3 CH H C 3 3 OH H3C OH H3C NHCOCH3 NHCOCH3
CH H3C 3 CH H3C 3
CH 2 H3C H3C 7 H3C H 3C 3 NHCOCH3 NHCOCH3 CH3CN CH CH H3C 3 H2O H 3C 3 H C NHCOCH 130 3 3
H3C
NHCOCH3
CH 125 H3C 3 Sch eme 30
Proposed mechanistic pathway for formation of the compound 125.
Loss of water from either intermediate can lead to the structure 130 with a tertiary carbenium ion at C3 (stabilised by the acetamido group) and a methylidene group at 135 Studies in Multicyclic Chemistry Chapter 4
C7. The internal cyclisation to the adamantyl ion, followed by Ritter reaction, then yields the compound 125 (Scheme 30).
Conclusions:
The chemistry of the unsaturated keto olefin 120 under Ritter reaction conditions proved to be quite complex. Five different rearrangement products were found, some involving deep-seated molecular rearrangements. Through careful variation of the reaction conditions, considerable control was obtained over which compounds were produced. Several of these materials could be obtained in moderate to good yields. It would be difficult to obtain some of these products easily using more conventional synthetic methods, but use of the Ritter reaction with rearrangement gave them simply in a one-flask reaction.
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Chapter 5 Results and Discussion
5 Tricyclo[5.3.1.13,9]dodecane System Chemistry
5.1 Synthetic Studies
As discussed in Section 1.4, the tricyclo[5.3.1.13,9]dodecane ring system is expected to show a number of differences with respect to less-strained alicyclic ring systems.
In this chapter, both the synthetic approaches used earlier by the Bishop group are used.
In the first of these (Scheme 31), Meerwein’s ester 131 was selectively hydrolysed using barium hydroxide to yield the diacid 132. This underwent decarboxylation on heating to produce the diester 79149. Deprotonation of the diester 79 using sodium hydride, followed by reaction with 1,3-dibromopropane, yielded the propano-bridged derivative 80. Subsequent hydrolysis and decarboxylation afforded the diketone
13375.
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CO2CH3 CO2CH3
OH OH
i. Ba(OH)2 H3CO2C CO2CH3 HO2C CO2H ii. HCl
HO HO
CO2CH3 CO CH 132 2 3 131 Heat
CO2CH3
OH O i. NaH O ii. Br-(CH2)3-Br
H3CO2C CO2CH3 HO
80 CO CH H+,Heat 79 2 3
O O i. CH3CN ii. H2SO4 NH2-NH2.H2O iii. Br2
133
O N N O HN NH Br Br C C O O
135 134 Scheme 31
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The availability of 80 and 133 made the preparation of other tricyclo[5.3.1.13,9]dodecane derivatives attractive targets, but the results obtained were mixed. Wolff-Kishner reduction of the diketone 133 did yield a small amount of the parent hydrocarbon as indicated by 13C NMR spectroscopy, but purification was difficult and the yield poor. However the bridgehead reactivity of the diketone
133 could be exploited by its conversion into the dibromide 134. Reaction of the bridged keto ester 80 with hydrazine hydrate led to the formation of the bis(pyrazolone) 135, but attempts to convert this into the bridgehead diacid derivative were not successful. This probably was due to the lack of solubility of this substance. Its structure, however, was confirmed by means of X-ray crystallography.
The alternative bridging reaction of compound 79 was also carried out. This process, using 3-chloro-2-chloromethylprop-1-ene 82, took place in the 75 % yield described earlier by Yue and Bishop77 to afford the product 83 (Scheme 14). This compound is a particularly suitable one for further study, since it carries ester substituents at its C3 and C7 sites. These are the bridgehead sites that are expected to show unusual reactivity when substituted with hydrogen atoms. Qualitative evidence in support of this is provided by the long term stability of 83 compared with many of the other tricyclo[5.3.1.13,9]dodecane analogues.
5.2 X-ray Studies on Tricyclo[5.3.1.13,9]dodecane Derivatives
5.2.1 Crystal Structure of the Bis(pyrazolone) 135
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The bis(pyrazolone) 135 was crystallized from methanol to yield crystals of the
– monohydrate in space group P1. Numerical details of the solution and refinement of this structure are presented in Table 10. Compound 135.H2O is hydrogen bonded into layers that lie in the (1 –2 1) plane (Figure 53). There are three motifs, all of which are centrosymmetric and which repeat within the layer. The first of these incorporates pairs of N__H…O hydrogen bonds The second and third alternate along a, one involving cycles of O__H…O hydrogen bonds from the lattice water molecules, and the second including N__H…O as well. In Etter’s notation150,the
2 2 4 three cycles can be described as R2 (8), R4 (8) and R4 (12).
Figure 53
Part of one hydrogen bonded layer in the crystal structure of 135.H2O showing the three hydrogen bonded packing motifs.
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Table 10 Numerical details of the solution and refinement of structure
135.H2O.
Compound number 135.H2O
Formula C15H18N4O3 Formula mass 302.3 – Space group P1 a /Å 6.478(1) b /Å 8.157(1) c /Å 14.812(2)
/ o 85.412(9) / o 88.369(8)
/ o 67.089(11)
V /Å3 718.6(2) T / K 294(1)
Z 2 -3 Dcalc. /gcm 1.40 Radiation, /Å CuK, 1.54184
μ /mm-1 0.819
Scan mode /2 o 2 max. / 70 No. of intensity meas. 2695 Criterion for obs. ref. I/(I)>2
No. of indep. obsd. ref. 2365 No. of reflections (m), 2365 variables (n) in final ref. 200 m m R = |F|/ |Fo| 0.045 m 2 m 2 1/2 Rw =[ w|F| / w|Fo| ] 0.089
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s =[mw|F|2/(m-n)]1/2 1.63 Crystal decay none Min.,max.trans.coeff. — R for mult. meas. —
Largest peak in final diff. map/ e Å-3 0.34
5.2.2 Crystal Structures of Compound 83 at 90 K and 300 K
As discussed in Section 1.4, the tricyclo[5.3.1.13.9]dodecane system has been predicted to show significant flattening at the C3 and C7 bridgehead sites66,67. Earlier
X-ray structures by the Bishop group on compounds 81, 84, 85 and 86 had suggested that such distortion was taking place, but it was now decided to investigate this in greater detail.
Ogawa has carried out much work on molecules that appear to show anomalous properties, such as unexpected bond length values, in their X-ray crystal structures.
In some cases these properties were confirmed. In others, the apparent values could be interpreted as arising from averages of disorder components or molecular motion151-154. Consequently, we asked Professor Keiichiro Ogawa (University of
Tokyo) to carry out X-ray determinations for us on compound 83 atboth90Kand
297 K, since our own diffractometer does not have a low temperature facility. His two sets of data, reported here, were in good agreement with each other. The molecular structure and unit cell of solid 83 are shown in Figures 54 and 55, respectively.
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Figure 54
The molecular structure of 83 determined at 90 K, and showing the crystallographic numbering system used.
Figure 55 The packing arrangement of 83 determined at 90 K.
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Table 11 The numerical details of solution and refinement of the structures of
83
Compound 83 90 K 300 K
Formula C17H20O6 C17H20O6 Formula mass 320.33 320.33 Space group C2/cC2/c a /Å 31.2183(17) 31. 8644(15) b /Å 7.8711(4) 7. 9242(4) c /Å 12.6219(7) 12. 7065(6)
/ o 108.291(1) 109.143(1)
V /Å3 2944.8(3) 3031.0(3)
T / K 90(1) 300(1) Z 88 -3 Dcalc. /gcm 1.445 1.404
Radiation, /Å MoK, 0.71073 MoK, 0.71073
μ /mm-1 0.109 0.106 Scan mode o 2 max. / 55.06 55.06 No. of intensity meas. 18816 19426 Criterion for obs. ref. I/(I)>2 I/(I)>2
No. of indep. obsd. ref. 3406 3503 No. of reflections (m), 3406 3503 variables (n) in final ref. 288 288
R = m|F|/m|Fo| 0.0329 0.0371 m 2 m 2 1/2 Rw =[ |F| / |Fo| ] 0.0909 0.1039 s =[m |F|2/(m-n)]1/2 1.067 1.069
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Crystal decay none none Min., max. trans. coeff. 0.92, 1.00 0.84, 1.00 R for mult. meas. 0.0165 0.0165 Largest peak in final diff. map/ e Å-3 0.41 0.27
The numerical details of solution and refinement of the structures of 83 are presented in Table 11. The interatomic distances and bond angles are given in Tables 12 and
13, respectively. Only the heavy atoms (C and O) are included here.
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Table 12 Interatomic distances (Å) in the two X-ray structures of 83
Atom numbers (see Figure 54) 90 K 300 K
O1—C2 1.2128(13) 1.2088(15)
O2—C8 1.2117(13) 1.2103(15) O3—C14 1.2001(13) 1.1914(16) O4—C14 1.3456(12) 1.3351(15) O4—C15 1.4512(12) 1.4457(16) O5—C16 1.2033(13) 1.1948(16) 6—C16 1.3388(13) 1.3328(16)
O6—C17 1.4508(13) 1.4447(19) C1—C2 1.5172(14) 1.5120(18)
C1—C10 1.5291(15) 1.5210(20) C1—C11 1.5480(14) 1.5452(18)
C2—C3 1.5434(14) 1.5420(17) C3—C14 1.5347(14) 1.5338(17)
C3—C4 1.5591(14) 1.5565(17) C3—C12 1.5620(14) 1.5585(18)
C4—C5 1.5095(14) 1.5046(19) C5—C13 1.3308(16) 1.3210(20)
C5—C6 1.5093(14) 1.5031(18)
C6—C7 1.5728(14) 1.5704(17) C7—C8 1.5386(14) 1.5318(18) C7—C16 1.5440(14) 1.5384(17)
C7—C11 1.5511(13) 1.5492(16) C8—C9 1.5158(14) 1.5052(18) C9—C10 1.5301(14) 1.5243(19) C9—C12 1.5426(14) 1.5367(19)
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From Table 12 it can be seen that a small number of C__C bonds are marginally shorter than ideal, and a few are slightly longer. The latter are the C3__C4, C3__C12,
C6__C7 and C7__C11 bonds around the C3 and C7 bridgehead sites. These values are, however, not substantially anomalous.
Table 13 Bond angles (degrees) in the X-ray structures of 83
Atom numbers (see Figure 54) 90 K 300 K
C14—O4—C15 114.99(8) 115.80(11)
C16—O6—C17 114.85(9) 116.15(13)
C2—C1—C10 109.67(9) 109.95(11)
C2—C1—C11 114.95(8) 115.17(10)
C10—C1—C11 110.32(8) 110.11(11)
O1—C2—C1 121.24(9) 121.34(12)
1—C2—C3 119.48(9) 119.50(12)
C1—C2—C3 119.27(8) 119.15(10)
C14—C3—C2 109.60(8) 109.57(9)
C14—C3—C4 107.58(8) 107.34(10)
C2—C3—C4 105.93(8) 106.30(10)
C14—C3—C12 105.21(8) 105.37(10)
C2—C3—C12 115.36(8) 114.84(10)
C4—C3—C12 112.95(8) 113.19(10)
C5—C4—C3 113.70(8) 114.59(11)
C13—C5—C6 120.63(10) 120.76(14)
C13—C5—C4 120.14(10) 120.13(13)
C6—C5—C4 119.23(9) 119.08(12)
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C5—C6—C7 117.71(8) 117.95(10)
C8—C7—C16 104.71(8) 105.23(10)
C8—C7—C11 111.57(8) 111.80(10)
C16—C7—C11 110.18(8) 110.20(10)
C8—C7—C6 108.53(8) 108.27(10)
C16—C7—C6 107.29(8) 107.21(10)
C11—C7—C6 114.06(8) 113.68(10)
O2—C8—C9 121.30(9) 120.94(12)
O2—C8—C7 120.56(9) 120.19(12)
C9—C8—C7 118.12(8) 118.84(10)
C8—C9—C10 108.76(8) 109.39(11)
C8—C9—C12 115.42(8) 115.14(10)
C10—C9—C12 110.47(8) 110.15(11)
C1—C10—C9 108.75(8) 108.68(10)
C1—C11—C7 116.06(8) 116.08(10)
C9—C12—C3 117.55(8) 117.55(11)
O3—C14—O4 123.51(10) 123.01(12)
O3—C14—C3 124.94(9) 125.00(12)
O4—C14—C3 111.41(9) 111.88(10)
O5—C16—O6 123.37(10) 123.21(12)
O5—C16—C7 125.54(9) 125.71(12)
O6—C16—C7 111.08(8) 111.05(10)
Greater deviations from normality are seen for some of the bond angles listed in
Table 13. The ideal tetrahedral angle for singly bonded sp3 carbon atoms is 109.5o, but in both structures of 83 there are eight high C__C__C bond angles. In the 90 K
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crystal structure these lie between 112.95(8) and 117.71(8)o. The latter value is close to the ideal 120o value expected for a planar sp2 bonded atom. These observations confirm the predictions of Schleyer66 that flattening of the C3 and C7 positions should be present in this ring system. The outcome, however, is more complex than this original model since there are also severe distortions around several other atoms of the ring system.
5.3 NMR Studies
5.3.1 Tricyclo[5.3.1.13.9]dodecane System Chemistry
As discussed in Section 1.4, the tricyclo[5.3.1.13,9]dodecane ring system exhibits unusual peak broadening in its NMR spectra at room temperature. This phenomenon appears to be quite general for its various derivatives but the extent varies slightly from one case to the next. Here, the behaviour of the compound 3,7- bis(methoxycarbonyl)-5-methylenetricyclo[5.3.1.13,9]dodecane-2,8-dione 83 was examined in greater detail.
13 The C NMR spectrum (75.6 MHz) of this material in CDCl3 at 300 K showed only six sharp peaks (at 172.9, 139.7, 124.1, 53.0, 42.7 and 30.1) even though it would be expected to have ten peaks because of its symmetry (Figure 56). In addition, there were two broad peaks at 59.0 (C) and 45.7 (CH2), and two very broad and extremely weak peaks at 210.8 (C=O) and 39.3 (CH2). These signals correspond to
C3/C7, C4/C6, C2/C8 and C11/C12, respectively.
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Figure 56 13 Broadband decoupled C NMR spectrum of 83 determined in CDCl3 at 300 K.
1 The corresponding H NMR spectrum (300 MHz) in CDCl3 at 300 K is shown as
Figure 57. This comprises peaks at = 4.90 (2H, s), 3.66 (6H, s), 3.17 (2H, d, J=12.4
Hz), 2.85 (2H, d, J=2.3 Hz), 2.56 – 2.50 (2H, dd), and 2.30 – 2.09 (6H, m). However,
1 the H NMR spectrum was temperature dependent. Spectra in CDCl3 between 225 and 300 K are illustrated in Figure 58. Figures 59 and 60 show the proton spectra over 300-330 K.
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Figure 57 1 H NMR spectrum of 83 determined in CDCl3 at 300 K.
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Figure 58
1 H NMR spectra of 83 in CDCl3 from 230 to 300 K.
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Figure 59
1 H NMR spectra of 83 in CDCl3 from 300 to 330 K.
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Figure 60
1 H NMR spectra of 83 in CDCl3 from 300 to 330 K. (3.4 – 2.0 delta region only)
A comparison of the 1H NMR spectra in different solvents and at different temperatures is presented in Table 14 below.
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Table 14 1H Variable Temperature NMR Experiments
Temp. Toluene- 8 Chloroform- (K) 4.80 (2H, s) 4.89 (2H, s) 3.36 (6H, s) 3.66 (6H, s) 3.20 (2H, d) 3.17 (2H, d, J=13.7) 330 2.52 – 2.50 (2H, m) 2.84 – 2.83 (2H, m) 2.27 – 2.09 (4H, m) 2.56 – 2.50 (2H, dd) 1.94 – 1.86 (4H, m) 2.25 – 2.12 (6H, m) 4.81 (2H, s) 4.90 (2H, s) 3.34 (8H, s) 3.66 (6H, s) 300 2.51 – 2.50 (2H, m) 3.17 (2H, d) 2.22 – 2.10 (4H, m) 2.85 (2H, d) 1.92 – 1.83 (4H, m) 2.56 – 2.50 (2H, dd) 2.30 – 2.09 (6H, m) 4.91 (1H, s) 4.94 (1H, s) 4.77 (1H, s) 4.78 (1H, s) 230 3.96 (1H, d, J=14.0) 3.63 (7H, s) 3.30 (3H, s) 2.91 – 2.65 (5H, m) 3.22 (3H, s) 2.32 – 2.05 (5H, m) 2.94 – 2.80 (2H, AB q) 1.68 (1H, d, J=13.9) 2.46 (2H, s) 2.24 (1H, d, J=9.5) 1.89 – 1.51 (6H, m)
10
O O 1 9 8 2 12 11
3 7 14 17 H3CO 2C 4 CO 2CH3 13 6 16 5
15 CH 2
Stru ctu re 83
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The 13C NMR spectra of compound 83 were studied systematically between 230 and
330 K using the solvents chloroform- and toluene-8 and found to be significantly
77 temperature dependent as suggested by Yue et.al. The spectra recorded in CDCl3 at
330, 300 and 230 K are presented as Figures 61, 56 and 62 respectively. Both solvents showed similar trends with variation in temperature (Table 15).
Several of the carbon atoms could be assigned easily from consideration of their chemical shifts. See structure 83 for the numbering system used. In CDCl3 solution the DEPT 135 spectrum showed the four CH2, groups: at = 124.1 (C15), 45.6
(broad at 300 K), 39.0 (extremely broad at 300 K) and 30.1 (C10). The DEPT 90 spectrum indicated only one CH peak at = 42.7 (C1/9). Considering the DEPT 135 and 90 spectra, the CH3 signal at = 53.0 (C14/17), the ketone C=O at = 210.8
(C2/8), ester C=O 172.8 (C13/16), alkene quaternary C 139.7 (C5), and bridgehead quaternary C 59.0 (C3/7), could be assigned. It was more difficult to differentiate the
C4/6 and C11/12 CH2 groups, and so this was done using 2-D correlated spectroscopy: through bond (COSY) and through space (NOESY). The extremely broad signal at = 39.0 was assigned to C4/6, and the broad peak at = 45.6 to
C11/12.
13 The C NMR spectrum in CDCl3 at 330 K (Figure 61) shows the ten line broadband decoupled signals that normally would be expected at room temperature. At 300K four of these signals had become reduced in intensity as reported by Yue.77 These chemical shifts were recorded in this work as being at 210.8 (C=O), 59.0 (C), 45.7
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(CH2), and 39.3 (CH2). These signals correspond to C2/C8, C3/C7, C4/C6, and
C11/C12, respectively. On decreasing the temperature from 330 to 300 K, the peak widths at half height for these four signals increased as follows:
= 39.3 from 11.34 to 56.37 Hz
= 45.7 from 2.95 to 19.75 Hz
= 59.0 from 3.34 to 21.40 Hz
= 210.8 from 4.42 to 30.78 Hz.
On reducing the temperature to 230 K all four of these signals had re-grown into the double peaks seen in Figure 62. However, there was no significant change observed for the remaining six signals. These remained as sharp singlet peaks over the entire
230 – 330 K temperature range.
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Table 15 13C Variable Temperature Experiments
Temp. Toluene- 8 Chloroform- 6 Assignment (K) 208.8 (C=O), ketone 210.2 (C=O), ketone C2/8 172.4 (C=O), ester 172.8 (C=O), ester C13/16 140.5 (C) 140.0 (C) C5 330 123.2 (CH2) 123.9 (CH2) C15 59.1 (C) 59.2 (C) C3/7 51.9 (CH3) 52.9 (CH3) C14/17 45.6 (CH2) 45.8 (CH2) C11/12 43.0(CH) 42.9 (CH) C1/9 38.9 (CH2) 39.2 (CH2) C4/6 30.2 (CH2) 30.3 (CH2) C10 209.1 (C=O), ketone 210.7 (C=O), ketone C2/8 172.5 (C=O), ester 172.8 (C=O), ester C13/16 140.4 (C) 139.7 (C) C5 123.4 (CH2) 124.1 (CH2) C15 300 59.0 (C), broad peak 59.0 (C)- broad peak C3/7 52.1 (CH3) 53.0 (CH3) C14/17 45.6 (CH2), broad peak 45.6 (CH2), broad peak C11/12 42.9 (CH) 42.7 (CH) C1/9 39.2 (CH2), broad peak 39.0 (CH2), extremely C4/6 30.1 (CH2) broad peak 30.1 (CH2) C10 213.1 and 207.2 (C=O), 214,8 and 209.3 (C=O), C2/8 ketone ketone 173.0 and172.5 (C=O), 173.5 and 173.0 (C=O), C13/16 ester ester 230 140.3 (C) 139.5 (C) C5 123.8 (CH2) 124.7 (CH2) C15 61.3 and 56.3 (C) 61.4 and 56.5 (C) C3/7 52.6 and 52.4 (CH3) 53.7 (CH3) C14/17 48.2 (CH2) 48.1 (CH2) C11/12 43.9 and 43.5 (CH) 44.5 and 43.4 (CH) C1/9 42.9 and 41,8 (CH2) 41.7 (CH2) C4/6 33.4 and 29.7 (CH2) 33.9 and 30.0 (CH2) C10
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Figure 61
13 C NMR spectrum of 83 in CDCl3 at 330 K.
Figure 62
13 C NMR spectrum of 83 in CDCl3 at 230 K.
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Initially, it appeared likely that the molecular motion operating in the tricyclo[5.3.1.13.9]dodecane system would involve a conformational change of the propano bridge bearing the alkene double bond. This bridge cannot be planar, and therefore the alkene group can be orientated endo-orexo- with respect to the rest of the carbon skeleton. This should have resulted in changes in the C4, C5, C6 and C15 signals of compound 83. However this was not observed experimentally.
It appears more likely that the restricted motion observed in this ring system has a different origin. A twisting action around the C2 rotation axis is also possible, and this can be duplicated when molecular models of 83 are examined. Because the tricyclo[5.3.1.13.9]dodecane system is significantly strained, as confirmed by the X- ray data in Section 5.2.2, it is reasonable that this motion would be difficult to carry out at 300 K (and lower temperatures).
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5.3.2 Dynamic NMR Analysis of Compound 83
In conjunction with Dr. Jim Hook and Dr. Graham Ball, work was carried out to determine the energy value associated with the dynamic NMR behaviour of the restricted motional change of molecule 83. Technical details of this study are presented in the Experimental Section.
1 1D H NMR spectra were recorded in CDCl3 on a Bruker DPX 300 spectrometer operating at 300.13 MHz over a range of 211.3 to 339.4 K with typically 6 K increments in temperature. The singlet alkene peak at 4.89 at 300 K that decoalesces into two peaks at 4.94 and 4.76 at 211 K was used for the dynamic
NMR calculations. Seven spectra recorded between 223.5 and 266.2 K were used for
- the calculation of activation parameters using the Eyring equation k = (kbT/h) e
AG‡/RT: where kb = Boltzmann’s constant
h = Planck’s constant
R = gas constant.155
The data were modelled using a simple two site mutual exchange model. Line shapes were calculated using the manual version of the MEXICO program156 and
SpinWorks processing package.157 Chemical shifts of the two sites above the coalesence temperature were estimated by a linear prediction based on shifts obtained from the simulations of spectra at or below the coalescence temperature.
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Figure 63 compares the experimental and simulated NMR peaks for the seven temperature values used. The results of the simulations are listed in Table 16.
Figure 63
Comparison of the experimental and simulated spectra for 83 used in the Eyring plot.
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Table 16 Simulation results for compound 83
Temperature (Kelvin) shift A (Hz) shift B (Hz) rate, k (s-1) ln(k/T) 1/T
223.5 1483.3 1435.2 16 -2.63682 0.004474
229.6 1483.8 1435.8 30 -2.03514 0.004355
235.7 1484.0 1436.4 54 -1.49227 0.004243
247.9 1484.3 1437.3 100 -0.90786 0.004034
254.0 1485.6 1438.1 182 -0.33333 0.003937
260.1 1486.1 1438.7 315 0.191506 0.003845
266.2 1486.5 1439.2 520 0.669581 0.003757
Figure 64 shows the Eyring plot, (lnk/T) versus 1/T, for the seven temperatures. A good straight line graph was obtained from these values, allowing calculation of H‡
= -36.6 kJ mol-1 and AS‡ = -55.6 J K-1 mol-1 for the dynamic process:
H‡ = -(slope)(R) = - (4400.6)(8.3144) = -36.6 kJ mol-1
S‡ = (intercept - 23.759)(R) = (17.075 – 23.759)(8.3144) = - 55.6 J K-1 mol-1.
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Eyring Plot
1
0.5
0 0.0036 0.0038 0.004 0.0042 0.0044 0.0046 -0.5
-1
ln(k/T) -1.5 y = -4400.6x + 17.075 -2 R2 = 0.9888 -2.5
-3 1/T
Figure 64 Eyring plot of ln(k/T) vs. 1/T
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Chapter 6 Results and Discussion.
6 The Structure of Schroeter and Vossen’s Red Salt
As described earlier (Section 1.5) an unusual Red Salt was discovered by Schroeter and Vossen in 1910, as a result of studies on the condensation reactions of chloral and dimethyl malonate. Subsequent work by Yates and Bhat, using IR and visible spectroscopy, confirmed that this material had the structure 88.82 There remained, however, several unanswered questions regarding this unusual compound:
1. It is not known if NMR spectroscopic measurements confirm the proposed
structure.
2. It is not known if the Red Salt exists in a chiral or achiral form.
3. The sharp melting point and crystalline nature of the Red Salt indicate that it
is probably obtained as a single isomer. It is not known, however, which of
the isomers 89a-c is produced.
4. Nothing has been determined about the sites in the structure that are
associated with the sodium ions.
5. It is usually prepared from methanol solution and is known to precipitate as a
methanol solvate. However, nothing is known about the detailed structure of
this inclusion compound.
It therefore was decided to re-investigate this remarkable compound with the benefit of modern analytical methods.
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CH2-CH3 Cl H HN CO2-CH3 CH -CH OH CO -CH Cl C C 2 3 2 3 H2C CCl3--CH--C CO -CH Cl O 2 3 CO2-CH3 136 137 138
H2SO4 CO2-CH3CO2-CH3 +-- CO -CH _ Na OCH3 CO2-CH3 2 3 + O O Na H C + CCl3-CH=C 2 CO -CH CH3OH CO2-CH3 2 3
CO2-CH3CO2-CH3 139
RED SALT, 88 Scheme 32
Preparation of Schroeter and Vossen’s Red Salt.
The Red Salt was prepared as shown in Scheme 32, which follows the procedure used by Yates and Bhat85. Commercial chloral hydrate was dehydrated using concentrated sulfuric acid, and then condensed with dimethyl malonate 137 to yield the hydroxy adduct 138. This was then treated with concentrated sulfuric acid to produce dimethyl (2,2,2-trichloroethylidene)malonate 139. Compound 139 was then condensed with further dimethyl malonate using sodium methoxide in methanol.
Following careful acidification and filtration to remove inorganic side products, a dark red solution was obtained. Crystals of the Red Salt methanol solvate grew from the solution at 0 °C. These were light pink when viewed as single crystals, but bright red in bulk (Figure 65).
166 Studies in Multicyclic Chemistry Chapter 6
Figure 65
Crystals of Schroeter and Vossen’s Red Salt 89a.(CH3OH)2.
167 Studies in Multicyclic Chemistry Chapter 6
The Red Salt was isolated in 73 % yield and had a sharp melting point of 206-208
°C. Within a few hours in air, however, the crystals crumbled to a red-purple powder.
Microanalysis demonstrated that this second substance had the composition
(C16H15O10Na).(CH3OH). Electrospray mass spectrometry also confirmed the
C16H15O10Na composition of the core structure.
The molecular structure 88 represents one resonance contributing structure of the
Red Salt skeleton. In solution, its structure is better represented by the delocalised arrangement illustrated as structure 89.
Na H3CO OCH3
O C CO
8 2 1
OO 7 5 3 6 4
R H 1 R2 R3 R4
a, R1 =R4 =H R2 =R3 =CO2Me b, R2 =R3 =H R1 =R4 =CO2Me c, R1 =R3 =H R2 =R4 =CO2Me
89
13 The C NMR spectrum reveals only nine signals in d6-DMSO solution. This observation confirms this interpretation, and demonstrates that the molecule has a mirror plane through C1 and C5 of the bicyclo[3.3.0]octane ring system. The carbon atom substitutions were obtained by DEPT measurements. These combined data
168 Studies in Multicyclic Chemistry Chapter 6
indicate either the structure 89a or 89b, where the C4 and C6 ester groups are syn to each other. The 1H NMR spectrum shows a coupled 2H doublet at 3.49 and 1H triplet at 3.64 . It also shows three 6H singlets from the two different types of ester groups, and the methanol guest molecules. Finally, single crystal X-ray determination showed that the structure of Red Salt core is isomer 89a.
If crystals of 89a were allowed to grow rapidly from methanol then the resulting red crystals quickly turned opaque without initially turning into a powder. Solution 1H
13 and C NMR spectra of these crystals were identical to 89a.(CH3OH)2, except that the methoxy singlet at 3.35 had shifted to 3.40 and had increased in intensity. The remaining methoxy signals at 3.51 and 3.60 were unchanged. The variable peak is therefore believed to be due to the methanol molecules complexed with sodium ion. Crystal data were recorded for a rapidly grown crystal coated in Araldite, and all the parameters were within 1 % of the original determination. It is believed that the extra solvent was trapped in small faults or voids in the crystal. Loss of this included solvent would lead to the opaque crystals. If the additional solvent had been included in another manner, then increases in the cell dimensions would be expected and, perhaps even a different space group. Numerical details of the structure and refinement of the crystal 89a.(CH3OH)2 are presented in Table 17.
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Table 17 Numerical details of solution and refinement of structure
89a.(CH3OH)2
Compound number 89a.(CH3OH)2
Formula (C16H15O10Na)).(CH3OH)2 Formula mass 454.4
Space group P1- a /Å 9.680(6) b /Å 10.925(7) c /Å 11.553(8) a/Å 66.78(3) b/Å 73.38(3) g/Å 76.74(3) V /Å3 1066(1) T / oC 21(1) Z 2 -3 Dcalc. /gcm 1.41 Radiation, /Å MoK, 0.71073 μ /cm-1 1.28 Scan mode /2 o 2max / 44 No. of intensity measurements 2601 Criterion for observed reflection I/(I)>3 No. of independent obsd. reflections 1849 No. of reflections (m) 1849 and variables (n) in final refinement 280 m m R = |F|/ |Fo| 0.055 m 2 m 2 1/2 Rw =[ |F| / |Fo| ] 0.073 s =[m |F|2/(m-n)]1/2 1.63 Crystal decay 1 to 0.64
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The molecular structure of the alicyclic skeleton is shown in Figure 66. The bicyclo[3.3.0]octane unit is chiral in the solid state because of different co-ordination at its two ends and therefore all the bond lengths have different values. Two neighbouring methanol molecules each donate a hydrogen atom to the C3 oxygen.
The carbonyl groups of the esters at C6 and C8 each co-ordinate with a different sodium ion, with the centrally located C7 oxygen providing a bridge between these ions. The interactions at both ends of the skeleton are favoured by the ring oxygens carrying a partial negative charge (see structure 89).
Figure 66 Structure of the bicyclo[3.3.0]octane region of the Red Salt compound
89a.(CH3OH)2, showing the bond lengths (Å) determined by X-ray crystallography. Black and white lines represent the hydrogen bonds between methanol and the C3 oxygen atom. Colour code: C of 89a green, methanol C orange, O red and Na+ blue. All hydrogen atoms are omitted for clarity.
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Both sodium ions are hexa-coordinated, as shown in Figure 67. Two molecules of
89a, of opposite handness, are linked to two adjacent sodium ions as just described.
The central C7 oxygen of each 89a links the two sodium ions as a doubly-bridged dimer. The remaining equatorial ligands are provided by C6 and C7 ester carbonyl groups of the 89a molecules. Finally, two methanol molecules are complexed at the axial sites of each Na+.
Figure 67
Structure of the sodium ion region of 89a.(CH3OH)2, showing details of the octahedral oxygen co-ordination and the bond lengths (Å) determined by X-ray crystallography.
Combination and repetition of these bonding sub-units produces a unidirectional structure with a configuration rather similar to that of a non-cyclised bicycle chain
(Figure 68). The links of the chain correspond to the molecules of 89a, with the
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sodium ions joining the separate links. However, molecules of one enantiomer form one edge of the chain, and these of the opposite enantiomer from the second edge.
Identical chains pack in parallel along the c direction to complete this crystal structure (Figure 69).
c
Figure 68
The structure of 89a.(CH3OH)2, which results when the features described in Figs. 66 and 65 are combined. The infinite unidirectional bicycle-chain structure, along the c direction, contains molecules of 89a of one handedness along the top edge and opposite handedness along the bottom edge. Centres of symmetry are present in the middle of each chain link and between the pairs of adjacent sodium ions.
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Figure 69 The lattice arrangement of the methanol solvate of the Schroeter and Vossen red salt showing how the chains (seen here as cross-sectional projections) pack parallel to each other in the ab plane.
In summary, the unusual Red Salt discovered accidentally by Schroeter and Vossen in 1910 has now been fully revealed for the first time and shown to have a most remarkable structure.
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Chapter 7 Results and Discussion.
7 Further Bicyclo[3.3.0]octane Chemistry
7.1 The Structure of the Tetraester 90
In Section 1.5 it was mentioned that Yates had found that the Schroeter and Vossen
Red Salt 89 could provide a convenient synthetic route to the tetraester 90 and thence to bicyclo[3.3.0]octane-3,7-dione 91.85 The first step requires a reduction using sodium amalgam, and then acidic hydrolysis yields the diketone (Scheme 33).
CO -CH CO2-CH3 2 3 CO2-CH3 CO2-CH3
Na-Hg O Na+-O O O
CO -CH CO2-CH3 CO2-CH3 CO2-CH3 2 3 88 90 HCl Reflux
O O
91
Scheme 33
A crystal structure determination was carried out on the tetraester in order to determine whether it existed in the keto-form 90 or an enol-form. Crystals grown from methanol were found to be in space group P21/n. The molecular structure of the tetraester in the solid state is shown in Figure 70, where it can be seen that it prefers
175 Studies in Multicyclic Chemistry Chapter7
the enolised structure 140. In this behaviour it shows the same choice as does
Meerwein’s Ester in the solid state.158 There is an intramolecular hydrogen bond present between the hydroxy hydrogen atom and the non-enolised carbonyl oxygen atom in each half of the molecule 140. Table 18 presents the numerical details of solution and refinement of this crystal structure.
CO2-CH3 CO2-CH3
HO OH
CO2-CH3 CO2-CH3 140
Figure 70
Molecular structure of the tetraester 140. The intramolecular hydrogen bonds are indicated by dashed lines.
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Table 18 Numerical details of solution and refinement of the crystal structure of 140.
Compound 140
Formula C16H18O10
Formula mass 370.3
Space group P21/n a / Å 12.261(6) b / Å 12.555(5) c / Å 12.522(6) / o 114.50(2)
V /Å3 1754(1) T / K 294(1)
Z 4 -3 Dcalc. /gcm 1.40 Radiation, /Å MoK, 0.71073
μ /mm-1 0.114
Scan mode /2 o 2max. / 46
No. of intensity meas. 2441 Criterion for obs. ref. I/(I)>2
No. of indep. obsd. ref. 1097 No. of reflections (m), 1097 variables (n) in final ref. 142 m m R = | F|/ |Fo| 0.047 m 2 m 2 1/2 Rw =[ w| F| / w|Fo| ] 0.055 s =[ mw| F|2/(m-n)]1/2 1.67 Crystal decay none
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Min.,max.trans.coeff. — R for mult. meas. 0.021
Largest peak in final diff. map/ e Å-3 0.68
The molecular shape of 140 could be described as a shallow dish. Centrosymmetric pairs of molecules associate to form a double dish, with concavities pointing outwards. One such double dish is shown in Figure 71. This arrangement repeats to generate the overall structure illustrated in Figure 72, in which the only intermolecular interactions of apparent significance are weak C-H…O contacts.
Figure 71 The centrosymmetric arrangement of formed by opposite enantiomers of 140 in its crystals.
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Figure 72 Cell diagram for the crystal structure of the tetraester 140.
7.2 Diquinoline-substituted Bicyclo[3.3.0]octanes
In Section 1.6, an account was presented of the inclusion chemistry of diquinoline derivatives that used bicyclo[3.3.0]octane-2,6-dione in the formation of their central
179 Studies in Multicyclic Chemistry Chapter7
alicyclic linker group. We were therefore interested in preparing analogous compounds based on bicyclo[3.3.0]octane-3,7-dione 91. Scheme 34 shows how this diketone was condensed with two equivalents of 2-aminobenzaldehyde 141 to produce the diquinoline derivative 142 in 82% yield.
CHO O O
NH2 MeOH - 141 OH 91
N
N
142
Scheme 34
This diquinoline product proved to be exceptionally insoluble compared to its isomeric analogue 93 (see Scheme 15). It had a melting point of 352-354 oC, and its
13C NMR spectrum could only be obtained with difficulty. No really satisfactory recrystallisation solvent could be found for this substance. A similar marked decrease in solubility had been observed earlier by Alshahateet in another case when switching from bicyclo[3.3.1]nonane-2,6-dione to bicyclo[3.3.1]nonane-3,7-dione122.
The reasons for these differences in isomeric behaviour are not obvious.
With assistance from Dr. Nick Roberts (UNSW) it was found possible to grow X-ray quality crystals of the protonated form of 142 from neat phosphoric acid. This
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material proved to have the structure (143).(H2PO4)2.(H3PO4), and crystallised as the layer structure shown in Figure 73.
H + N
N + 143 H
Figure 73
The layer structure of (143).(H2PO4)2.(H3PO4). Opposite enantiomers of the host dication are shown in light or dark green. The dihydrogenphosphate ions are indicated by a purple phosphorus atom, and the phosphoric acid guest molecules by a black coloured phosphorus. Hydrogen atoms are omitted from the inorganic species.
181 Studies in Multicyclic Chemistry Chapter7
The packing of the charged and neutral species in the inorganic layer of this structure is shown in Figure 74. Table 19 shows the numerical details of solution and refinement.
Figure 74 Packing of the dihydrogen phosphate anions and phosphoric acid guests in the
(143).(H2PO4)2.(H3PO4) structure. The hydrogen bonding network is marked in red.
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Table 19 Numerical details of solution and refinement of the crystal structure of (143).(H2PO4)2.(H3PO4).
Formula C22H18N2.H7O12P3 Formula mass 602.4 Space group P2/c a /Å 11.843(6) b /Å 7.327(1) c /Å 16.835(7) / o 124.54(2) V /Å3 1203(1) T / oC 294(1) Z 2 -3 Dcalc. /gcm 1.66 Radiation, /Å MoK, 0.7107 μ /mm-1 0.314 Scan mode /2 o 2max. / 46 No. of intensity meas. 1674 Criterion for obs. ref. I/(I)>2 No. of indep. obsd. ref. 1508 No. of reflections (m), 1508 variables (n)infinal 155 ref. m m R = | F|/ |Fo| 0.052
Rw = 0.084 m 2 m 2 1/2 [ w| F| / w|Fo| ] s =[ mw| F|2/(m-n)]1/2 1.85 Crystal decay none Min.,max.trans.coeff. — R for mult. meas. 0.042 Largest peak in final 0.52 diff. map/ e Å-3
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The diquinoline 142 was also converted into the dibromo derivative 144 in 53% yield as indicated in Scheme 35. It is expected that this substance will be a further example of a new lattice inclusion host molecule. Unfortunately, the move of the
School of Chemistry into our new building coincided with this preparative work and our X-ray equipment will not be operational before this thesis must be submitted for examination. Investigation of the precise means by which 144 includes its guest molecules must therefore be temporarily deferred.
O N
N Br
N
142 O CCl4 Reflux
Br N
N Br 144
Scheme 35
184 Studies in Multicyclic Chemistry Chapter 8
Chapter 8 Experimental
8.1 General information
The compounds prepared are presented in numerical order, and according to the
Chapter in which they first appear.
The term light petroleum refers to the b.p. 60 – 80 ˚C fraction.
The infrared (IR) spectra were recorded using a Perkin-Elmer PE298 infrared spectrophotometer as liquid films or paraffin mulls using sodium chloride plates.
Peak intensities are indicated by: s (strong), m (medium) or w (weak).
Melting points were determined with a Kofler instrument and are uncorrected.
Mass spectra were recorded using a VG Quattro Triple Quadrupole instrument employing impact (EI) or electrospray (water-acetonitrile solvent system) methods.
1H (300 MHz) and 13C (75.4 MHz) NMR spectra were recorded using a Bruker
ACF300 spectrometer and are reported as chemical shifts () relative to SiMe4.
The substitution of the carbon atoms was determined using the DEPT procedure, and coupling constants (J) are measured in hertz (Hz).
Elemental analyses were carried out at The University of New South Wales by Dr.
H. P. Pham, and at the Australian National University, Canberra.
Single crystal X-ray structure determinations were carried out by Mr. Donald Craig
(UNSW) using an Enraf-Nonius CAD-4 diffractometer. Tuition in data interpretation was provided by Dr. Marcia Scudder (UNSW), who also carried out the Cambridge
Structural Database searches. Crystallographic data for the unpublished structures described in this thesis are presented as cif on the attached compact disk.
185 Studies in Multicyclic Chemistry Chapter 8
8.2 Experimental for products discussed in Chapters 2 and 3
8.2.1 5H-Dibenzo[a,d]cyclohepten-5-ol (dibenzosuberenol) 35a
Sodium borohydride (4.00 g, 105.7 mmol) was added
gradually to a stirred solution of dibenzosuberenone
OH (15.00 g, 72.7 mmol) in methanol (500 ml) in a round- bottomed flask fitted with a condenser and drying tube. The mixture was refluxed overnight. The cooled mixture was evaporated to dryness under reduced pressure, and then acidified to pH 3-4 using hydrochloric acid (1M). Organic material was extracted several times with chloroform, and then the combined extracts washed with water, and dried (Na2SO4). The filtrate was evaporated to dryness to give dibenzosuberenol159 35a as a white solid.
Yield: 13.50 g, 89 %.
Melting point: 120 – 122 °C (from petrol/chloroform); lit.159 120 °C.
-1 vmax: 3400s, 1200m, 1075m, 798s, 774m, 738s, 710m cm .
13 C NMR (75.4 MHz, DMSO-d6) : 142.1 (C), 132.4 (C), 131.3 (CH), 138.5 (CH),
127.8 (CH), 126.2 (CH), 123.1 (CH), 70.1 (CH).
8.2.2 N-(5H-Dibenzo[a,d]cyclohepten-5-yl)acetamide 37
Dibenzosuberenol 35a (0.42 g, 2.0 mmol) was
dissolved in acetonitrile (5.0 mL), then this solution
was added dropwise to concentrated sulfuric acid (0.8 NHCOCH3
186 Studies in Multicyclic Chemistry Chapter 8
mL) in a round-bottomed flask fitted with a condenser and drying tube at room temperature. The reaction mixture was stirred at room temperature for not less than
16 hours. Water (10 mL) was added, then stirring continued for a further 30 minutes.
The material was then transferred to a separating funnel containing aqueous sodium hydroxide (1M, 30 mL). Organic material was extracted several times with chloroform. The combined extracts were washed with water and then dried
(Na2SO4). The filtrate was evaporated to dryness to give 37.
Yield: 0.35 g, 70 %; lit.44 78 %.
Melting point: 289 – 291 °C (from chloroform/diethyl ether); lit.44 289 – 290 °C
(from dioxane).
-1 vmax: 3280s, 1630s, 1535m, 785m, 765w, 730m cm .
13 C NMR (75.4 MHz, DMSO-d6) : 169.0 (C), 139.0 (C), 133.7 (CH), 131.4 (CH),
128.6 (CH), 128.5 (C), 126.7 (CH), 124.7 (CH, weak and broad), 53.3 (CH, weak and broad), 22.4 (CH3).
8.2.3 (5R,10S,11S)-N-{12-Methyl-10,11-dihydro-5,10-(nitrilometheno)-5H-
dibenzo[a,d]cyclohepten-11-yl}acetamide 36a
H3COCHN CH3 A solution of dibenzosuberenol 35a (0.42 g, 2.0
C mmol) in acetonitrile (5.0 mL) was added dropwise N into cool (0 °C) sulfuric acid (98 %, 0.8 mL) in a round-bottomed flask fitted with a condenser and drying tube. The mixture was stirred at 0 °C for about 30 minutes, and then for not less than 16 hours at room temperature. Water (10 mL) was added, then stirring continued for another 30
187 Studies in Multicyclic Chemistry Chapter 8
minutes. The mixture was transferred to a separating funnel containing aqueous sodium hydroxide (1M, 30 mL). Organic material was extracted several times with chloroform. The combined extracts were washed (H2O), then dried (Na2SO4). The filtrate was then evaporated to dryness under reduced pressure to give the bridged amide 36a.
Yield: 0.33 g, 57 %; lit.43 64 %.
Melting point: 242 – 244 °C (from benzene); lit.43 223 – 224 °C (from diethyl ether).
Crystallisation using benzene gave an unstable inclusion compound, which rapidly lost solvent at room temperature. Grinding and warming gave the compound with microanalytical data for the pure host.
Found: C = 78.90, H = 6.40, N = 9.64. C19H18N2O requires: C = 78.59, H = 6.25, N =
9.65 %. vmax: 3275s, 3180w, 3030m, 1650s, 1535s, 1275m, 1170m, 1080m, 975m, 935w,
785m, 765s, 745m, 735m, 695s, 685s, 620m cm-1.
1 H NMR (300 MHz, DMSO-d6) : 8.61 (1H, d, J=8.2,NH),7.44-7.01(8H,m),5.76
(1H,s),4.88(1H,dd,J=8.2 and 3.8), 4.14 (1H, d, J=3.8), 2.16 (3H, s), 1.95 (3H, s).
13 C NMR (75.4 MHz, DMSO-d6) : 173.0 (C), 169.3 (C), 143.4 (C), 140.5 (C), 135.2
(C), 134.0 (C), 132.1 (CH), 128.1 (CH), 127.8 (CH), 127.5 (CH), 127.2 (CH), 126.94
(CH), 126.86 (CH), 124.0 (CH), 67.4 (CH), 50.3 (CH), 49.2 (CH), 27.9 (CH3), 22.8
(CH3): plus 128.6 (CH), C6H6 guest.
The structure of the inclusion compound (36a).(C6H6) was confirmed by means of X- ray crystallography.
188 Studies in Multicyclic Chemistry Chapter 8
8.2.4 (5R,10S,11S)-N-{12-Phenyl-10,11-dihydro-5,10-(nitrilometheno)-5H-
dibenzo[a,d]cyclohepten-11-yl}benzamide 100
C6H5OCHN C6H5 A solution of dibenzosuberenol 35a (0.42 g, 2.0
C mmol) in benzonitrile (5.0 mL) was added dropwise N into cool (0 °C) sulfuric acid (98 %, 0.8 mL) in a round-bottomed flask fitted with a condenser and drying tube. The mixture was stirred at 0 °C for about 30 minutes, and then for not less than 16 hours at room temperature. Water (10 mL) was added, then stirring continued for another 30 minutes. The mixture was transferred to a separating funnel containing aqueous sodium hydroxide (1M, 30 mL). Organic material was extracted several times with chloroform. The combined extracts were washed with water (4 25 mL), then dried
(Na2SO4). The filtrate then was evaporated to dryness to give a suspension of solid in unreacted benzonitrile. Trituration with light petroleum (50 mL) gave more solid which was filtered to yield 100.
Yield: 0.32 g, 39 %.
Melting point: 275 – 277 °C (from benzene).
Found: C = 84.10, H = 5.55, N = 6.81. C29H22N2O requires: C = 84.03, H = 5.35, N =
6.76 %. vmax: 3220s, 1630s, 1615m, 1575w, 1540m, 1000w, 800w, 780w, 760s, 700m, 685m cm-1.
1 H NMR (300 MHz, CDCl3) : 8.02 (2H, d, J=7.0), 7.63 - 7.13 (16H, m), 6.14 (1H, d, J=8.1), 6.09 (1H, s), 5.54 (1H, dd, J=8.1 and 4.4), 5.39 (1H, d, J=4.4).
189 Studies in Multicyclic Chemistry Chapter 8
13 C NMR (75.4 MHz, CDCl3) : 170.7 (C), 167.2 (C), 143.0 (C), 139.6 (C), 137.5
(C), 134.6 (C), 133.9 (C), 132.8 (C), 132.0 (CH), 131.7 (CH), 130.9 (CH), 128.8
(CH), 128.6 (CH), 128.5 (CH), 128.2 (CH), 127.5 (CH), 127.4 (CH), 127.2 (CH),
126.8 (CH), 124.1 (CH), 69.2 (CH), 50.4 (CH), 45.7 (CH), (two additional Ar-H peaks were obscured and not observed). m/z (electrospray): 415 [(M + 1)+, 11 %), 294 [{(M + 1) – 121}+, loss of benzamide,
100].
8.2.5 (5R,10S,11S)-N-{12-Benzoyl-10,11-dihydro-5,10-(nitrilometheno)-5H-
dibenzo[a,d]cyclohepten-11-yl}phenylacetamide 101
C6H5-H 2COCHN CO-C6H5 A solution of dibenzosuberenol 35a (0.42 g, 2.0
C mmol) in benzyl cyanide (5.0 mL) was added N dropwise into cool (0 °C) sulfuric acid (98 %, 0.8 mL) in a round-bottomed flask fitted with a condenser and drying tube. The mixture was stirred at 0 °C for about 30 minutes, and then for 3 days at room temperature.
Water (10 mL) was added, then stirring continued for another 30 minutes. The mixture was transferred to a separating funnel containing aqueous sodium hydroxide
(1M, 30 mL). Organic material was extracted several times with chloroform. The combined extracts were washed with water (4 25 mL), then dried (Na2SO4).
Solvent was evaporated from the filtrate to give a slurry of white solid
(phenylacetamide) suspended in a pale yellow oil. This crude mixture was eluted through a column of activated alumina commencing with light petroleum and then using increasing amounts of chloroform. The initial fraction comprised unreacted
190 Studies in Multicyclic Chemistry Chapter 8
benzyl cyanide containing about one third of the total amount of 101. After 3 days at room temperature, some solid 101 had precipitated from this fraction and was filtered. Passage of the bulk of 101 down the column could be monitored as a pale yellow band, which finally eluted using light petroleum-chloroform (2:3). This oily material from the column solidified on standing, and gave further 101.
Yield: 0.27 g, 30 %.
Melting point: 240 – 241 °C (from benzene)
Found: C = 81.71, H = 5.94, N = 6.12. C31H24N2O2 requires: C = 81.56, H = 5.30, N
= 6.14%. vmax: 3310s, 3040w, 1675s, 1655s, 1605w, 1580w, 1260m, 1150m, 1010w, 990w,
935m, 885m, 830w, 775m, 765m, 740m, 735m, 690m cm-1.
1 H NMR (300 MHz, CDCl3) : 7.97 (2H, d, J=7.4), 7.55 - 7.05 (15H, m), 6.71 (1H, d, J=7.3), 6.06 (1H, s), 5.66 (1H, dd, J=9.3 and 4.2), 5.46 (1H, d, J=9.3), 4.76 (1H, d,
J=4.2), 3.69 and 3.64 (1H, HAB, J=15.4), 3.54 and 3.48 (1H, HAB, J=15.4).
13 C NMR (75.4 MHz, CDCl3) : 191.2 (C), 170.2 (C), 170.0 (C), 141.8 (C), 137.7
(C), 135.4 (C), 134.73 (C), 134.65 (C), 133.4 (CH), 132.3 (CH), 130.8 (CH), 129.4
(CH), 129.1 (CH), 129.0 (CH), 128.3 (CH), 128.2 (CH), 128.0 (CH), 127.6 (CH),
127.44 (CH), 127.41 (CH), 124.6 (CH), 69.9 (CH), 45.8 (CH), 45.5 (CH), 44.0
(CH2), one Ar quaternary and one Ar-H signal were obscured and not observed). m/z (EI, >20 %, plus significant peaks): 456 [(M+, 7 %), 351 [(M – 105)+, loss of
+ C6H5CO, 9], 337 (16), 322 (44), 321 [(M-135) , loss of benzyl cyanide, 95], 293
(51), 292 (100), 291 (27), 217 (24), 216 (50), 206 (27), 191 (47), 189 (31), 178 (38),
+ + + 128 (23), 105 [(C6H5CO) , 86], 91 [C7H7) , 94], 77 [(C6H5) , 81].
The structure of this compound was confirmed by means of X-ray crystallography.
191 Studies in Multicyclic Chemistry Chapter 8
8.2.6 8,9-Dimethoxy-10b-methyl-6,10b-dihydro-5H-thiazolo[2,3-a]-
isoquinoline-3(2H)-one 107
H3CO A mixture of 6,7-dimethoxy-1-methyl-
3,4-dihydroisoquinoline 104 (1.00 g, 4.9 N O mmol), mercaptoacetic acid (0.67 g, 7.3 H3CO H3C S mmol), and p-toluenesulfonic acid monohydrate (0.04 g, 0.19 mmol) were added to a round-bottomed flask containing benzene (25 mL). The mixture was refluxed overnight using a Dean-Stark water separator. The reaction mixture was allowed to cool, and then solvent evaporated under reduced pressure to give a viscous orange-brown residue which was dissolved in a small amount of chloroform. This was applied to a column of silica which was eluted first with light petroleum, then petroleum containing increasing amounts of chloroform. A white solid was eluted by using petroleum-chloroform (4:1) and recrystallised to give 107.
Yield: 0.32 g, 24 %; lit.134 53 %, tan colour.
Melting point: 137 – 138 °C (from diethyl ether); lit.134 124 °C (from benzene- hexane).
Found: C = 60.22, H = 6.35, N = 4.76. C14H17NO3S requires: C = 60.19, H = 6.13, N
=5.01%.
-1 vmax: 1665s, 1605w, 1510m, 1260s, 1230m, 1210w, 1145m cm .
1 H NMR (300 MHz, CDCl3) : 6.61 (1H, s), 6.52 (1H, s), 4.38 (1H, dd, J=12.8 and
6.2), 3.85 (3H, s), 3.83 and 3.78 (1H, HAB, J=15.3), 3.81 (3H, s), 3.60 and 3.55 (1H,
192 Studies in Multicyclic Chemistry Chapter 8
HAB, J=15.3), 3.17 - 3.07 (1H, m), 2.97-2.85 (1H, m), 2.64 (1H, dd, J=15.9 and 3.6),
1.90 (3H, s).
13 C NMR (75.4 MHz, CDCl3) : 169.1 (C), 148.4 (C), 148.2 (C), 132.1 (C), 123.6
(C), 111.2 (CH), 107.8 (CH), 68.0 (C), 56.0 (CH3), 55.8 (CH3), 36.7 (CH2), 34.0
(CH2), 32.4 (CH3), 27.8 (CH2). m/z (>20 %): 279 [(M+, 22 %)], 265 (27), 264 (100), 246 (20), 205 (24), 204 (49),
190 (28), 118 (22), 77 (26), 46 (51).
8.2.7 (5R,10S,11S,12R)-N-{12-Methyl-14-oxo-10,11,14,15-tetrahydro-5H,12H-
5,10[3',2']thiazolodibenzo[a,d]cyclohepten-11-yl}acetamide 108
The imine 36a (0.05 g, 1.7 mmol), mercaptoacetic
H acid (0.18 g, 2.0 mmol), and p-toluenesulfonic O N acid monohydrate (0.05 g, 0.3 mmol) were added
to a round-bottomed flask containing benzene (15 S mL). The mixture was refluxed overnight using a CH 3
H NH-CO-CH3 Dean-Stark water separator. The reaction mixture was allowed to cool, and then solvent was evaporated under reduced pressure to give a viscous orange-brown residue which was dissolved in a small amount of chloroform. This was applied to a column of silica, eluting first with petroleum, then petroleum containing increasing amounts of chloroform. The product 108 was obtained as white solid.
Yield: 0.34 g, 54 %.
Melting point: 284 – 286 °C (from benzene).
193 Studies in Multicyclic Chemistry Chapter 8
Found: C = 69.03, H = 5.78, N = 7.42. C21H20N2O2S requires: C = 69.20, H = 5.53,
N = 7.69 %. vmax: 3280m, 3050m, 1665s, 1630m, 1535m, 1280m, 1200w, 1145m, 1105w, 775m,
750w cm-1.
1 H NMR (300 MHz, CDCl3) : 7.42 (1H, d, NH), 7.21 - 7.11 (8H, m), 5.73 (1H, dd,
J=9.2 and 4.1), 5.70 (1H, s), 3.94 and 3.89 (1H, HAB, J=15.4), 3.54 (1H, d, J=4.1),
3.37 and 3.32 (1H, HAB, J=15.4), 2.14 (3H, s), 1.46 (3H, s).
13 C NMR (75.4 MHz, DMSO-d6) : 170.7 (C), 169.3 (C), 140.7 (C), 137.1 (C), 136.0
(C), 134.4 (C), 130.8 (CH), 128.7 (CH), 128.5 (CH), 128.4 (CH), 128.3 (CH), 127.4
(CH), 127.3 (CH), 125.6 (CH), 70.8 (C), 60.3 (CH), 54.3 (CH), 53.0 (CH), 34.5
(CH2), 33.5 (CH3), 23.8 (CH3). m/z (> 20 %, plus significant peaks): 364 (M+, 8 %), 349 (5), 307 (8), 289 (9), 263
(8), 250 (20), 249 (100), 232 (32), 231 (60), 230 (28), 207 (21), 206 (26), 191 (32),
178 (32).
8.2.8 (5R,10S,11S)-N-{13-[(E)-1,2-Bis(methoxycarbonyl)ethenyl]-10,11-
dihydro-12-methylidene-5,10-(nitrilometheno)-5H-
dibenzo[a,d]cyclohepten-11-yl}acetamide 110
H3CO 2C H The imine 36a (0.60 g, 2.0 mmol) C C was dissolved in chloroform (50 mL) N CO 2CH 3 in a round-bottomed flask fitted with
CH 2 a condenser and drying tube. H NH-CO-CH3
194 Studies in Multicyclic Chemistry Chapter 8
Dimethyl acetylenedicarboxylate (DMAD) (0.60 g) was added to the stirred solution, which was then refluxed vigorously for not less than 16 hours. The reaction was evaporated to dryness to give viscous red-brown material. This material was heated in boiling benzene (10 mL), filtered while hot, and the filtrate allowed to stand at room temperature for 3 days. Filtration of the yellow solid yielded 110.
Yield: 0.40 g, 44 %.
Melting point: 227 – 229 °C.
Found: C = 69.72, H = 5.80, N = 6.32. C25H24N2O5 requires: C = 69.43, H = 5.59, N
=6.48%. vmax: 3390m, 1740m, 1715m, 1675m, 1650m, 1590s, 1525m, 1405m, 1165s, 1045w,
1000w, 930w, 875m, 825m, 765m, 750m, 635m cm-1.
1 H NMR (300 MHz, DMSO-d6) : 7.76 (1H, d, J=8.8,NH),7.48-7.19(8H,m),5.95
(2H, s, =CH2), 5.20 (1H, dd, J=8.8 and 4.4), 4.49 (1H, s), 4.42 (1H, s), 3.97 (1H, d,
J=4.4), 3.74 (3H, s, OCH3), 3.59 (3H, s, OCH3), 1.95 (3H, s, CH3).
13 C NMR (75.4 MHz, DMSO-d6) : 169.0 (C), 166.6 (C), 166.0 (C), 148.6 (C), 143.2
(C), 140.4 (C), 139.1 (C), 135.8 (C), 135.5 (C), 132.2 (CH), 129.0 (CH), 128.7 (CH),
127.7 (CH), 127.6 (CH), 127.0 (CH), 124.7 (CH), 99.9 (CH), 97.2 (CH2), 64.6 (CH),
53.0 (CH3), 52.8 (CH), 51.4 (CH3), 50.4 (CH), 23.0 (CH3), one Ar-H was obscured and not observed. m/z (EI, >20 % plus significant peaks): 432 [(M+, 1 %), 431 [(M – 1)+, 2], 373 [(M –
+ + 59) , loss of acetamide or CO2CH3, 6], 314 [(M – 2 x 59) , 100], 254 (22), 231 (26),
78 (43), 43 (32).
The same product was also obtained if benzene was employed as the solvent (0.36 g,
40 %).
195 Studies in Multicyclic Chemistry Chapter 8
8.2.9 (5R,10S,11S,13aR,14R,15R,15aR)-N-{13a,14,15,15a-
Tetrakis(methoxycarbonyl)-10,11,13a,14,15a-hexahydro-5H-5,10-
[1,2]cyclobutan[b]pyrrolodibenzo[a,d]cyclohepten-11-yl}acetamide 112
H3CO 2C CO 2CH3 The imine 36a (0.60 g, 2.0 mmol) was N dissolved in methanol (50 mL) in a
CO CH round-bottomed flask fitted with a CO 2CH3 2 3
H NHCOCH3 condenser and drying tube. Dimethyl acetylenedicarboxylate (DMAD) (0.60 g) was added to the stirred solution, which was then refluxed vigorously for not less than 16 hrs. The mixture was evaporated to dryness under reduced pressure to give viscous red-brown material. This material was heated in benzene (10 mL), and the solution allowed to stand at room temperature for 3 days. Filtration then yielded the tetraester 112.
Yield: 0.40 g, 35 %.
Melting point (from benzene) indistinct over 212 – 240 °C, with decomposition and colour change (yellow to orange).
Found: C = 66.58, H = 5.52, N = 4.55. (C31H30N2O9).(C6H6)0.5 requires: C = 66.55, H
= 5.42, N = 4.57 %. vmax: 3380m, 3085w, 1760s, 1740s, 1710m, 1675s, 1640m, 1505m, 1295m, 1270m,
1215m, 1195m, 1145m, 1045w, 1025m, 1000w, 930w, 890m, 865m, 820w, 765s,
745w, 710w, 685s, 625m cm-1.
1 H NMR (300 MHz, DMSO-d6) : 7.42 - 7.21 (9H, m, Ar-H and NH), 5.32 (1H, s),
5.19 (1H, dd, J=9.4 and 3.8), 4.58 (1H, s), 3.90 (1H, d, J=3.8), 3.85 (1H, d, J=9.5),
196 Studies in Multicyclic Chemistry Chapter 8
3.73 (3H, s, OCH3), 3.69 (3H, s, OCH3), 3.59 (3H, s, OCH3), 3.56 (3H, s, OCH3),
3.16 (1H, d, J=9.5), 2.06 (3H, s, OCH3).
13 C NMR (75.4 MHz, DMSO-d6) : 171.8 (C), 170.1 (C), 169.9 (C), 168.9 (C), 168.7
(C), 151.3 (C), 142.7 (C), 138.2 (C), 135.7 (C), 133.3 (C), 131.7 (CH), 129.2 (CH),
128.8 (CH), 128.1 (CH), 127.7 (CH), 127.63 (CH), 127.57 (CH), 124.2 (CH), 92.9
(CH), 74.1 (C), 62.5 (C), 60.6 (CH), 52.9 (CH3), 52.7 (CH3), 52.33 (CH), 52.33
(CH3), 52.27 (CH3), 48.2 (CH), 43.9 (CH), 42.9 (CH), 23.2 (CH3), plus guest benzene Ar-H at 128.6. m/z (EI, >10 % plus significant peaks): 575 [(M + 1)+,0.5%],574[M+, 0.6], 430 [M
+ + – 144) , loss of CH3CO2CH=CHCO2CH3), 25], 371 [(430-59) , loss of acetamide or
+ + CO2CH3, 19], 313 (25), 312 [(371 – 59) , 100], 79 (13), 78 [(included benzene) , 99],
77 (33), 74 (14).
The structure of this product as its benzene inclusion compound was confirmed by means of X-ray crystallography.
8.2.10 (5R,10S,11S,12R)-N-{15,15-Dimethoxy-14-methoxycarbonylmethylidene-
12-phenyl-10,11,12,13,14,15-hexahydro-5H-5,10-
[3,2]oxazolodibenzo[a,d]cyclohepten-11-yl}benzamide 111
The imine 100 (0.60 g, 2.0 mmol) was CO 2CH3 C H dissolved in boiling benzene (100 mL) in
C OCH3 a round-bottomed flask fitted with a N C condenser and drying tube. DMAD (0.60 O OCH3 C6H5
HNHCOC6H5 197 Studies in Multicyclic Chemistry Chapter 8
g) was added to the stirred solution which was then refluxed vigorously for 16 hrs.
The mixture was evaporated to dryness under reduced pressure to give viscous brown material. This material was dissolved in methanol (50 mL), and the solution allowed to stand at room temperature for a week. Filtration then yielded 111.
Yield: 0.12 g, 14 %.
Melting point: 259 – 261 °C (from methanol)
Found: C = 73.42, H = 5.41, N = 5.01. C36H32N2O6 requires: C = 73.45, H = 5.48, N
=4.76%. vmax: 3460m, 1715s, 1660s, 1590m, 1510s, 1285s, 1215s, 1165s, 1140w, 1120s,
1070w, 1060s, 980s, 960m, 900m, 880m, 830s, 770s, 715s, 620s cm-1.
1 H NMR (300 MHz, CDCl3) : 7.98 (1H, d, J=7.9), 7.64 – 6.94 (17H, m), 6.64 (1H, s,=CH),5.61(1H,d,J=9.2), 5.06 (1H, s), 5.03 (1H, d, partly obscured by peak at
5.06), 4.19 (1H, d, J=2.5), 3.82 (3H, s, OCH3). 2.96 (3H, s, OCH3), 2.34 (3H, s,
OCH3).
13 C NMR (75.4 MHz, CDCl3) : 167.4 (C), 166.3 (C), 156.4 (C), 143.2 (C), 141.5
(C), 136.6 (C), 136.4 (C), 136.2 (C), 133.5 (C), 132.0 (CH), 130.3(CH), 129.4 (CH),
129.1 (CH), 129.0 (CH), 128.9 (CH), 128.84 (CH), 128.77 (CH), 128.5 (CH), 127.8
(CH), 127.7 (CH), 127.2 (CH), 127.1 (CH), 124.8 (CH), 119.9 (C), 99.3 (C), 89.8
(CH), 66.0 (CH), 53.3 (CH), 52.9 (CH), 51.5 (CH3), 51.4 (CH3), 50.1 (CH3).
+ + m/z (Electrospray): 589 [(M + 1) , 15 %], 557 [(M – OCH3) , 100].
The structure of this product was confirmed by means of X-ray crystallography.
198 Studies in Multicyclic Chemistry Chapter 8
8.2.11 (5R)-N-{5-[4,5-Bis(methoxycarbonyl)-2-oxo-3-phenyl-2,5-
dihydropyrrolyl]-5H-dibenzo[a,d]cyclohepten-10-yl}phenylacetamide
115
H3CO 2C H The imine 101 (0.60 g, 2.0 mmol) was C N dissolved in boiling chloroform (40 C CO 2CH3 mL) in a round-bottomed flask fitted O C
C6H5 with a condenser and drying tube. NHCOCH 2C6H5 DMAD(0.80g)wasaddedtothe stirred solution which was then refluxed vigorously for 14 days. The reaction mixture was evaporated to dryness to give viscous brown material. This was boiled with methanol (10 mL), filtered while hot, and the filtrate allowed to stand at room temperature for 3 days. Filtration then yielded 115.
Yield: 0.07 g, 10 %.
Melting point: 253 – 255 °C (from methanol)
Found: C = 73.74, H = 5.33, N = 4.60. C37H30N2O6 requires: C = 74.23, H = 5.05, N
=4.68%. m/z (EI, M+ and >10 %): 598 [(M+, 6 %), 421 (30), 325 (26), 324 (100), 232 (38),
216 (15), 207 (22), 206 (63), 179 (17), 178 (54), 129 (17), 91 (98).
This material was insufficiently soluble in DMSO for adequate NMR data to be obtained, and consequently the structure of this product was determined by means of
X-ray crystallography.
199 Studies in Multicyclic Chemistry Chapter 8
8.3 Experimental for products discussed in Chapter 4
8.3.1 3,3,7,7-Tetramethylbicyclo[3.3.1]nonane-2,6-dione
CH3 Potassium t-butoxide (62.70 g, 558.7 mmol) was dissolved with O CH3 stirring in t-butyl alcohol (500 mL) in a round-bottomed flask
fitted with a condenser and drying tube. Bicyclo[3.3.1]nonane- O 2,6-dione149 (15.00 g, 98.6 mmol) was then added and stirring
H3C CH3 continued for 20 minutes, before iodomethane (156.60 g, 1.10 mol) was added. Precipitation of potassium iodide commenced almost at once and the reaction warmed up considerably. The mixture was stirred for not less than 5 hours, then water (250 mL) was added. The t-butyl alcohol was evaporated under reduced pressure. The residue was acidified with hydrochloric acid (2.5M) and extracted several times with dichloromethane. The combined extracts were washed with saturated sodium bicarbonate, followed by water, then dried (Na2SO4).
Evaporation of the dichloromethane gave a pale yellow oil which was distilled (b.p.
280 - 285 °C using an open flame to give a clear, light yellow solution of the diketone.
Yield: 19.15 g, 93 %; lit.146 91 %.
8.3.2 3,3,7,7-Tetramethyl-2-6-bis(methylidene)bicyclo[3.3.1]nonane 117
200 Studies in Multicyclic Chemistry Chapter 8
146 CH3 3,3,7,7-Tetramethylbicyclo[3.3.1]nonane-2,6-dione (19.15 H2C CH3 g, 92.0 mmol), methyltriphenylphosphonium iodide (80.00 g,
198.0 mmol), triethylbenzylammonium chloride (50 mg), CH2 hydroquinone (50 mg) and potassium t-butoxide (22.40 g, H3C CH3 200.0 mmol) were placed in a round-bottomed flask fitted with a condenser/drying tube, and containing dry benzene (350 mL). The mixture was refluxed and stirred for not less than 10 hours. Heating was ended, and stirring continued at room temperature overnight. Light petroleum (350 mL) was added, causing precipitation of much triphenylphosphine oxide as a white precipitate. This mixture was filtered through silica gel under suction to give a clear yellow solution, which was distilled to remove most of the solvent, and yielding an orange-yellow clear solution.
The oil was chromatographed through a column of activated alumina, eluting first with petroleum, followed by petroleum containing increasing amounts of diethyl ether. Some of the diene 117, was eluted first as a colourless oil (using light petroleum only).
Yield: 5.70 g, 53 %; lit.146 68 %.
-1 vmax: 3075w, 1825m, 885s cm .
8.3.3 3,3,7,7-Tetramethyl-6-methylidenebicyclo[3.3.1]nonane-2-one 120
CH3 Further elution of the column in Experiment 8.3.2, with H2C CH3 petroleum : diethyl ether (1:1) gave the keto olefin 120 as an
orange yellow oil. O
H3C CH3 201 Studies in Multicyclic Chemistry Chapter 8
Yield: 2.42 g, 22 %; lit.146 30 %.
-1 vmax: 3075w, 1700 m, 1625m, 885s cm .
13 C NMR (75.4 MHz, CDCl3) : 220.7 (C), 160.2 (C), 108.1 (CH2), 45.0 (CH2), 43.1
(C), 42.5 (CH2), 42.2 (CH), 37.2 (CH), 35.2 (C), 32.7 (CH3), 32.2 (CH3), 31.3 (CH3),
29.4 (CH2), 28.0 (CH3).
8.3.4 3,3,6,6,7-Pentamethylbicyclo[3.3.1]non-7-en-2-one 121
CH3 Keto olefin 120 (1.03 g, 5.0 mmol) and acetonitrile (8 mL) H3C CH H3C 3 were stirred at room temperature in a flask fitted with CH 3 condenser and drying tube. Concentrated sulfuric acid (98 O %, 0.5 mL) was added dropwise, causing warming up and producing a pale yellow solution. After 15 minutes, water (30 mL) was added, causing a yellowish oil to separate. The reaction was extracted using diethyl ether, and the combined ether extracts washed with saturated aqueous sodium bicarbonate, followed by water, then dried (Na2SO4). After evaporation of solvent from the filtrate, the oil was eluted through a short plug of alumina using light petroleum. Evaporation of solvent gave the rearrangement ketone 121 as a colourless liquid.
Yield: 0.78 g, 76 %.
Boiling point: 281 °C.
Found: C = 81.35, H = 10.63. C14H22O requires: C = 81.50, H = 10.75 %. vmax: 2980s, 2940s, 1715s, 1455m, 1270w, 1155w, 1120w, 1100w, 1030m, 1010w,
850m cm-1.
202 Studies in Multicyclic Chemistry Chapter 8
1 H NMR (300 MHz, CDCl3) : 5.27 (1H, d, J=6.3, =CH), 2.86 (1H, br m, C1 bridgehead H-C), 2.25 – 1.70 (5H, m), 1.65 (3H, br s, =CH-CH3), 1.15 (6H, s, CH3),
1.10 (3H, s, CH3), 1.07 (3H, s, CH3).
13 C NMR (75.4 MHz, CDCl3) = 216.2 (C), 145.0 (C), 120.4 (CH), 48.2 (CH), 42.5
(C), 40.8 (CH2), 39.9 (CH), 37.7 (C), 32.7 (CH3), 30.3 (CH3), 29.7 (CH3), 27.1
(CH2), 24.7 (CH3), 19.0 (CH3). m/z (EI, > 10 %): 206 (M+, 11 %), 191 (12), 135 (29), 134 (100), 122 (11), 121 (69),
119 (34), 107 (51), 105 (17), 96 (11), 93 (14), 91 (26), 79 (11), 77 (11), 57 (14), 43
(11), 41 (29), 39 (11), 32 (11), 29 (11), 28 (51).
8.3.5 4,4,7,8,8-Pentamethylbicyclo[3.3.1]non-6-en-3-one 122
CH3 Reaction carried out exactly as for Experiment 8.3.4, but H3C using concentrated sulfuric acid (1.5 mL) caused considerable O H3C warming and generation of a dark orange solution. After the
H3C CH3 same isolation procedure a yellowish oil was obtained. 13C
NMR spectroscopy indicated this to be a 3:1 mixture of 121 and 122. The latter was a second unsaturated, non-conjugated ketone believed to be 4,4,7,8,8- pentamethylbicyclo[3.3.1]non-6-en-3-one.
13 C NMR (75.4 MHz, CDCl3) : 218.3 (C), 123.6 (C), 121.0 (CH), (and other peaks).
8.3.6 {7-Anti-hydroxy-3,4,4,8,8-pentamethylbicyclo[3,2,2]non-2-en-1-
yl}acetamide monohydrate 123
203 Studies in Multicyclic Chemistry Chapter 8
H3C CH 3 Keto olefin 120 (1.30 g, 6.3 mmol) and acetonitrile (10 mL)
H3C were stirred at 0 °C in flask fitted with a reflux condenser
and drying tube. Concentrated sulfuric acid (98 %, 3.0 mL) CH3
H OH CH3 was added slowly and dropwise via the condenser. NHCOCH3 +H2O Acetonitrile (10 mL) was used to wash in the final traces of the acid. The mixture was stirred for 30 minutes at 0 °C, then at room temperature for 6 days. Water (50 mL) was added, and after 30 minutes the pH was raised to 11 using aqueous sodium hydroxide (2M). The organic material was extracted using chloroform. The combined extracts were washed with water (4 x 100 mL) and dried
(Na2SO4). Evaporation of solvent from the filtrate gave the crude products (0.90 g).
Trituration with a little diethyl ether, followed by filtration, removed a small amount of the bis(amide) 125. Evaporation of solvent from the filtrate gave a waxy yellowish-orange solid. Recrystallisation from aqueous-ethanol (1:1) gave acetamide
123 as its monohydrate.
Yield: 0.20 g, 12 %.
Melting point: 176 – 178 °C (from diethyl ether), water loss at 167 °C.
Found: C = 68.01, H = 10.43, N = 4.61. C16H27NO2.H2O requires: C = 67.81, H =
10.31, N = 4.94 %. vmax: 3430m, 3300s, 3200m, 1640s, 1500s, 1280m, 1170w, 1065m, 995w, 845m,
710m cm-1.
1 H NMR (300 MHZ, CDCl3) : 5.68 (1H, br s), 5.34 (1H, q, J=1.6), 4.68 (1H, t,
J=9.2), 2.75 (1H, br s), 2.50 – 2.40 (1H, m), 2.03 (3H, s), 1.78 – 1.49 (4H, m), 1.63
(3H, d, J=1.6), 1.16 (3H, s), 1.07 (3H, s), 1.00 (3H, s), 0.96 (3H, s).
204 Studies in Multicyclic Chemistry Chapter 8
13 C NMR (75.4 MHZ, CDCl3) : 170.9 (C), 141.3 (C), 131.2 (CH), 69.8 (CH), 65.1
(C), 42.0 (C), 39.8 (CH), 38.9 (CH2), 37.2 (C), 31.3 (CH2), 29.1 (CH3), 27.8 (CH3),
27.7 (CH3), 26.5 (CH3), 24.4 (CH3), 20.8 (CH3). m/z (M+ and > 15 %): 265 (M+, 6 %), 108 (15), 91 (18), 79 (15), 67 (16), 57 (18), 55
(27 ), 53 (18), 44 (41) , 43 (100), 42 (78).
The structure of this product was confirmed by means of X-ray crystallography.
The acetamide 123.(monohydrate) (0.10 g, 0.35 mmol) and acetonitrile (2 mL) were stirred at 0 °C in a flask fitted with reflux condenser and drying tube. Concentrated sulfuric acid (0.4 mL) was added dropwise. The mixture was allowed to warm to room temperature and was stirred for 6 days. Water (5 mL) was added, and after 30 minutes the pH was raised to 11 using aqueous sodium hydroxide (2M). Organic material was extracted using chloroform (3 x 10 mL). The combined extracts were washed with water (4 x 50 mL), and dried (Na2SO4). Evaporation of the solvent from the filtrate gave no either product 124 or bis(acetamide) 125. Only trace of oily material was recovered. This finding demonstrates that 123 is not on the reaction pathway to product 125.
8.3.7 {3,4,4,8,8-Pentamethyl-2-oxatricyclo[3.3.1.13,7]dec-1-yl}acetamide 124
CH3 Keto olefin 120 (1.30 g, 6.3 mmol) and acetonitrile H3C O H3C (10 mL) were stirred at 0 °C in a round-bottomed NHCOCH3 flask fitted with reflux condenser and drying tube. CH H3C 3
205 Studies in Multicyclic Chemistry Chapter 8
Concentrated sulfuric acid (98 %, 5.0 mL) was added slowly and dropwise via condenser. Further acetonitrile (10 mL) was used to wash in the final traces of acid.
The mixture was stirred for 30 minutes at 0 °C, then at room temperature overnight.
Water (50 mL) was added, and after 30 minutes the pH was raised to 11 using aqueous sodium hydroxide (2M). The organic material was extracted using chloroform. The combined extracts were washed with water (4 x 100 mL) and dried
(Na2SO4). Evaporation of the solvent from the filtrate gave the crude products (1.33 g). Trituration with a small amount of acetone, followed by filtration, removed a small quantity of the solid bis(acetamide) 125. Solvent was removed from the filtrate and the residue dissolved in a minimum volume of chloroform. This was chromatographed on silica, eluting first with light petroleum, followed by petrol containing increasing proportions of chloroform. The hemi-aminal 124 was obtained using 1:1 light petroleum and chloroform, and recrystallised from hot water : alcohol
(1:1) to give 124 as white needles.
Yield: 0.64 g, 38 %.
Melting point: 159 – 161 °C.
Found: C = 72.23, H = 10.06, N = 5.04. C16 H27NO2 requires: C = 72.41, H = 10.25,
N = 5.28 %. vmax: 3320s, 1650s, 5125s, 1370s, 1350s, 1335m, 1285m, 1245w, 1150w, 1080m,
1030m, 930w cm-1.
1 H NMR (300MHz, CDCl3) : 5.53 (1H, br s), 2.67 and 2.58 (1H, d, JAB=13.9), 2.51 and 2.47 (1H, dd, JAB=13.9 and 2.6), 1.95 (3H, s), 1.89 – 1.56 (6H, m), 1.11 (3H, s),
1.09 (3H, s), 1.04 (3H, s), 1.01 (3H, s), 0.97 (3H, s).
206 Studies in Multicyclic Chemistry Chapter 8
13 C NMR (75.4MHz, CDCl3) : 168.8 (C), 87.7 (C), 78.2 (C), 40.3 (CH), 40.0 (CH),
39.3 (C), 36.8 (C), 32.8 (CH2), 29.7 (CH2), 27.3 (CH2), 24.9 (CH3), 24.14 (CH3),
24.06 (CH3), 23.8 (CH3), 22.7 (CH3), 22.5 (CH3). m/z (EI, >20 %): 265 (M+, 41 %), 164 (21), 127 (30), 55 (30), 43 (100), 42 (72).
The structure of this product was confirmed by means of X-ray crystallography.
8.3.8 {4,4,8,8-Tetramethyltricyclo[3.3.1.13,7]dec-1,3-diyl}bis(actamide) 125
H3C NHCOCH 3 Keto olefin 120 (1.30 g, 6.3 mmol) and acetonitrile H C 3 (20 mL) were stirred at 0 °C in a round-bottomed NHCOCH3 flask fitted with a reflux condenser and drying tube. CH H3C 3 Concentrated sulfuric acid (98 %, 5.0 mL) was added slowly and dropwise. The reaction mixture was stirred for 30 minutes at 0 °C, then at room temperature for 6 days. Water (50 mL) was added, and after 30 minutes the pH was raised to 11 using aqueous sodium hydroxide (2M). The organic material was extracted using chloroform. The combined extracts were washed with water (4 x 100 mL) and dried
(Na2SO4). Evaporation of solvent from the filtrate gave the bis(acetamide) 125.
Yield: 1.48 g, 77 %.
Melting point: 285 – 287 °C (from toluene).
Found: C = 70.86, H = 10.13, N = 8.90, C18H30N2O2, requires: C = 70.55, 9.87, N =
9.14 %.
-1 vmax: 3360s, 3300m, 1635s, 1510m, 1340w, 1285w, 1260w, 1165w, 715w cm .
1 H NMR (300 MHz, CDCl3) :5.12(2H,brs,NH),2.81–2.67(4H,m,CH2), 1.90
[6H, s, (CH3CO-)], 1.94 – 1.54 (6H, m), 1.14 (6H, s), 1.07 (6H, s).
207 Studies in Multicyclic Chemistry Chapter 8
13 C NMR (75.4 MHz, CDCl3) : 169.8 (C), 58.1 (C), 41.3 (CH), 38.6 (C), 34.1
(CH2), 30.2 (CH2), 27.3 (CH2), 24.9 (CH3), 23.3 (CH3), 22.7 (CH3). m/z (EI, > 20 %): 307 (21 %), 306 (M+, 100), 291 (73), 263 (67), 232 (72), 222 (21),
221 (73), 122 (27), 121 (27), 120 (27), 109 (23), 109 (23), 108 (23), 107 (35(), 105
(29), 99 (22), 94 (27), 93 (24), 91 (31), 86 (24), 84 (36), 79 (20), 69 (20), 60 (21), 43
(50).
The structure of this product was confirmed by means of X-ray crystallography.
Keto olefin 120 (1.03 g, 5.0 mmol) and acetonitrile (5 mL), were stirred at room temperature in a flask fitted with a reflux condenser and drying tube. Concentrated sulfuric acid (3 mL) was added dropwise. Addition of the final 0.5 mL was strongly exothermic, resulting in vigorous refluxing and generation of a light red-brown colour. Water (40 mL) was added after 1 hour, producing a pale yellow solution and precipitation of a white solid. Extraction using chloroform, was followed by washing
(saturated aqueous sodium bicarbonate, then water), and evaporation to give the bis(acetamide) 125 as a white solid (0.59 g, 39 %) with identical spectral data to material prepared by Experiment 8.3.8.
The bis(acetamide) 125 may also be prepared through reaction of the hemi-aminal derivative 124 (as described under Experiment 8.3.7).
Concentrated sulfuric acid (5 mL) was placed in a flask fitted with a reflux condenser and drying tube, and cooled to 0 °C. Acetonitrile (5 mL) was added dropwise with stirring. A solution of compound 124 (1.00 g, 3.77 mmol) in benzene (5 mL) was
208 Studies in Multicyclic Chemistry Chapter 8
added dropwise. The reaction was allowed to warm to room temperature, and then was stirred for a further 6 days. Water (20 mL) was added and then the pH raised to
11 (2M aqueous NaOH). Organic material was extracted using chloroform (3 x 50 mL), the combined extracts washed with water (4 x 100 mL) and dried (Na2SO4).
Evaporation of solvent from the filtrate gave a light yellow solid. This was dissolved in hot toluene, filtered, and allowed to stand. Fluffy white crystals of the bis(acetamide) 125 (0.55 g, 48 %) were obtained. This material was identical in all respects to that obtained from the reactions of keto olefin 120 described earlier.
8.4 Experimental for products discussed in Chapter 5
8.4.1 3,7-Didicarbomethoxy-1,5-dicarboxybicyclo[3.3.1]nona-2,6-diene-2,6-diol
132
CO 2CH3 A hot solution of barium hydroxide OH octahydrate (154.00 g, 488.1 mmol) in
distilled water (750 mL) was filtered into a HO2C CO 2H round-bottomed flask containing powdered
HO Meerwein’ ester 131 (77.00 g, 210.4
CO 2CH3 mmol). The mixture was refluxed for 1 hour. The white precipitate of barium salt was filtered from the cooled mixture, then washed with water. The white solid was dissolved and then reprecipitated as the diacid 132, by addition of hydrochloric acid (2.5M). It was important to ensure that all lumps were thoroughly broken up by continued stirring for not less than 1 hour.
209 Studies in Multicyclic Chemistry Chapter 8
The solid was then washed with cold water to a filtrate pH of 5-6, then dried to constant yield the diacid 132.
Yield: 64.9 g, 90 %; lit. 149 88%.
Melting point: 239 - 240 °C; lit.149 240 °C.
-1 vmax: 1720s, 1660m, 1620w, 1340w, 1270s, 1220m, 830w cm .
8.4.2 3,7-Dicarbomethoxybicyclo[3.3.1]nona-2,6-diene-2,6-diol 79
CO 2CH3 The diacid 132 (24.00 g, 67.4 mmol) was OH decarboxylated at 230 - 245 °C using a Woods metal
bath until evolution of gas had ceased. Methanol (15
mL) was added while the mixture was still hot. The
HO brownish diester 79 was separated from the CO CH 2 3 methanol by decantation, and then recrystallised using acetone.
Yield: 12.10 g, 67 %; lit. 149 69 %.
Melting point: 139 - 140 °C: lit.149 140 °C.
-1 vmax: 1760m, 1610w, 1280s, 1210s, 820w, 720w cm .
1 H NMR (300 MHz, CDCl3) : 12.0 (2H, s), 4.0 (6H, s), 2.6 - 2.4 (6H, m)1.8 (2H, s).
13 C NMR (75.4 MHz, CDCl3) : 173.2 (C), 172.8 (C), 95.9 (C), 51.3 (CH3), 32.5
(CH), 27.7 (CH2), 27.0 (CH2).
210 Studies in Multicyclic Chemistry Chapter 8
8.4.3 3,7-Dicarbomethoxy tricyclo[5.3.1.13,9]dodecane-2,8-dione 80
The diester 79 (7.50 g, 28.0 mmol) was O O dissolved in dry, freshly distilled
CO 2CH3 monoglyme (25 mL). Sodium hydride H3CO 2C (3.40 g, 50 % in oil) was added in portions into the stirred diester solution, followed by 1,3 dibromopropane (18.00 g, 3 fold excess). The mixture was refluxed overnight, and then filtered while hot to remove sodium bromide precipitate which was, then washed with chloroform.
Evaporation of the solvents gave a pale brown viscous oil. This was redissolved in as little as possible of chloroform, and then passed through an alumina column using light petroleum and chloroform (3:1) to gave the diester dione 80 as a white solid.
Yield: 2.26 g, 26 %; lit.74 26 %
Melting point: 193 - 195 °C; lit.74 193 – 194 °C.
-1 vmax: 1740s, 1700s, 1260m, 1230s,1195s, 1085m, 1075m, 1010m, 710 cm .
13 C NMR (75.4 MHz, CDCl3) : 212.3 (C) very broad peak, 173.4 (C), 58.0 (C) broad peak, 52.9 (CH3), 42.9 (CH), 36.8 (CH), 36.8 (CH2) very broad peak, 29.9
(CH2), 21.1 (CH2).
8.4.4 Tricyclo[5.3.1.13,9]dodecane-2,8-dione 133
The diester dione 80 (3.50 g, 11.4 mmol) was O O transferred to a round-bottomed flask fitted with
H H 211 Studies in Multicyclic Chemistry Chapter 8
condenser, followed by glacial acetic acid (17M, 20 mL) and hydrochloric acid
(10M, 14 mL). The mixture was refluxed overnight, cooled to room temperature, then solvent evaporated to dryness under reduced pressure. The slightly viscous clear yellow-brownish solution was extracted with chloroform (3 x 50 mL), the combined extracts washed with sodium bicarbonate solution, and then dried (Na2SO4).
Evaporation of the solvent to dryness yielded a waxy solid of diketone 133.The waxy solid was sublimed at reduced pressure, and then recrystallised from ether/light petrol.
Yield: 2.00 g, 95 %; lit.74 92 %.
Melting point: 215 – 217 °C.
-1 vmax: 1700s, 1320m, 1300m, 1245m, 1220m, 1025m, 1010m, 890m, 760s cm .
1 H NMR (300 MHz, CDCl3) : 7.3 (1H, s), 2.77 - 2.62 (4H, d), 2.12 – 1.94 (7H, m),
1.4 (4H, s).
13 C NMR (75.4 MHz, CDCl3) : 218.0 (C), 72.2 (CH), 43.5 (CH), 43.4 (CH2), 34.5
(CH2), 32.2 (CH2), 21.6 (CH2).
8.4.5 2,8-Dimethyltricyclo[5.3.1.13,9]dodecane-syn-2,syn-8-diol 81
The diketone 133 (0.80 g, 4.16 mmol) was H3C CH3 dissolved in dry freshly distilled tetrahydrofuran HO OH (25 mL) in a three neck flask fitted with
condenser, septum and drying tube. Methyllithium
(10.0 mL, 15 mmol) was added dropwise into the flask at -10 °C using a syringe.
Stirring was continued at -10 °C for 2 hours, then overnight at room temperature.
212 Studies in Multicyclic Chemistry Chapter 8
Diethyl ether (20 mL) was added, followed by water (20 mL) and stirring continued for a further 10 minutes. The mixture was first extracted with light petroleum, then with diethyl ether. The combined extracts were dried (Na2SO4), filtered, then evaporated to dryness under reduced pressure. A light yellow waxy material was obtained. This was dissolved in boiling cyclohexane, filtered and the filtrate left at room temperature overnight. Diol 81 was obtained as pale yellow solid.
Yield: 0.65 g, 70 %.
Melting point: 208 - 210 °C; lit.74.
-1 vmax: 3450s 1130m, 1100s, 1030m, 1020m, 935m, 900w, 875m, 840w cm .
1 H NMR (300 MHz, CDCl3) : 1.97 - 2.25 (6H), 1.70 - 1.81 (6H), 1.43-1.60 (2H),
1.29 - 1.40 (4H), 1.34 (6H)
13 C NMR (75.4 MHz, CDCl3) : 74.1 (C), 39.4 (CH), 38.2 (CH), 34.1 (CH3), 31.2
(CH2), 30.0 (CH2), 28.0 (CH2), 23.1 (CH2).
X-ray
8.4.6 Bis(pyrazolone) of 3,7-dicarbomethoxy tricyclo[5.3.1.13,9]dodecane-2,8-
dione 135
N N The diester 79 (1.00g, 3.24 mmol) was ground HN NH C C to a fine powder, then placed in a flask. The O O hydrazine hydrate was added, then mixed the mixture for 30 minutes. The reaction was filtrated and washed with a small amount of ether, then dried to yield a creamy material of bis(pyrazolone) 135. The creamy material then was recrystallised using methanol to give shiny crystals of 135.
213 Studies in Multicyclic Chemistry Chapter 8
Yield: 0.60 g, 68 %.
Melting point: 335 – 343 °C (with decomposition).
Found: C = 61.90, H = 6.24, N = 20.97. C14H16N4O2 requires: C = 61.75, H = 5.93, N
= 20.58 %. vmax: 1695s, 1580w, 1305w, 1035w.
The structure of this product 135 was confirmed by means of X-ray crystallography.
8.4.7 3,7-Dibromotricyclo[5.3.1.13,9]dodecane-2,8-dione 134
A solution of diketone 133 (0.50 g, 2.60 mmol) in O O acetonitrile (7.5 mL) was added dropwise into cool
(0 °C) sulfuric acid (98 %, 2.0 mL) in a round- Br Br bottomed flask fitted with condenser and drying tube. Bromine (0.7 mL, ~ 2.0 g) was added dropwise to the stirred mixture. Stirring was continued for 30 minutes at 0 °C, then at room temperature for 3 days. Ice (50 g) was added into the stirred mixture, followed by sodium metabisulfite solution (25 mL), and stirring was continued for further 30 minutes. A yellow precipitate was produced. This was removed by filtration, then dissolved in chloroform (100 mL), and washed (NaHCO3). The chloroform extracts were dried over Na2SO4, filtered, then evaporated to dryness under reduced pressure to give the dibromoketone 134 as a light brown solid.
Recrystallisation from chloroform gave yellowish transparent crystals.
Yield: 0.12 g (sublimation), 13 %.
Melting point; decomposed at about 290 °C.
214 Studies in Multicyclic Chemistry Chapter 8
Found: C = 41.40, H = 4.26. C12 H14O2 Br2 requires: C = 41.17, H = 4.03 %.
-1 vmax: 1710s, 1445m, 1360w, 725m cm . m/z (EI >20 %, plus significant peaks): 350 (M+, 9), 269 (M-1, 24).
8.4.7 3,7-dicarbomethoxy-5-methylentricyclo[5.3.1.13.9] dodecane-2,8-dione 83
O The diester 79 (11.26 g, 42.0 mmol] was O dissolved in freshly distilled
CO 2CH 3 H3CO 2C tetrahydrofuran (THF) (240 mL). At
room temperature, sodium hydride (10.4 CH 2 g of 50 % suspension in paraffin oil), was added in portions, the reaction continued and stirred until complete (no more H2 produced). Then 3-chloro-2-chloromethylprop-1-ene 82 was added into the reaction.
The mixture was refluxed overnight, then filtered while hot to removed NaCl, which was then washed with chloroform. Evaporation of the solvents under reduced pressure gave a viscous yellow-orange material.This was chromatographed through a silica gel column using chloroform. Evaporation of the solvent to dryness, followed by addition of a little amount of acetone, gave a clear solution. Addition of light petroleum precipitated the product 83.
Yield; 6.80 g, 51 %; lit.77 75 %.
1 H NMR (300 MHz, CDCl3) : 4.90 (2H, s), 3.66 (6H, s), 3.20 (2H, d, J=12.42), 2.85
(2H, s), 2.56 – 2.50 (4H, m), 2.30 – 2.09 (6H, m).
215 Studies in Multicyclic Chemistry Chapter 8
13 C NMR (75.4 MHz, CDCl3), only 6 sharp peaks were observed at 300 K : 172.8
(C=O), 139,7 (C), 124.1 (CH2), 53.0 (CH3), 42.7 (CH) and 30.1 (CH2),while this compound would be expected has ten peaks as a symmetrical. The additional 4 peaks were very broad and were best seen at high or low temperature as explained in
Section 5.3.1.
8.5 Experimental for products discussed in Chapter 6
8.5.1 Chloral 136
Cl H Sulfuric acid (98 %, 100 mL) was added slowly and Cl C C carefully to a round-bottomed flask containing chloral
Cl O hydrate (100.0 g, 0.61 mol). This flask was connected to a distillation set up, and the mixture gently heated. The first few drops of distillate were discarded, then anhydrous chloral 136 was collected (b.p. 97.5 °C)160.
Yield: 62.00 g, 72 %.
-1 vmax: 3500w, 2860w, 1760s, 1360m, 1102w, 1022m, 1064w, 988m, 850s, 730s cm .
8.5.2 Dimethyl (2,2,2-trichloro-1-hydroxyethyl)malonate 138
Cl HO Diethylamine (1.00 g) was added slowly to a CO 2CH3 Cl C CH CH stirred mixture of dimethyl malonate 137
Cl CO 2CH 3
216 Studies in Multicyclic Chemistry Chapter 8
(33.00 g, 0.25 mol) and anhydrous chloral 136 (36.90 g, 0.26 mol). The reaction temperature was kept below 40 °C by vigorous stirring and slow addition. If the temperature rose above 40 °C, an ice-bath was used to reduce the temperature. After completion of addition, the reaction was continued at room temperature for not less than 2 hours. The semi-solid mixture was added to light petroleum (500 mL), brought to boiling, and then left overnight. The yellow oily layer was separated, and the light petroleum evaporated. This gave the hydroxy ester 138.
Yield: 52.60 g, 75 %; lit.85 83 %. vmax: 3450m, 1740s, 1280m, 1200m, 1150m, 1096m, 1008w, 940m, 820s, 798s,
760m cm-1.
8.5.3 Dimethyl (2,2,2-trichloroethylidene)malonate 139
Cl Concentrated sulfuric acid (98 %, 125.0 mL) CO 2CH3 Cl C C C was added slowly and carefully with stirring H CO CH Cl 2 3 into a flask containing dimethyl (2,2,2- trichloro-1-hydroxyl)malonate 138 (35.50 g, 125 mmol) and protected by a drying tube. The mixture was stirred overnight, then poured onto crushed ice (1 kg) with vigorous stirring. A white precipitate was produced. This was filtered off, washed with water, and dried in a vacuum desiccator to give the unsaturated ester 139 as a white solid.
Yield: 31.90 g, 98 %; lit.85 100%.
Melting point: 62 – 64 °C; lit.85 62.5 – 64.0 °C.
-1 vmax: 1720s, 1240s, 1100m, 1068w, 922w, 900w, 820w, 782w, 750m cm .
217 Studies in Multicyclic Chemistry Chapter 8
8.5.4 Sodium 2,4,6,8-tetracarbomethoxybicyclo[3.3.0]octa-1,7-diene-3-one-7-
oxide (methanol solvate): Schroeter and Vossen’s Red Salt 88
CO 2-CH 3 CO 2-CH 3 Dimethyl malonate (7.90 g) was added to a sodium methoxide solution made by dissolving Na+O - O sodium (1.40 g) in anhydrous methanol (30.0
mL). The mixture was cooled in an ice-salt CO 2-CH 3 CO 2-CH 3 bath, then finely powdered dimethyl (2,2,2-trichloroethylidene)malonate 139 was added, all at once. Then the ice-bath was removed, and the flask contents swirled vigorously, till the temperature reached 30 - 40 °C. If the temperature rose above 40
°C, the ice-bath was used to control the temperature.
When the temperature showed no further rise, the mixture was left to stir at room temperature overnight. The mixture was carefully acidified to pH 5-6 using methanolic hydrogen chloride. It was then filtered immediately and rapidly to remove NaCl. The filtrate was a clear dark red solution. On standing at 0 °C
85 overnight, bright red crystals of the Red Salt (88).(CH3OH)2 were deposited .
Yield: 2.80 g, 73 %; lit.85 51 %.
Melting point = 206 - 208 °C (from methanol).
Found: C = 48.24, H = 4.53. (C16H15O10Na).(CH3OH) requires C = 48.35, H = 4.53
%. This determination was performed on a sample recrystallised from methanol that had stood in air for 6 days at room temperature. After a few hours, crystals of the
Red Salt crumble to a red-purple powder, due to loss of one equivalent of methanol from the structure.
218 Studies in Multicyclic Chemistry Chapter 8
vmax: 3500s, 1710m, 1680s, 1620m, 1600m, 1525s, 1320m, 1225s, 1190m, 1145s,
1115m, 1025m, 990s, 815w, 785w, 750w, 705w cm-1.
1 H NMR (300MHz, DMSO-d6) : 3.35 (6H, s), 3.49 (2H, d, J=7.9 Hz), 3.51 (6H, s),
3.60 (6H, s), 3.64 (1H, t, J=7.9 Hz).
13 C NMR (75.4 MHz, DMSO-d6) : 47.4 (CH), 50.6 (CH3), 52.1 (CH3), 56.9 (CH),
104.5 (C), 165.7 (C), 171.4 (C), 180.4 (C), 191.5 (C).
+ m/z (electrospray): 413 (36%) [(C16H15O10Na).Na] , 803 (100)
+ + [(C16H15O10Na)2.Na] , 1193 (24) [(C16H15O10Na)3.Na] .
The structure of (88).(CH3OH)2 was determined by X-ray crystallography.
8.5.5 2,4,6,8-Tetracarbomethoxybicyclo[3.3.0]octa-2,6-diene-3,7-diol 140
CO 2-CH 3 CO 2-CH 3 A mixture of the Red Salt 88 (10.00 g, 26.2
mmol), water (100 mL), ice (150 g), and HO OH diethyl ether (200 mL) were placed in a 1 L
round-bottomed flask, and cooled using an CO 2-CH 3 CO 2-CH 3 ice-bath. Then sodium amalgam (2 %, 54.0 g) was added to the mixture in small portions, with stirring, and keeping the temperature as low as possible. The pH was maintained at 3-4 by addition of small amount of sulfuric acid solution (2M).
Addition of the Na-Hg took 2 hours. Then the mixture was stirred at room temperature overnight. The mixture was acidified to pH 1 using 2M H2SO4 solution, and the diethyl ether layer separated. The aqueous layer was extracted with diethyl ether (2 x 100 mL), then dried (Na2SO4). Solvent was evaporated from the filtrate
219 Studies in Multicyclic Chemistry Chapter 8
down to a volume of approximately 25 mL. The solution was stored overnight in a freezer, thereby producing a yellowish precipitate of 140. This material was recrystallised from methanol to give the tetraester 140 as shiny white crystals.
Yield = 3.10 g, 32 %; lit. 85 36 %
Melting point = 103 - 105 °C (from methanol); lit. 104 - 107.5 °C. vmax: 1730s, 1650s, 1620m, 1320m, 1250s, 1190m,1150m, 1040w, 1010w, 980w,
780m cm-1.
1 H NMR (300 MHz, CDCl3) : 3.56 (1H, s), 3.61 (1H, t, J=2.6 Hz), 3.75 (6H, s),
3.77 (6H, s), 3.84 (1H, t, J=2.6 Hz).
13 C NMR (75.4 MHz, CDCl3) : 43.8 (CH), 51.6 (CH3), 52.3 (CH3), 55.2 (CH),
103.8 (C), 169.0 (C), 170.6 (C), 170.8 (C).
The structure of 140 was determined by X-ray crystallography and found to exist in the enolic form.
8.5.6 Bicyclo[3.3.0]octane-3,7-dione 91
The tetraester 140 (2.50 g, 6.8 mmol) and O O hydrochloric acid (32 %, 43.0 mL) were refluxed
overnight. Hydrochloric acid was removed by evaporation under vacuum pressure, and the residue made slightly basic with sodium hydroxide solution (1M). Organic material was extracted several times with chloroform (3 x 50 mL). The combined extracts were washed with water (4 x 100 mL), then dried (Na2SO4). Evaporation of solvent from the filtrate gave a brownish
220 Studies in Multicyclic Chemistry Chapter 8
viscous liquid (1.05 g). This gave a brownish material after standing at room temperature overnight. Sublimation under reduced pressure at 80 °C gave the dione
91 as white needle-like crystals.
Yield: 0.80 g, 9 %; lit. 85 90 %
Melting point: 85 - 87 °C; lit. 85 84 - 86 °C
13 C NMR (75.4MHz, CDCl3) : 217.8 (C), 43.5 (CH2), 36.3 (CH).
8.6 Experimental for products discussed in Chapter 7
8.6.1 2-Aminobenzaldehyde 141
CHO A mixture of iron (II) sulfate heptahydrate (105.00 g, 380
mmol) and nitrobenzaldehyde (6.00 g, 40.0 mmol) in a
round-bottomed flask containing 175 mL of water was NH2 stirred and 0.5 mL of hydrochloric acid (32 %) was added. The mixture was heated to 90 °C in oil bath with continuing stirring. The temperature was maintained at 90
°C while adding 25.0 mL of concentrated ammonium hydroxide in one portion. At 2 minute intervals, three additional amounts of 10.0 mL concentrated ammonium hydroxide were added. Stirring and heating were continued for another 10 minutes, then water (100 mL) was added. The reaction was steam-distilled as rapidly as possible to give about 1 litre of distillate. Light green distillate was saturated with sodium chloride, then extracted with diethyl ether (3 x 100 mL). The combined ether extracts were dried over anhydrous sodium sulfate, then filtered. Evaporation of the
221 Studies in Multicyclic Chemistry Chapter 8
filtrate gave a light yellow semi-solid product 140. This was dried over P2O5 in a desiccator, yielding 141 as a pale yellow solid.
Yield: 2.90 g, 60 %; lit.161 69 - 75 %.
Melting point: 38 - 39 °C; lit161.
8.6.2 6,6a,13,13a-Tetrahydropentaleno[1,2-b:4,5-b’]diquinoline 142
N
N
Bicyclo[3.3.0]octane-3,7-dione 91 (0.85 g, 6.2 mmol) and 2-aminobenzaldehyde 141
(1.82 g, 15.0 mmol) were dissolved in methanol (12.0 mL) in a round-bottomed flask. This mixture was cooled by an ice-bath, then sodium hydroxide (1.6 mL, 2M) was added dropwise with vigorous stirring. When the ice had melted, the reaction was left stirring overnight at room temperature. The diquinoline 142 was filtered, washed with methanol, and dried in a desiccator.
Yield: 1.56 g, 82 %.
Melting point: 352 - 354 °C (Mettler FP900, at Abbott Australasia Pty. Ltd. Sydney,
Australia).
Found: C = 84.21, H = 5.63, N = 8.69. (C22H16N2)4.(CH3OH) , requires: C = 84.47, H
= 5.42, N = 8.85 %.
-1 vmax: 1605w, 1560w, 1400m, 1300w, 1205w, 1145w, 1005w, 950w cm .
222 Studies in Multicyclic Chemistry Chapter 8
1 H NMR (300 MHz, CDCl3) : 8.06 (2H, s), 7.94 (2H, d, J=8.3), 7.74 (2H, d, J=7.9)
7.61 – 7.56 (2H, m), 7.45 – 7.40 (2H,m), 4.32 (2H, d, J=7.2), 3.87 and 3.82 (2H, d,
J=1.73 and 7.2), 3.59 and 3.54 (2H, JAB=17.3). The methanol CH3 was also present at
3.49 .
13 C NMR (75.4 MHz, CDCl3) : 165.6 (C), 148.2 (C), 137.3 (C), 131.7 (CH), 128.8
(CH), 128.5 (CH), 127.6 (CH), 127.4 (C), 45.0 (CH), 40.6 (CH2). m/z (EI, > 15 %)): 309 (21 %), 308 (M+, 100), 307 (64), 306 (17), 305 (16), 154 (21),
153 (28), 81 (15), 73 (15), 69 (28), 57 (17), 55 (15), 43 (25).
The structure of 142 (as its dication) was determined by X-ray crystallography. The sample was dissolved in warm neat phosphoric acid and the solution left open to the atmosphere. Absorption of water from the air allowed suitable crystals to form as the solvent composition changed.
8.6.3 6,13-Dibromo-6,6a,13,13a-tetrahydropentaleno[1,2-b,4,5-b]diquinoline
144
Br
N
N
Br
223 Studies in Multicyclic Chemistry Chapter 8
A mixture of the diquinoline 142 (1.50 g, 4.9 mmol), N-bromosuccinimide (NBS)
(2.25 g, 12.6 mmol) and carbon tetrachloride (150 mL) was refluxed for not less than four hours. The reaction was allowed to cool and precipitated succinimide filtered.
This was washed with a small volume of CCl4, and then combined filtrates were evaporated to dryness, giving the dibromide 144 as an orange solid.
Yield: 1.20 g (53 %). vmax: 1685s, 1450s, 1375s, 1285w, 1185m.
1 H NMR (300 MHz, CDCl3) : 8.31 (2H, s), 7.98 (2H, d, J=8.7 Hz), 7.77 (2H, d,
J=8.3 Hz), 7.67 – 7.62 (2H, m), 7.54 – 7.47 (2H, m), 5.83 (2H, s), 4.83 (2H, s).
13 C NMR (75.4 MHz, CDCl3) : 163.2 (C), 149.3 (C), 134.1 (CH), 133.1 (C), 130.5
(CH), 129.8 (C), 128.4 (C), 128.2 (CH), 127.8 (CH), 55.4 (CH), 52.7 (CH).
224 Studies in Multicyclic Chemistry Chapter 9
Chapter 9 References
1. J.J. Ritter and P.P. Minieri, J. Am. Chem. Soc., 1948, 70, 4045
2. J.J. Ritter and J. Kalish, J. Am. Chem. Soc., 1948, 70, 4048
3. F. Möller, Methoden Org. Chem. (Houben-Weyl), 1957, 11 (1), 994
4. E.N. Zil’berman, Usp. Khim., 1960, 29, 709; Russ. Chem. Rev. (Engl.
Transl,), 1960, 29, 331
5. F. Johnson and R. Madronero, in Advances in Heterocyclic Chemistry,ed.
A.R. Katritzky and A.J. Boulton, Academic Press, New York, 1966, Vol. 6.
p.95
6. K. Sisido and T. Isida, Yuki Gosei Kagaku Kyokai Shi, 1967, 25, 298
7. A.L.J. Beckwith, in The Chemistry of Amides, ed. J. Zabicky, Interscience,
London, 1970, p. 73
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_audit_creation_method SHELXL-97 _chemical_name_systematic ; 3,7-Bis(methoxycarbonyl)-5-methylenetricyclo [5.3.1.1^3,9^]-dodecane-2,8-dione ; _chemical_name_common ? _chemical_melting_point ? _chemical_formula_moiety ? _chemical_formula_sum 'C17 H20 O6' _chemical_formula_weight 320.33 loop_ _atom_type_symbol _atom_type_description _atom_type_scat_dispersion_real _atom_type_scat_dispersion_imag _atom_type_scat_source 'C' 'C' 0.0033 0.0016 'International Tables Vol C Tables 4.2.6.8 and 6.1.1.4' 'H' 'H' 0.0000 0.0000 'International Tables Vol C Tables 4.2.6.8 and 6.1.1.4' 'O' 'O' 0.0106 0.0060 'International Tables Vol C Tables 4.2.6.8 and 6.1.1.4'
_symmetry_cell_setting monoclinic _symmetry_space_group_name_H-M C_1_2/c_1 loop_ _symmetry_equiv_pos_as_xyz 'x, y, z' '-x, y, -z+1/2' 'x+1/2, y+1/2, z' '-x+1/2, y+1/2, -z+1/2' '-x, -y, -z' 'x, -y, z-1/2' '-x+1/2, -y+1/2, -z' 'x+1/2, -y+1/2, z-1/2'
_cell_length_a 31.2183(17) _cell_length_b 7.8711(4) _cell_length_c 12.6219(7) _cell_angle_alpha 90.00 _cell_angle_beta 108.291(1) _cell_angle_gamma 90.00 _cell_volume 2944.8(3) _cell_formula_units_Z 8 _cell_measurement_temperature 90 _cell_measurement_reflns_used 5032 _cell_measurement_theta_min 2.7 _cell_measurement_theta_max 27.5
_exptl_crystal_description plate _exptl_crystal_colour colorless _exptl_crystal_size_max 0.35 _exptl_crystal_size_mid 0.30 _exptl_crystal_size_min 0.15 _exptl_crystal_density_meas ? _exptl_crystal_density_diffrn 1.445 _exptl_crystal_density_method 'not measured' _exptl_crystal_F_000 1360 _exptl_absorpt_coefficient_mu 0.109 _exptl_absorpt_correction_type multi_scan _exptl_absorpt_correction_T_min 0.92 _exptl_absorpt_correction_T_max 1.00 _exptl_absorpt_process_details 'SADABS (Sheldrick, 2002)'
_exptl_special_details ; ? ;
_diffrn_ambient_temperature 90 _diffrn_radiation_wavelength 0.71073 _diffrn_radiation_type MoK\a _diffrn_radiation_source 'fine-focus sealed tube' _diffrn_radiation_monochromator graphite _diffrn_measurement_device_type 'Bruker SMART 1000 CCD diffractometer' _diffrn_measurement_method \w_scan _diffrn_detector_area_resol_mean 8.192 _diffrn_standards_number ? _diffrn_standards_interval_count ? _diffrn_standards_interval_time ? _diffrn_standards_decay_% 0 _diffrn_reflns_number 18816 _diffrn_reflns_av_R_equivalents 0.0165 _diffrn_reflns_av_sigmaI/netI 0.0131 _diffrn_reflns_limit_h_min -40 _diffrn_reflns_limit_h_max 40 _diffrn_reflns_limit_k_min -10 _diffrn_reflns_limit_k_max 10 _diffrn_reflns_limit_l_min -16 _diffrn_reflns_limit_l_max 16 _diffrn_reflns_theta_min 1.37 _diffrn_reflns_theta_max 27.53 _reflns_number_total 3406 _reflns_number_gt 3001 _reflns_threshold_expression >2sigma(I)
_computing_data_collection 'SMART (Bruker, 1998)' _computing_cell_refinement 'SAINT (Bruker, 1998)' _computing_data_reduction SAINT _computing_structure_solution 'SHELXS-97 (Sheldrick, 1990)' _computing_structure_refinement 'SHELXL-97 (Sheldrick, 1997)' _computing_molecular_graphics 'SHELXTL (Bruker, 2000)' _computing_publication_material SHELXTL
_refine_special_details ; Refinement of F^2^ against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F^2^, conventional R-factors R are based on F, with F set to zero for negative F^2^. The threshold expression of F^2^ > 2sigma(F^2^) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F^2^ are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. ;
_refine_ls_structure_factor_coef Fsqd _refine_ls_matrix_type full _refine_ls_weighting_scheme calc _refine_ls_weighting_details 'calc w=1/[\s^2^(Fo^2^)+(0.0553P)^2^+1.4234P] where P=(Fo^2^+2Fc^2^)/3' _atom_sites_solution_primary direct _atom_sites_solution_secondary ? _atom_sites_solution_hydrogens difmap _refine_ls_hydrogen_treatment refall _refine_ls_extinction_method none _refine_ls_extinction_coef ? _refine_ls_number_reflns 3406 _refine_ls_number_parameters 288 _refine_ls_number_restraints 0 _refine_ls_R_factor_all 0.0370 _refine_ls_R_factor_gt 0.0329 _refine_ls_wR_factor_ref 0.0931 _refine_ls_wR_factor_gt 0.0909 _refine_ls_goodness_of_fit_ref 1.067 _refine_ls_restrained_S_all 1.067 _refine_ls_shift/su_max 0.001 _refine_ls_shift/su_mean 0.000 loop_ _atom_site_label _atom_site_type_symbol _atom_site_fract_x _atom_site_fract_y _atom_site_fract_z _atom_site_U_iso_or_equiv _atom_site_adp_type _atom_site_occupancy _atom_site_symmetry_multiplicity _atom_site_calc_flag _atom_site_refinement_flags _atom_site_disorder_assembly _atom_site_disorder_group O1 O 0.14350(3) 0.92030(10) 1.14478(6) 0.01961(18) Uani 1 1 d . . . O2 O 0.13025(3) 0.67600(10) 0.68367(6) 0.02092(18) Uani 1 1 d . . . O3 O 0.20808(3) 1.26953(10) 1.06047(7) 0.02317(19) Uani 1 1 d . . . O4 O 0.23368(2) 1.02157(9) 1.14416(6) 0.01815(18) Uani 1 1 d . . . O5 O 0.02118(3) 0.68707(10) 0.64699(6) 0.02156(18) Uani 1 1 d . . . O6 O 0.06227(3) 0.46519(10) 0.73372(6) 0.02106(18) Uani 1 1 d . . . C1 C 0.14074(3) 0.69781(13) 1.01469(8) 0.0152(2) Uani 1 1 d . . . C2 C 0.14965(3) 0.87831(13) 1.05824(8) 0.0139(2) Uani 1 1 d . . . C3 C 0.16605(3) 1.01151(13) 0.98992(8) 0.0136(2) Uani 1 1 d . . . C4 C 0.12505(4) 1.13122(13) 0.93770(9) 0.0164(2) Uani 1 1 d . . . C5 C 0.08067(3) 1.03865(13) 0.89288(8) 0.0150(2) Uani 1 1 d . . . C6 C 0.07240(4) 0.92858(13) 0.79048(8) 0.0153(2) Uani 1 1 d . . . C7 C 0.08810(3) 0.73789(13) 0.80806(8) 0.0138(2) Uani 1 1 d . . . C8 C 0.13172(3) 0.71899(12) 0.77693(8) 0.0144(2) Uani 1 1 d . . . C9 C 0.17632(3) 0.75040(13) 0.86695(9) 0.0154(2) Uani 1 1 d . . . C10 C 0.17824(4) 0.64100(14) 0.96854(9) 0.0181(2) Uani 1 1 d . . . C11 C 0.09397(4) 0.66885(13) 0.92689(8) 0.0150(2) Uani 1 1 d . . . C12 C 0.18662(3) 0.93766(13) 0.90167(9) 0.0158(2) Uani 1 1 d . . . C13 C 0.04907(4) 1.05634(15) 0.94241(9) 0.0200(2) Uani 1 1 d . . . C14 C 0.20380(3) 1.11902(13) 1.06854(8) 0.0148(2) Uani 1 1 d . . . C15 C 0.27199(4) 1.11224(15) 1.21781(9) 0.0201(2) Uani 1 1 d . . . C16 C 0.05277(3) 0.63119(13) 0.72019(8) 0.0153(2) Uani 1 1 d . . . C17 C 0.03303(5) 0.35617(16) 0.64875(10) 0.0254(3) Uani 1 1 d . . . H1 H 0.1411(4) 0.6318(17) 1.0805(11) 0.019(3) Uiso 1 1 d . . . H41 H 0.1230(5) 1.2108(18) 0.9971(12) 0.022(3) Uiso 1 1 d . . . H42 H 0.1306(5) 1.1988(17) 0.8756(11) 0.020(3) Uiso 1 1 d . . . H61 H 0.0397(5) 0.9234(18) 0.7550(12) 0.024(3) Uiso 1 1 d . . . H62 H 0.0858(5) 0.9798(19) 0.7375(12) 0.024(3) Uiso 1 1 d . . . H9 H 0.1996(4) 0.7165(16) 0.8336(10) 0.014(3) Uiso 1 1 d . . . H101 H 0.1746(5) 0.5230(19) 0.9484(12) 0.025(4) Uiso 1 1 d . . . H102 H 0.2080(5) 0.6570(18) 1.0253(13) 0.026(4) Uiso 1 1 d . . . H111 H 0.0702(5) 0.7132(17) 0.9524(11) 0.016(3) Uiso 1 1 d . . . H112 H 0.0897(5) 0.5462(19) 0.9210(11) 0.023(3) Uiso 1 1 d . . . H121 H 0.2196(5) 0.9427(17) 0.9341(11) 0.020(3) Uiso 1 1 d . . . H122 H 0.1785(5) 1.0099(18) 0.8369(12) 0.021(3) Uiso 1 1 d . . . H131 H 0.0529(5) 1.1281(19) 1.0061(13) 0.027(4) Uiso 1 1 d . . . H132 H 0.0202(5) 0.9958(19) 0.9142(11) 0.023(3) Uiso 1 1 d . . . H151 H 0.2881(5) 1.0264(19) 1.2711(13) 0.028(4) Uiso 1 1 d . . . H152 H 0.2906(5) 1.1548(18) 1.1744(13) 0.027(4) Uiso 1 1 d . . . H153 H 0.2613(5) 1.2078(19) 1.2550(12) 0.029(4) Uiso 1 1 d . . . H171 H 0.0466(6) 0.247(2) 0.6637(15) 0.046(5) Uiso 1 1 d . . . H172 H 0.0313(5) 0.3967(18) 0.5755(12) 0.025(4) Uiso 1 1 d . . . H173 H 0.0029(6) 0.357(2) 0.6537(14) 0.039(4) Uiso 1 1 d . . . loop_ _atom_site_aniso_label _atom_site_aniso_U_11 _atom_site_aniso_U_22 _atom_site_aniso_U_33 _atom_site_aniso_U_23 _atom_site_aniso_U_13 _atom_site_aniso_U_12 O1 0.0213(4) 0.0224(4) 0.0146(4) -0.0007(3) 0.0049(3) 0.0002(3) O2 0.0240(4) 0.0227(4) 0.0169(4) -0.0020(3) 0.0076(3) -0.0007(3) O3 0.0216(4) 0.0142(4) 0.0285(4) 0.0019(3) 0.0004(3) -0.0014(3) O4 0.0162(4) 0.0144(4) 0.0180(4) -0.0007(3) -0.0030(3) -0.0003(3) O5 0.0201(4) 0.0218(4) 0.0182(4) -0.0026(3) -0.0006(3) 0.0020(3) O6 0.0261(4) 0.0131(4) 0.0192(4) -0.0015(3) 0.0001(3) -0.0026(3) C1 0.0179(5) 0.0133(5) 0.0127(4) 0.0029(4) 0.0024(4) 0.0007(4) C2 0.0108(4) 0.0156(5) 0.0132(4) 0.0018(4) 0.0004(3) 0.0021(4) C3 0.0133(5) 0.0128(4) 0.0134(4) 0.0003(4) 0.0022(4) 0.0004(3) C4 0.0156(5) 0.0135(5) 0.0176(5) 0.0012(4) 0.0015(4) 0.0025(4) C5 0.0153(5) 0.0126(5) 0.0144(5) 0.0011(4) 0.0007(4) 0.0034(4) C6 0.0172(5) 0.0131(5) 0.0139(5) 0.0006(4) 0.0026(4) 0.0030(4) C7 0.0149(5) 0.0125(4) 0.0128(4) 0.0003(3) 0.0026(4) 0.0004(4) C8 0.0175(5) 0.0104(4) 0.0150(5) 0.0014(4) 0.0046(4) 0.0007(4) C9 0.0135(5) 0.0161(5) 0.0168(5) -0.0011(4) 0.0051(4) 0.0029(4) C10 0.0188(5) 0.0152(5) 0.0180(5) 0.0022(4) 0.0026(4) 0.0053(4) C11 0.0167(5) 0.0142(5) 0.0133(5) 0.0010(4) 0.0035(4) -0.0012(4) C12 0.0146(5) 0.0171(5) 0.0158(5) -0.0013(4) 0.0048(4) -0.0016(4) C13 0.0172(5) 0.0221(5) 0.0191(5) -0.0020(4) 0.0032(4) 0.0038(4) C14 0.0142(5) 0.0153(5) 0.0146(5) 0.0000(4) 0.0039(4) 0.0011(4) C15 0.0163(5) 0.0195(5) 0.0198(5) -0.0057(4) -0.0012(4) -0.0010(4) C16 0.0163(5) 0.0162(5) 0.0140(5) -0.0002(4) 0.0057(4) -0.0008(4) C17 0.0329(7) 0.0180(6) 0.0212(6) -0.0051(4) 0.0027(5) -0.0065(5)
_geom_special_details ; All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. ; loop_ _geom_bond_atom_site_label_1 _geom_bond_atom_site_label_2 _geom_bond_distance _geom_bond_site_symmetry_2 _geom_bond_publ_flag O1 C2 1.2128(13) . ? O2 C8 1.2117(13) . ? O3 C14 1.2001(13) . ? O4 C14 1.3456(12) . ? O4 C15 1.4512(12) . ? O5 C16 1.2033(13) . ? O6 C16 1.3388(13) . ? O6 C17 1.4508(13) . ? C1 C2 1.5172(14) . ? C1 C10 1.5291(15) . ? C1 C11 1.5480(14) . ? C1 H1 0.977(14) . ? C2 C3 1.5434(14) . ? C3 C14 1.5347(14) . ? C3 C4 1.5591(14) . ? C3 C12 1.5620(14) . ? C4 C5 1.5095(14) . ? C4 H41 0.994(14) . ? C4 H42 1.007(14) . ? C5 C13 1.3308(16) . ? C5 C6 1.5093(14) . ? C6 C7 1.5728(14) . ? C6 H61 0.979(14) . ? C6 H62 0.980(15) . ? C7 C8 1.5386(14) . ? C7 C16 1.5440(14) . ? C7 C11 1.5511(13) . ? C8 C9 1.5158(14) . ? C9 C10 1.5301(14) . ? C9 C12 1.5426(14) . ? C9 H9 0.985(13) . ? C10 H101 0.960(15) . ? C10 H102 0.986(15) . ? C11 H111 0.962(14) . ? C11 H112 0.974(15) . ? C12 H121 0.983(14) . ? C12 H122 0.963(14) . ? C13 H131 0.959(15) . ? C13 H132 0.982(15) . ? C15 H151 0.975(15) . ? C15 H152 0.974(16) . ? C15 H153 0.998(15) . ? C17 H171 0.951(19) . ? C17 H172 0.963(15) . ? C17 H173 0.963(18) . ? loop_ _geom_angle_atom_site_label_1 _geom_angle_atom_site_label_2 _geom_angle_atom_site_label_3 _geom_angle _geom_angle_site_symmetry_1 _geom_angle_site_symmetry_3 _geom_angle_publ_flag C14 O4 C15 114.99(8) . . ? C16 O6 C17 114.85(9) . . ? C2 C1 C10 109.67(9) . . ? C2 C1 C11 114.95(8) . . ? C10 C1 C11 110.32(8) . . ? C2 C1 H1 103.8(8) . . ? C10 C1 H1 111.3(8) . . ? C11 C1 H1 106.7(8) . . ? O1 C2 C1 121.24(9) . . ? O1 C2 C3 119.48(9) . . ? C1 C2 C3 119.27(8) . . ? C14 C3 C2 109.60(8) . . ? C14 C3 C4 107.58(8) . . ? C2 C3 C4 105.93(8) . . ? C14 C3 C12 105.21(8) . . ? C2 C3 C12 115.36(8) . . ? C4 C3 C12 112.95(8) . . ? C5 C4 C3 113.70(8) . . ? C5 C4 H41 108.5(8) . . ? C3 C4 H41 107.5(8) . . ? C5 C4 H42 109.0(8) . . ? C3 C4 H42 109.2(8) . . ? H41 C4 H42 108.8(11) . . ? C13 C5 C6 120.63(10) . . ? C13 C5 C4 120.14(10) . . ? C6 C5 C4 119.23(9) . . ? C5 C6 C7 117.71(8) . . ? C5 C6 H61 106.8(8) . . ? C7 C6 H61 105.0(8) . . ? C5 C6 H62 110.7(9) . . ? C7 C6 H62 108.0(9) . . ? H61 C6 H62 108.2(11) . . ? C8 C7 C16 104.71(8) . . ? C8 C7 C11 111.57(8) . . ? C16 C7 C11 110.18(8) . . ? C8 C7 C6 108.53(8) . . ? C16 C7 C6 107.29(8) . . ? C11 C7 C6 114.06(8) . . ? O2 C8 C9 121.30(9) . . ? O2 C8 C7 120.56(9) . . ? C9 C8 C7 118.12(8) . . ? C8 C9 C10 108.76(8) . . ? C8 C9 C12 115.42(8) . . ? C10 C9 C12 110.47(8) . . ? C8 C9 H9 105.3(7) . . ? C10 C9 H9 111.5(7) . . ? C12 C9 H9 105.3(8) . . ? C1 C10 C9 108.75(8) . . ? C1 C10 H101 110.0(9) . . ? C9 C10 H101 110.6(9) . . ? C1 C10 H102 110.1(8) . . ? C9 C10 H102 108.5(9) . . ? H101 C10 H102 108.8(12) . . ? C1 C11 C7 116.06(8) . . ? C1 C11 H111 111.0(8) . . ? C7 C11 H111 109.1(8) . . ? C1 C11 H112 106.0(8) . . ? C7 C11 H112 107.5(8) . . ? H111 C11 H112 106.6(11) . . ? C9 C12 C3 117.55(8) . . ? C9 C12 H121 104.8(8) . . ? C3 C12 H121 107.4(8) . . ? C9 C12 H122 110.3(8) . . ? C3 C12 H122 109.2(8) . . ? H121 C12 H122 106.9(11) . . ? C5 C13 H131 122.7(9) . . ? C5 C13 H132 120.6(8) . . ? H131 C13 H132 116.7(12) . . ? O3 C14 O4 123.51(10) . . ? O3 C14 C3 124.94(9) . . ? O4 C14 C3 111.41(9) . . ? O4 C15 H151 104.2(9) . . ? O4 C15 H152 109.0(9) . . ? H151 C15 H152 110.9(12) . . ? O4 C15 H153 110.0(9) . . ? H151 C15 H153 112.0(12) . . ? H152 C15 H153 110.6(12) . . ? O5 C16 O6 123.37(10) . . ? O5 C16 C7 125.54(9) . . ? O6 C16 C7 111.08(8) . . ? O6 C17 H171 104.5(11) . . ? O6 C17 H172 110.3(9) . . ? H171 C17 H172 112.2(14) . . ? O6 C17 H173 110.3(10) . . ? H171 C17 H173 112.3(15) . . ? H172 C17 H173 107.3(13) . . ? loop_ _geom_torsion_atom_site_label_1 _geom_torsion_atom_site_label_2 _geom_torsion_atom_site_label_3 _geom_torsion_atom_site_label_4 _geom_torsion _geom_torsion_site_symmetry_1 _geom_torsion_site_symmetry_2 _geom_torsion_site_symmetry_3 _geom_torsion_site_symmetry_4 _geom_torsion_publ_flag C10 C1 C2 O1 -138.69(10) . . . . ? C11 C1 C2 O1 96.35(11) . . . . ? C10 C1 C2 C3 42.39(12) . . . . ? C11 C1 C2 C3 -82.56(11) . . . . ? O1 C2 C3 C14 43.87(12) . . . . ? C1 C2 C3 C14 -137.19(9) . . . . ? O1 C2 C3 C4 -71.91(11) . . . . ? C1 C2 C3 C4 107.03(10) . . . . ? O1 C2 C3 C12 162.35(9) . . . . ? C1 C2 C3 C12 -18.71(12) . . . . ? C14 C3 C4 C5 -159.06(9) . . . . ? C2 C3 C4 C5 -41.91(11) . . . . ? C12 C3 C4 C5 85.29(11) . . . . ? C3 C4 C5 C13 111.80(11) . . . . ? C3 C4 C5 C6 -69.19(12) . . . . ? C13 C5 C6 C7 -93.07(12) . . . . ? C4 C5 C6 C7 87.93(12) . . . . ? C5 C6 C7 C8 -103.72(10) . . . . ? C5 C6 C7 C16 143.65(9) . . . . ? C5 C6 C7 C11 21.34(13) . . . . ? C16 C7 C8 O2 20.62(12) . . . . ? C11 C7 C8 O2 139.79(10) . . . . ? C6 C7 C8 O2 -93.71(11) . . . . ? C16 C7 C8 C9 -157.55(8) . . . . ? C11 C7 C8 C9 -38.39(12) . . . . ? C6 C7 C8 C9 88.12(10) . . . . ? O2 C8 C9 C10 -125.47(10) . . . . ? C7 C8 C9 C10 52.69(11) . . . . ? O2 C8 C9 C12 109.75(11) . . . . ? C7 C8 C9 C12 -72.09(11) . . . . ? C2 C1 C10 C9 -64.99(10) . . . . ? C11 C1 C10 C9 62.59(11) . . . . ? C8 C9 C10 C1 -63.28(11) . . . . ? C12 C9 C10 C1 64.36(11) . . . . ? C2 C1 C11 C7 75.03(11) . . . . ? C10 C1 C11 C7 -49.59(12) . . . . ? C8 C7 C11 C1 35.98(12) . . . . ? C16 C7 C11 C1 151.84(9) . . . . ? C6 C7 C11 C1 -87.45(11) . . . . ? C8 C9 C12 C3 83.57(11) . . . . ? C10 C9 C12 C3 -40.32(12) . . . . ? C14 C3 C12 C9 138.27(9) . . . . ? C2 C3 C12 C9 17.38(12) . . . . ? C4 C3 C12 C9 -104.67(10) . . . . ? C15 O4 C14 O3 0.68(15) . . . . ? C15 O4 C14 C3 176.55(8) . . . . ? C2 C3 C14 O3 -139.96(11) . . . . ? C4 C3 C14 O3 -25.23(14) . . . . ? C12 C3 C14 O3 95.44(12) . . . . ? C2 C3 C14 O4 44.25(11) . . . . ? C4 C3 C14 O4 158.98(8) . . . . ? C12 C3 C14 O4 -80.35(10) . . . . ? C17 O6 C16 O5 3.65(15) . . . . ? C17 O6 C16 C7 -174.89(9) . . . . ? C8 C7 C16 O5 -110.04(11) . . . . ? C11 C7 C16 O5 129.87(11) . . . . ? C6 C7 C16 O5 5.16(14) . . . . ? C8 C7 C16 O6 68.46(10) . . . . ? C11 C7 C16 O6 -51.64(11) . . . . ? C6 C7 C16 O6 -176.34(8) . . . . ?
_diffrn_measured_fraction_theta_max 0.998 _diffrn_reflns_theta_full 27.53 _diffrn_measured_fraction_theta_full 0.998 _refine_diff_density_max 0.411 _refine_diff_density_min -0.176 _refine_diff_density_rms 0.044 data_bishoprt
_audit_creation_method SHELXL-97 _chemical_name_systematic ; 3,7-Bis(methoxycarbonyl)-5-methylenetricyclo [5.3.1.1^3,9^]-dodecane-2,8-dione ; _chemical_name_common ? _chemical_melting_point ? _chemical_formula_moiety ? _chemical_formula_sum 'C17 H20 O6' _chemical_formula_weight 320.33 loop_ _atom_type_symbol _atom_type_description _atom_type_scat_dispersion_real _atom_type_scat_dispersion_imag _atom_type_scat_source 'C' 'C' 0.0033 0.0016 'International Tables Vol C Tables 4.2.6.8 and 6.1.1.4' 'H' 'H' 0.0000 0.0000 'International Tables Vol C Tables 4.2.6.8 and 6.1.1.4' 'O' 'O' 0.0106 0.0060 'International Tables Vol C Tables 4.2.6.8 and 6.1.1.4'
_symmetry_cell_setting monoclinic _symmetry_space_group_name_H-M C_1_2/c_1 loop_ _symmetry_equiv_pos_as_xyz 'x, y, z' '-x, y, -z+1/2' 'x+1/2, y+1/2, z' '-x+1/2, y+1/2, -z+1/2' '-x, -y, -z' 'x, -y, z-1/2' '-x+1/2, -y+1/2, -z' 'x+1/2, -y+1/2, z-1/2'
_cell_length_a 31.8644(15) _cell_length_b 7.9242(4) _cell_length_c 12.7065(6) _cell_angle_alpha 90.00 _cell_angle_beta 109.143(1) _cell_angle_gamma 90.00 _cell_volume 3031.0(3) _cell_formula_units_Z 8 _cell_measurement_temperature 300 _cell_measurement_reflns_used 6863 _cell_measurement_theta_min 2.7 _cell_measurement_theta_max 27.3
_exptl_crystal_description plate _exptl_crystal_colour colorless _exptl_crystal_size_max 0.35 _exptl_crystal_size_mid 0.30 _exptl_crystal_size_min 0.15 _exptl_crystal_density_meas ? _exptl_crystal_density_diffrn 1.404 _exptl_crystal_density_method 'not measured' _exptl_crystal_F_000 1360 _exptl_absorpt_coefficient_mu 0.106 _exptl_absorpt_correction_type multi_scan _exptl_absorpt_correction_T_min 0.84 _exptl_absorpt_correction_T_max 1.00 _exptl_absorpt_process_details 'SADABS (Sheldrick, 2002)'
_exptl_special_details ; The data collection covered over a full sphere of reciprocal space by a combination of four sets of exposures; each set had a different \f angle (0, 90, 180 and 270\%) for the crystal and each exposure of 10s covered 0.3\% in \w. The crystal-to-detector distance was 4 cm and the detector swing angle was -32\%. Crystal decay was monitored by repeating the measurement of the initial 50 frames at the end of data collection and analyzing the duplicate reflections. ;
_diffrn_ambient_temperature 300 _diffrn_radiation_wavelength 0.71073 _diffrn_radiation_type MoK\a _diffrn_radiation_source 'fine-focus sealed tube' _diffrn_radiation_monochromator graphite _diffrn_measurement_device_type 'Bruker SMART 1000 CCD diffractometer' _diffrn_measurement_method \w_scan _diffrn_detector_area_resol_mean 8.192 _diffrn_standards_number ? _diffrn_standards_interval_count ? _diffrn_standards_interval_time ? _diffrn_standards_decay_% 0 _diffrn_reflns_number 19426 _diffrn_reflns_av_R_equivalents 0.0165 _diffrn_reflns_av_sigmaI/netI 0.0154 _diffrn_reflns_limit_h_min -41 _diffrn_reflns_limit_h_max 41 _diffrn_reflns_limit_k_min -10 _diffrn_reflns_limit_k_max 10 _diffrn_reflns_limit_l_min -16 _diffrn_reflns_limit_l_max 16 _diffrn_reflns_theta_min 2.66 _diffrn_reflns_theta_max 27.53 _reflns_number_total 3503 _reflns_number_gt 2750 _reflns_threshold_expression >2sigma(I)
_computing_data_collection 'SMART (Bruker, 1998)' _computing_cell_refinement 'SAINT (Bruker, 1998)' _computing_data_reduction SAINT _computing_structure_solution 'SHELXS-97 (Sheldrick, 1990)' _computing_structure_refinement 'SHELXL-97 (Sheldrick, 1997)' _computing_molecular_graphics 'SHELXTL (Bruker, 2000)' _computing_publication_material SHELXTL
_refine_special_details ; Refinement of F^2^ against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F^2^, conventional R-factors R are based on F, with F set to zero for negative F^2^. The threshold expression of F^2^ > 2sigma(F^2^) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F^2^ are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. ;
_refine_ls_structure_factor_coef Fsqd _refine_ls_matrix_type full _refine_ls_weighting_scheme calc _refine_ls_weighting_details 'calc w=1/[\s^2^(Fo^2^)+(0.0602P)^2^+0.6598P] where P=(Fo^2^+2Fc^2^)/3' _atom_sites_solution_primary direct _atom_sites_solution_secondary ? _atom_sites_solution_hydrogens difmap _refine_ls_hydrogen_treatment refall _refine_ls_extinction_method none _refine_ls_extinction_coef ? _refine_ls_number_reflns 3503 _refine_ls_number_parameters 288 _refine_ls_number_restraints 0 _refine_ls_R_factor_all 0.0472 _refine_ls_R_factor_gt 0.0371 _refine_ls_wR_factor_ref 0.1096 _refine_ls_wR_factor_gt 0.1039 _refine_ls_goodness_of_fit_ref 1.069 _refine_ls_restrained_S_all 1.069 _refine_ls_shift/su_max 0.001 _refine_ls_shift/su_mean 0.000 loop_ _atom_site_label _atom_site_type_symbol _atom_site_fract_x _atom_site_fract_y _atom_site_fract_z _atom_site_U_iso_or_equiv _atom_site_adp_type _atom_site_occupancy _atom_site_symmetry_multiplicity _atom_site_calc_flag _atom_site_refinement_flags _atom_site_disorder_assembly _atom_site_disorder_group O1 O 0.14501(3) 0.91270(14) 1.14293(7) 0.0501(3) Uani 1 1 d . . . O2 O 0.12882(4) 0.68135(15) 0.68234(8) 0.0569(3) Uani 1 1 d . . . O3 O 0.20558(4) 1.26181(13) 1.05933(10) 0.0619(3) Uani 1 1 d . . . O4 O 0.23285(3) 1.01950(12) 1.14140(8) 0.0467(3) Uani 1 1 d . . . O5 O 0.02203(4) 0.67900(14) 0.64700(9) 0.0613(3) Uani 1 1 d . . . O6 O 0.06363(4) 0.46191(12) 0.73228(8) 0.0525(3) Uani 1 1 d . . . C1 C 0.14105(4) 0.69295(16) 1.01273(10) 0.0364(3) Uani 1 1 d . . . C2 C 0.15016(4) 0.87140(16) 1.05640(9) 0.0331(3) Uani 1 1 d . . . C3 C 0.16565(4) 1.00365(15) 0.98804(10) 0.0325(3) Uani 1 1 d . . . C4 C 0.12509(4) 1.12090(17) 0.93412(12) 0.0414(3) Uani 1 1 d . . . C5 C 0.08119(4) 1.03082(16) 0.89069(10) 0.0369(3) Uani 1 1 d . . . C6 C 0.07202(5) 0.92062(17) 0.78935(11) 0.0407(3) Uani 1 1 d . . . C7 C 0.08823(4) 0.73238(15) 0.80674(9) 0.0326(3) Uani 1 1 d . . . C8 C 0.13080(4) 0.71786(15) 0.77634(10) 0.0350(3) Uani 1 1 d . . . C9 C 0.17488(4) 0.74455(16) 0.86599(11) 0.0379(3) Uani 1 1 d . . . C10 C 0.17718(5) 0.63580(18) 0.96669(12) 0.0449(3) Uani 1 1 d . . . C11 C 0.09476(4) 0.66410(17) 0.92530(10) 0.0361(3) Uani 1 1 d . . . C12 C 0.18595(4) 0.92889(18) 0.90197(11) 0.0387(3) Uani 1 1 d . . . C13 C 0.05080(5) 1.0527(2) 0.93944(14) 0.0546(4) Uani 1 1 d . . . C14 C 0.20250(4) 1.11273(16) 1.06653(10) 0.0363(3) Uani 1 1 d . . . C15 C 0.26980(5) 1.1113(2) 1.21657(15) 0.0536(4) Uani 1 1 d . . . C16 C 0.05354(4) 0.62552(16) 0.71934(10) 0.0381(3) Uani 1 1 d . . . C17 C 0.03509(8) 0.3496(3) 0.65005(17) 0.0664(5) Uani 1 1 d . . . H1 H 0.1413(5) 0.6269(19) 1.0764(13) 0.045(4) Uiso 1 1 d . . . H41 H 0.1232(6) 1.200(2) 0.9902(15) 0.059(5) Uiso 1 1 d . . . H42 H 0.1302(5) 1.183(2) 0.8718(14) 0.052(4) Uiso 1 1 d . . . H61 H 0.0402(6) 0.909(2) 0.7582(14) 0.058(5) Uiso 1 1 d . . . H62 H 0.0839(6) 0.976(2) 0.7320(15) 0.061(5) Uiso 1 1 d . . . H9 H 0.1971(5) 0.7110(19) 0.8326(12) 0.043(4) Uiso 1 1 d . . . H101 H 0.1723(5) 0.519(2) 0.9443(14) 0.054(4) Uiso 1 1 d . . . H102 H 0.2065(5) 0.6470(19) 1.0258(14) 0.050(4) Uiso 1 1 d . . . H111 H 0.0720(5) 0.7047(18) 0.9509(11) 0.037(4) Uiso 1 1 d . . . H112 H 0.0910(5) 0.544(2) 0.9184(12) 0.043(4) Uiso 1 1 d . . . H121 H 0.2186(6) 0.9309(19) 0.9370(13) 0.053(4) Uiso 1 1 d . . . H122 H 0.1788(5) 1.001(2) 0.8368(14) 0.051(4) Uiso 1 1 d . . . H131 H 0.0563(6) 1.123(2) 1.0054(17) 0.074(6) Uiso 1 1 d . . . H132 H 0.0222(7) 0.994(2) 0.9155(15) 0.068(5) Uiso 1 1 d . . . H151 H 0.2870(7) 1.029(3) 1.2716(17) 0.074(6) Uiso 1 1 d . . . H152 H 0.2885(8) 1.159(3) 1.1760(19) 0.089(7) Uiso 1 1 d . . . H153 H 0.2585(6) 1.199(2) 1.2501(16) 0.071(5) Uiso 1 1 d . . . H171 H 0.0503(10) 0.248(4) 0.665(2) 0.133(11) Uiso 1 1 d . . . H172 H 0.0306(7) 0.391(2) 0.5806(18) 0.074(6) Uiso 1 1 d . . . H173 H 0.0056(10) 0.347(3) 0.655(2) 0.122(10) Uiso 1 1 d . . . loop_ _atom_site_aniso_label _atom_site_aniso_U_11 _atom_site_aniso_U_22 _atom_site_aniso_U_33 _atom_site_aniso_U_23 _atom_site_aniso_U_13 _atom_site_aniso_U_12 O1 0.0599(6) 0.0592(6) 0.0310(5) -0.0049(4) 0.0149(4) -0.0033(5) O2 0.0640(7) 0.0733(7) 0.0365(5) -0.0102(5) 0.0206(5) -0.0096(6) O3 0.0566(7) 0.0341(5) 0.0756(8) 0.0056(5) -0.0048(5) -0.0048(5) O4 0.0421(5) 0.0373(5) 0.0432(5) -0.0031(4) -0.0099(4) 0.0000(4) O5 0.0553(6) 0.0582(7) 0.0484(6) -0.0110(5) -0.0128(5) 0.0070(5) O6 0.0649(7) 0.0345(5) 0.0449(6) -0.0043(4) 0.0002(5) -0.0073(4) C1 0.0430(7) 0.0344(6) 0.0267(6) 0.0087(5) 0.0046(5) 0.0012(5) C2 0.0290(6) 0.0394(6) 0.0257(5) 0.0025(5) 0.0019(4) 0.0031(5) C3 0.0326(6) 0.0315(6) 0.0284(6) 0.0017(5) 0.0031(5) 0.0023(5) C4 0.0387(7) 0.0341(7) 0.0423(7) 0.0028(6) 0.0009(5) 0.0067(5) C5 0.0344(6) 0.0344(6) 0.0337(6) -0.0003(5) 0.0001(5) 0.0110(5) C6 0.0443(7) 0.0364(7) 0.0320(6) -0.0001(5) -0.0001(6) 0.0103(6) C7 0.0353(6) 0.0311(6) 0.0270(6) 0.0005(4) 0.0039(5) 0.0015(5) C8 0.0447(7) 0.0283(6) 0.0316(6) 0.0003(5) 0.0119(5) 0.0006(5) C9 0.0344(6) 0.0413(7) 0.0388(7) -0.0024(5) 0.0131(5) 0.0085(5) C10 0.0453(8) 0.0376(7) 0.0441(7) 0.0063(6) 0.0041(6) 0.0148(6) C11 0.0398(7) 0.0362(7) 0.0297(6) 0.0020(5) 0.0080(5) -0.0034(5) C12 0.0350(7) 0.0461(7) 0.0342(6) -0.0028(6) 0.0101(5) -0.0046(6) C13 0.0412(8) 0.0650(10) 0.0523(9) -0.0109(8) 0.0083(7) 0.0133(7) C14 0.0357(6) 0.0339(6) 0.0348(6) -0.0004(5) 0.0054(5) 0.0009(5) C15 0.0430(8) 0.0526(9) 0.0493(8) -0.0183(7) -0.0063(7) 0.0003(7) C16 0.0403(7) 0.0407(7) 0.0306(6) -0.0018(5) 0.0077(5) -0.0011(5) C17 0.0888(15) 0.0503(10) 0.0498(10) -0.0150(8) 0.0085(9) -0.0212(10)
_geom_special_details ; All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. ; loop_ _geom_bond_atom_site_label_1 _geom_bond_atom_site_label_2 _geom_bond_distance _geom_bond_site_symmetry_2 _geom_bond_publ_flag O1 C2 1.2088(15) . ? O2 C8 1.2103(15) . ? O3 C14 1.1914(16) . ? O4 C14 1.3351(15) . ? O4 C15 1.4457(16) . ? O5 C16 1.1948(16) . ? O6 C16 1.3328(16) . ? O6 C17 1.4447(19) . ? C1 C2 1.5120(18) . ? C1 C10 1.521(2) . ? C1 C11 1.5452(18) . ? C1 H1 0.961(16) . ? C2 C3 1.5420(17) . ? C3 C14 1.5338(17) . ? C3 C4 1.5565(17) . ? C3 C12 1.5585(18) . ? C4 C5 1.5046(19) . ? C4 H41 0.967(18) . ? C4 H42 0.990(17) . ? C5 C13 1.321(2) . ? C5 C6 1.5031(18) . ? C6 C7 1.5704(17) . ? C6 H61 0.964(17) . ? C6 H62 1.023(19) . ? C7 C8 1.5318(18) . ? C7 C16 1.5384(17) . ? C7 C11 1.5492(16) . ? C8 C9 1.5052(18) . ? C9 C10 1.5243(19) . ? C9 C12 1.5367(19) . ? C9 H9 0.975(15) . ? C10 H101 0.967(18) . ? C10 H102 0.991(16) . ? C11 H111 0.943(15) . ? C11 H112 0.963(16) . ? C12 H121 0.989(17) . ? C12 H122 0.971(17) . ? C13 H131 0.97(2) . ? C13 H132 0.98(2) . ? C15 H151 0.98(2) . ? C15 H152 0.98(2) . ? C15 H153 0.95(2) . ? C17 H171 0.93(3) . ? C17 H172 0.91(2) . ? C17 H173 0.96(3) . ? loop_ _geom_angle_atom_site_label_1 _geom_angle_atom_site_label_2 _geom_angle_atom_site_label_3 _geom_angle _geom_angle_site_symmetry_1 _geom_angle_site_symmetry_3 _geom_angle_publ_flag C14 O4 C15 115.80(11) . . ? C16 O6 C17 116.15(13) . . ? C2 C1 C10 109.95(11) . . ? C2 C1 C11 115.17(10) . . ? C10 C1 C11 110.11(11) . . ? C2 C1 H1 104.6(9) . . ? C10 C1 H1 111.2(9) . . ? C11 C1 H1 105.5(9) . . ? O1 C2 C1 121.34(12) . . ? O1 C2 C3 119.50(12) . . ? C1 C2 C3 119.15(10) . . ? C14 C3 C2 109.57(9) . . ? C14 C3 C4 107.34(10) . . ? C2 C3 C4 106.30(10) . . ? C14 C3 C12 105.37(10) . . ? C2 C3 C12 114.84(10) . . ? C4 C3 C12 113.19(10) . . ? C5 C4 C3 114.59(11) . . ? C5 C4 H41 107.7(10) . . ? C3 C4 H41 107.8(10) . . ? C5 C4 H42 108.6(9) . . ? C3 C4 H42 108.6(9) . . ? H41 C4 H42 109.4(13) . . ? C13 C5 C6 120.76(14) . . ? C13 C5 C4 120.13(13) . . ? C6 C5 C4 119.08(12) . . ? C5 C6 C7 117.95(10) . . ? C5 C6 H61 106.9(10) . . ? C7 C6 H61 102.7(10) . . ? C5 C6 H62 110.4(10) . . ? C7 C6 H62 109.0(10) . . ? H61 C6 H62 109.5(14) . . ? C8 C7 C16 105.23(10) . . ? C8 C7 C11 111.80(10) . . ? C16 C7 C11 110.20(10) . . ? C8 C7 C6 108.27(10) . . ? C16 C7 C6 107.21(10) . . ? C11 C7 C6 113.68(10) . . ? O2 C8 C9 120.94(12) . . ? O2 C8 C7 120.19(12) . . ? C9 C8 C7 118.84(10) . . ? C8 C9 C10 109.39(11) . . ? C8 C9 C12 115.14(10) . . ? C10 C9 C12 110.15(11) . . ? C8 C9 H9 105.3(9) . . ? C10 C9 H9 111.7(9) . . ? C12 C9 H9 105.1(9) . . ? C1 C10 C9 108.68(10) . . ? C1 C10 H101 109.2(10) . . ? C9 C10 H101 109.7(10) . . ? C1 C10 H102 109.0(9) . . ? C9 C10 H102 111.1(9) . . ? H101 C10 H102 109.2(13) . . ? C1 C11 C7 116.08(10) . . ? C1 C11 H111 111.2(9) . . ? C7 C11 H111 110.0(8) . . ? C1 C11 H112 105.8(9) . . ? C7 C11 H112 106.5(9) . . ? H111 C11 H112 106.5(12) . . ? C9 C12 C3 117.55(11) . . ? C9 C12 H121 104.7(9) . . ? C3 C12 H121 107.2(9) . . ? C9 C12 H122 110.0(10) . . ? C3 C12 H122 109.8(9) . . ? H121 C12 H122 107.0(13) . . ? C5 C13 H131 121.7(12) . . ? C5 C13 H132 122.9(11) . . ? H131 C13 H132 115.3(16) . . ? O3 C14 O4 123.01(12) . . ? O3 C14 C3 125.00(12) . . ? O4 C14 C3 111.88(10) . . ? O4 C15 H151 106.3(12) . . ? O4 C15 H152 110.4(13) . . ? H151 C15 H152 109.7(17) . . ? O4 C15 H153 108.5(12) . . ? H151 C15 H153 111.8(16) . . ? H152 C15 H153 110.0(16) . . ? O5 C16 O6 123.21(12) . . ? O5 C16 C7 125.71(12) . . ? O6 C16 C7 111.05(10) . . ? O6 C17 H171 102.7(19) . . ? O6 C17 H172 110.0(13) . . ? H171 C17 H172 115(2) . . ? O6 C17 H173 111.4(17) . . ? H171 C17 H173 115(3) . . ? H172 C17 H173 103(2) . . ? loop_ _geom_torsion_atom_site_label_1 _geom_torsion_atom_site_label_2 _geom_torsion_atom_site_label_3 _geom_torsion_atom_site_label_4 _geom_torsion _geom_torsion_site_symmetry_1 _geom_torsion_site_symmetry_2 _geom_torsion_site_symmetry_3 _geom_torsion_site_symmetry_4 _geom_torsion_publ_flag C10 C1 C2 O1 -138.19(12) . . . . ? C11 C1 C2 O1 96.72(14) . . . . ? C10 C1 C2 C3 42.73(14) . . . . ? C11 C1 C2 C3 -82.36(14) . . . . ? O1 C2 C3 C14 42.40(15) . . . . ? C1 C2 C3 C14 -138.51(11) . . . . ? O1 C2 C3 C4 -73.29(14) . . . . ? C1 C2 C3 C4 105.81(12) . . . . ? O1 C2 C3 C12 160.73(11) . . . . ? C1 C2 C3 C12 -20.17(15) . . . . ? C14 C3 C4 C5 -157.71(11) . . . . ? C2 C3 C4 C5 -40.53(15) . . . . ? C12 C3 C4 C5 86.45(14) . . . . ? C3 C4 C5 C13 111.94(15) . . . . ? C3 C4 C5 C6 -70.00(15) . . . . ? C13 C5 C6 C7 -95.83(16) . . . . ? C4 C5 C6 C7 86.13(16) . . . . ? C5 C6 C7 C8 -101.91(14) . . . . ? C5 C6 C7 C16 145.02(12) . . . . ? C5 C6 C7 C11 22.97(17) . . . . ? C16 C7 C8 O2 22.83(15) . . . . ? C11 C7 C8 O2 142.46(12) . . . . ? C6 C7 C8 O2 -91.55(14) . . . . ? C16 C7 C8 C9 -155.33(11) . . . . ? C11 C7 C8 C9 -35.71(15) . . . . ? C6 C7 C8 C9 90.28(12) . . . . ? O2 C8 C9 C10 -127.73(13) . . . . ? C7 C8 C9 C10 50.42(14) . . . . ? O2 C8 C9 C12 107.62(14) . . . . ? C7 C8 C9 C12 -74.23(14) . . . . ? C2 C1 C10 C9 -64.79(14) . . . . ? C11 C1 C10 C9 63.15(14) . . . . ? C8 C9 C10 C1 -62.73(14) . . . . ? C12 C9 C10 C1 64.78(14) . . . . ? C2 C1 C11 C7 75.16(14) . . . . ? C10 C1 C11 C7 -49.84(15) . . . . ? C8 C7 C11 C1 34.60(15) . . . . ? C16 C7 C11 C1 151.26(11) . . . . ? C6 C7 C11 C1 -88.36(14) . . . . ? C8 C9 C12 C3 82.05(14) . . . . ? C10 C9 C12 C3 -42.20(15) . . . . ? C14 C3 C12 C9 140.39(11) . . . . ? C2 C3 C12 C9 19.72(16) . . . . ? C4 C3 C12 C9 -102.61(13) . . . . ? C15 O4 C14 O3 1.5(2) . . . . ? C15 O4 C14 C3 177.85(12) . . . . ? C2 C3 C14 O3 -138.12(14) . . . . ? C4 C3 C14 O3 -23.09(18) . . . . ? C12 C3 C14 O3 97.82(16) . . . . ? C2 C3 C14 O4 45.63(14) . . . . ? C4 C3 C14 O4 160.65(11) . . . . ? C12 C3 C14 O4 -78.44(13) . . . . ? C17 O6 C16 O5 2.6(2) . . . . ? C17 O6 C16 C7 -175.86(14) . . . . ? C8 C7 C16 O5 -110.13(15) . . . . ? C11 C7 C16 O5 129.19(14) . . . . ? C6 C7 C16 O5 4.98(18) . . . . ? C8 C7 C16 O6 68.23(13) . . . . ? C11 C7 C16 O6 -52.45(14) . . . . ? C6 C7 C16 O6 -176.65(11) . . . . ?
_diffrn_measured_fraction_theta_max 0.999 _diffrn_reflns_theta_full 27.53 _diffrn_measured_fraction_theta_full 0.999 _refine_diff_density_max 0.273 _refine_diff_density_min -0.131 _refine_diff_density_rms 0.035 data_drb156 _audit_creation_method 'RAELSPUB and manual entry'
# SUBMISSION DETAILS
_publ_contact_author_name ? _publ_contact_author_address ? _publ_contact_author_email ? _publ_contact_letter ? _publ_requested_journal ? _publ_requested_category ?
# TITLE AND AUTHOR LIST
_publ_section_title ? _publ_section_title_footnote ? loop_ _publ_author_name _publ_author_footnote _publ_author_address ? ? ?
# TEXT
_publ_section_abstract ? _publ_section_comment ? _publ_section_acknowledgements ? _publ_section_references
; Altomare, A., Burla, M.C., Camalli, M., Cascarano, G.,Giacovazzo, C., Guagliardi, A., Polidori, G., J. Appl. Cryst., 1994, 27, 435.
Ibers, J.A. and Hamilton, W.C., (Eds) International Tables for X-Ray Crystallography Vol. 4 , Kynoch Press, Birmingham, 1974.
Johnson, C.K.,'ORTEP-II', Oak Ridge National Laboratory, Tennessee, U.S.A., 1976.
Rae, A.D., RAELS. A comprehensive Constrained Least Squares Refinement Program, University of New South Wales, 1996.
Schagen, J.D., Straver, L., van Meurs, F., Williams, G., CAD4 Version 5.0, Delft Instruments X-ray Diffraction, 1989. ;
_publ_section_figure_captions ? _publ_section_exptl_prep ? _publ_section_exptl_refinement ? _computing_data_collection 'CAD4 Version 5.0, (Schagen et al, 1989)' _computing_cell_refinement 'CAD4 Version 5.0, (Schagen et al, 1989)' _computing_data_reduction 'Local program' _computing_structure_solution 'SIR92 (Altomare et al, 1994)' _computing_structure_refinement 'RAELS, (Rae, 1996)' _computing_molecular_graphics 'ORTEP-II, (Johnson, 1976)' _computing_publication_material 'Local programs'
# CHEMICAL DATA
_chemical_name_systematic ? _chemical_formula_moiety ? _chemical_formula_sum 'C15 H18 N4 O3' _chemical_formula_iupac ? _chemical_formula_weight 302.3 _chemical_absolute_configuration ?
# CRYSTAL DATA
_space_group_crystal_system triclinic _space_group_name_H-M_alt 'P -1' loop_ _space_group_symop_id _space_group_symop_operation_xyz 1 x,y,z 2 -x,-y,-z
_cell_length_a 6.478(1) _cell_length_b 8.157(1) _cell_length_c 14.812(2) _cell_angle_alpha 85.412(9) _cell_angle_beta 88.369(8) _cell_angle_gamma 67.089(11) _cell_volume 718.6(2) _cell_formula_units_Z 2 _cell_measurement_reflns_used 10 _cell_measurement_theta_min 20 _cell_measurement_theta_max 25 _cell_measurement_temperature 294 _exptl_crystal_description irregular _exptl_crystal_colour colourless _exptl_crystal_size_max ? _exptl_crystal_size_mid ? _exptl_crystal_size_min ? _exptl_crystal_size_rad 0.15 _exptl_crystal_density_diffrn 1.40 _exptl_crystal_density_meas ? _exptl_crystal_density_method 'not measured' _exptl_crystal_F_000 320.0 _exptl_absorpt_coefficient_mu 0.819 _exptl_absorpt_correction_type none _exptl_absorpt_process_details ? _exptl_absorpt_correction_T_min ? _exptl_absorpt_correction_T_max ?
# EXPERIMENTAL DATA
_diffrn_radiation_probe x-ray _diffrn_radiation_type 'Cu K\a' _diffrn_radiation_wavelength 1.54184 _diffrn_measurement_device_type 'Nonius CAD-4' _diffrn_measurement_method \w--2\q _diffrn_reflns_number 2695 _diffrn_reflns_av_R_equivalents ? _diffrn_reflns_theta_max 70 _diffrn_measured_fraction_theta_max 1.00 _diffrn_reflns_theta_full 70 _diffrn_measured_fraction_theta_full 1.00 _diffrn_reflns_limit_h_min -7 _diffrn_reflns_limit_h_max 7 _diffrn_reflns_limit_k_min -9 _diffrn_reflns_limit_k_max 9 _diffrn_reflns_limit_l_min -18 _diffrn_reflns_limit_l_max 18 _diffrn_standards_number 1 _diffrn_standards_interval_time 30 _diffrn_standards_decay_% 0
# REFINEMENT DATA
_refine_special_details ? _reflns_number_total 2695 _reflns_number_gt 2365 _reflns_threshold_expression I>2\s(I) _refine_ls_structure_factor_coef F _refine_ls_R_factor_gt 0.045 _refine_ls_wR_factor_ref 0.089 _refine_ls_abs_structure_details _refine_ls_abs_structure_Flack ? _refine_ls_hydrogen_treatment noref _refine_ls_number_reflns 2365 _refine_ls_number_parameters 200 _refine_ls_goodness_of_fit_ref 1.63 _refine_ls_weighting_scheme calc _refine_ls_weighting_details 'w = 1/[\s^2^(F) + 0.0004F^2^]' _refine_ls_shift/su_max 0.003 _refine_diff_density_max 0.34 _refine_diff_density_min -0.22 _refine_ls_extinction_method none _refine_ls_extinction_coef ? _atom_type_scat_source 'International Tables for X-ray Crystallography, Vol. IV'
# ATOMIC COORDINATES AND DISPLACEMENT PARAMETERS loop_ _atom_site_label _atom_site_fract_x _atom_site_fract_y _atom_site_fract_z _atom_site_U_iso_or_equiv _atom_site_adp_type _atom_site_type_symbol _atom_site_occupancy O1 0.2514(2) 0.7919(2) 0.4384(1) 0.0547(4) Uani O 1.0 O2 0.52057(28) 0.21558(20) -0.00821(9) 0.0554(5) Uani O 1.0 N1 0.7575(3) 0.6072(2) 0.3265(1) 0.0466(4) Uani N 1.0 N2 0.6047(3) 0.7258(2) 0.3836(1) 0.0445(4) Uani N 1.0 N3 0.3972(3) 0.0850(2) 0.2088(1) 0.0454(4) Uani N 1.0 N4 0.4022(3) 0.0817(2) 0.1133(1) 0.0448(4) Uani N 1.0 C1 0.7516(3) 0.2115(3) 0.3103(1) 0.0471(5) Uani C 1.0 C2 0.7756(3) 0.3580(3) 0.2444(1) 0.0422(5) Uani C 1.0 C3 0.6519(3) 0.5264(2) 0.2887(1) 0.0358(4) Uani C 1.0 C4 0.4109(3) 0.5823(2) 0.3178(1) 0.0327(4) Uani C 1.0 C5 0.3649(3) 0.4205(2) 0.3612(1) 0.0390(4) Uani C 1.0 C6 0.5016(3) 0.2421(2) 0.3198(1) 0.0397(4) Uani C 1.0 C7 0.4370(3) 0.2211(2) 0.2270(1) 0.0355(4) Uani C 1.0 C8 0.4733(3) 0.3267(2) 0.1447(1) 0.0344(4) Uani C 1.0 C9 0.6970(3) 0.3513(3) 0.1481(1) 0.0420(5) Uani C 1.0 C10 0.2364(3) 0.7009(2) 0.2481(1) 0.0407(5) Uani C 1.0 C11 0.1747(3) 0.6505(2) 0.1653(1) 0.0399(4) Uani C 1.0 C12 0.2666(3) 0.4970(2) 0.1200(1) 0.0414(5) Uani C 1.0 C13 -0.0245(4) 0.7970(3) 0.1192(2) 0.0678(7) Uani C 1.0 C14 0.4063(3) 0.7115(2) 0.3883(1) 0.0379(4) Uani C 1.0 C15 0.4741(3) 0.2025(2) 0.0724(1) 0.0386(4) Uani C 1.0 OW 0.1914(3) 1.1246(2) 0.5054(1) 0.0587(5) Uani O 1.0 HN2 0.6409 0.8126 0.4174 0.045 Uani H 1.0 HN4 0.3573 -0.0013 0.0801 0.045 Uani H 1.0 H1C1 0.8131 0.2156 0.3709 0.047 Uani H 1.0 H2C1 0.8364 0.0922 0.2866 0.047 Uani H 1.0 HC2 0.9376 0.3391 0.2415 0.042 Uani H 1.0 H1C5 0.2021 0.4463 0.3535 0.039 Uani H 1.0 H2C5 0.4019 0.4065 0.4272 0.039 Uani H 1.0 HC6 0.4903 0.1431 0.3614 0.040 Uani H 1.0 H1C9 0.6791 0.4657 0.1126 0.042 Uani H 1.0 H2C9 0.8151 0.2494 0.1194 0.042 Uani H 1.0 H1C10 0.2860 0.8001 0.2289 0.041 Uani H 1.0 H2C10 0.0935 0.7490 0.2830 0.041 Uani H 1.0 HC12 0.1873 0.4968 0.0631 0.041 Uani H 1.0 H1C13 -0.0600 0.7551 0.0622 0.068 Uani H 1.0 H2C13 -0.1567 0.8283 0.1606 0.068 Uani H 1.0 H3C13 0.0114 0.9048 0.1042 0.068 Uani H 1.0 H1OW 0.2311 1.0062 0.4799 0.059 Uani H 1.0 H2OW 0.0336 1.1679 0.5279 0.059 Uani H 1.0 loop_ _atom_site_aniso_label _atom_site_aniso_U_11 _atom_site_aniso_U_22 _atom_site_aniso_U_33 _atom_site_aniso_U_12 _atom_site_aniso_U_13 _atom_site_aniso_U_23 _atom_site_aniso_type_symbol O1 0.0467(8) 0.0599(9) 0.0643(9) -0.0225(7) 0.0129(6) -0.0381(7) O O2 0.086(1) 0.0524(8) 0.0353(7) -0.0326(8) 0.0049(7) -0.0159(6) O N1 0.0380(8) 0.057(1) 0.052(1) -0.0223(7) 0.0051(7) -0.0231(8) N N2 0.0427(9) 0.0488(9) 0.0496(9) -0.0229(7) 0.0021(7) -0.0214(7) N N3 0.058(1) 0.0381(8) 0.0435(9) -0.0206(7) 0.0034(7) -0.0110(6) N N4 0.059(1) 0.0390(8) 0.0418(9) -0.0228(7) 0.0003(7) -0.0145(6) N C1 0.043(1) 0.038(1) 0.047(1) 0.0005(8) -0.0127(8) -0.0095(8) C C2 0.0272(8) 0.049(1) 0.048(1) -0.0082(7) 0.0012(7) -0.0206(8) C C3 0.0312(8) 0.0402(9) 0.0378(9) -0.0142(7) 0.0001(7) -0.0115(7) C C4 0.0288(8) 0.0331(8) 0.0361(9) -0.0098(6) -0.0001(6) -0.0135(7) C C5 0.047(1) 0.0374(9) 0.0351(9) -0.0173(8) 0.0045(7) -0.0102(7) C C6 0.052(1) 0.0315(9) 0.0328(9) -0.0128(7) -0.0029(7) -0.0040(6) C C7 0.0395(9) 0.0294(8) 0.0361(9) -0.0108(7) 0.0012(7) -0.0073(6) C C8 0.0405(9) 0.0308(8) 0.0311(8) -0.0117(7) -0.0004(6) -0.0089(6) C C9 0.041(1) 0.046(1) 0.041(1) -0.0179(8) 0.0087(7) -0.0176(7) C C10 0.0389(9) 0.0305(9) 0.050(1) -0.0086(7) -0.0060(8) -0.0092(7) C C11 0.0378(9) 0.0352(9) 0.0403(9) -0.0071(7) -0.0043(7) -0.0017(7) C C12 0.047(1) 0.0333(9) 0.0419(9) -0.0115(8) -0.0105(7) -0.0063(7) C C13 0.063(1) 0.050(1) 0.066(2) 0.007(1) -0.023(1) -0.012(1) C C14 0.0400(9) 0.0362(9) 0.0395(9) -0.0147(7) 0.0000(7) -0.0147(7) C C15 0.046(1) 0.0347(9) 0.0349(9) -0.0133(7) -0.0015(7) -0.0107(7) C OW 0.0514(8) 0.063(1) 0.074(1) -0.0308(7) 0.0046(7) -0.0307(8) O
# MOLECULAR GEOMETRY loop_ _geom_bond_atom_site_label_1 _geom_bond_atom_site_label_2 _geom_bond_distance _geom_bond_site_symmetry_1 _geom_bond_site_symmetry_2 _geom_bond_publ_flag O1 C14 1.229(2) 1_555 1_555 no O2 C15 1.229(2) 1_555 1_555 no N1 N2 1.403(2) 1_555 1_555 no N1 C3 1.283(2) 1_555 1_555 no N2 C14 1.334(2) 1_555 1_555 no N3 N4 1.415(2) 1_555 1_555 no N3 C7 1.283(2) 1_555 1_555 no N4 C15 1.342(2) 1_555 1_555 no C1 C2 1.535(3) 1_555 1_555 no C1 C6 1.543(3) 1_555 1_555 no C2 C3 1.489(2) 1_555 1_555 no C2 C9 1.541(3) 1_555 1_555 no C3 C4 1.507(2) 1_555 1_555 no C4 C5 1.550(2) 1_555 1_555 no C4 C10 1.528(2) 1_555 1_555 no C4 C14 1.534(2) 1_555 1_555 no C5 C6 1.544(2) 1_555 1_555 no C6 C7 1.491(2) 1_555 1_555 no C7 C8 1.502(2) 1_555 1_555 no C8 C9 1.542(2) 1_555 1_555 no C8 C12 1.535(2) 1_555 1_555 no C8 C15 1.530(2) 1_555 1_555 no C10 C11 1.438(3) 1_555 1_555 no C11 C12 1.380(3) 1_555 1_555 no C11 C13 1.510(3) 1_555 1_555 no loop_ _geom_angle_atom_site_label_1 _geom_angle_atom_site_label_2 _geom_angle_atom_site_label_3 _geom_angle _geom_angle_site_symmetry_1 _geom_angle_site_symmetry_2 _geom_angle_site_symmetry_3 _geom_angle_publ_flag N2 N1 C3 107.0(1) 1_555 1_555 1_555 no N1 N2 C14 113.4(1) 1_555 1_555 1_555 no N4 N3 C7 106.9(2) 1_555 1_555 1_555 no N3 N4 C15 112.4(1) 1_555 1_555 1_555 no C2 C1 C6 109.5(1) 1_555 1_555 1_555 no C1 C2 C3 104.3(2) 1_555 1_555 1_555 no C1 C2 C9 112.0(2) 1_555 1_555 1_555 no C3 C2 C9 115.7(2) 1_555 1_555 1_555 no N1 C3 C2 120.9(2) 1_555 1_555 1_555 no N1 C3 C4 113.8(2) 1_555 1_555 1_555 no C2 C3 C4 122.8(1) 1_555 1_555 1_555 no C3 C4 C5 110.9(1) 1_555 1_555 1_555 no C3 C4 C10 115.8(2) 1_555 1_555 1_555 no C3 C4 C14 98.9(1) 1_555 1_555 1_555 no C5 C4 C10 114.7(1) 1_555 1_555 1_555 no C5 C4 C14 111.8(1) 1_555 1_555 1_555 no C10 C4 C14 103.3(1) 1_555 1_555 1_555 no C4 C5 C6 114.4(1) 1_555 1_555 1_555 no C1 C6 C5 111.6(2) 1_555 1_555 1_555 no C1 C6 C7 103.6(2) 1_555 1_555 1_555 no C5 C6 C7 116.8(1) 1_555 1_555 1_555 no N3 C7 C6 121.7(2) 1_555 1_555 1_555 no N3 C7 C8 113.8(2) 1_555 1_555 1_555 no C6 C7 C8 122.5(2) 1_555 1_555 1_555 no C7 C8 C9 112.6(1) 1_555 1_555 1_555 no C7 C8 C12 112.7(2) 1_555 1_555 1_555 no C7 C8 C15 99.0(1) 1_555 1_555 1_555 no C9 C8 C12 115.5(2) 1_555 1_555 1_555 no C9 C8 C15 112.1(1) 1_555 1_555 1_555 no C12 C8 C15 103.3(1) 1_555 1_555 1_555 no C2 C9 C8 114.2(2) 1_555 1_555 1_555 no C4 C10 C11 127.6(2) 1_555 1_555 1_555 no C10 C11 C12 132.1(2) 1_555 1_555 1_555 no C10 C11 C13 112.8(2) 1_555 1_555 1_555 no C12 C11 C13 115.0(2) 1_555 1_555 1_555 no C8 C12 C11 129.1(2) 1_555 1_555 1_555 no O1 C14 N2 125.4(2) 1_555 1_555 1_555 no O1 C14 C4 128.1(2) 1_555 1_555 1_555 no N2 C14 C4 106.5(1) 1_555 1_555 1_555 no O2 C15 N4 126.6(2) 1_555 1_555 1_555 no O2 C15 C8 127.0(2) 1_555 1_555 1_555 no N4 C15 C8 106.3(2) 1_555 1_555 1_555 no data_drb244 _audit_creation_method 'RAELSPUB and manual entry'
# SUBMISSION DETAILS
_publ_contact_author_name ? _publ_contact_author_address ? _publ_contact_author_email ? _publ_contact_letter ? _publ_requested_journal ? _publ_requested_category ?
# TITLE AND AUTHOR LIST
_publ_section_title ? _publ_section_title_footnote ? loop_ _publ_author_name _publ_author_footnote _publ_author_address ? ? ?
# TEXT
_publ_section_abstract ? _publ_section_comment ? _publ_section_acknowledgements ? _publ_section_references
; Altomare, A., Burla, M.C., Camalli, M., Cascarano, G.,Giacovazzo, C., Guagliardi, A., Polidori, G., J. Appl. Cryst., 1994, 27, 435.
Ibers, J.A. and Hamilton, W.C., (Eds) International Tables for X-Ray Crystallography Vol. 4 , Kynoch Press, Birmingham, 1974.
Johnson, C.K.,'ORTEP-II', Oak Ridge National Laboratory, Tennessee, U.S.A., 1976.
Rae, A.D., RAELS. A comprehensive Constrained Least Squares Refinement Program, University of New South Wales, 1996.
Schagen, J.D., Straver, L., van Meurs, F., Williams, G., CAD4 Version 5.0, Delft Instruments X-ray Diffraction, 1989. ;
_publ_section_figure_captions ? _publ_section_exptl_prep ? _publ_section_exptl_refinement ? _computing_data_collection 'CAD4 Version 5.0, (Schagen et al, 1989)' _computing_cell_refinement 'CAD4 Version 5.0, (Schagen et al, 1989)' _computing_data_reduction 'Local program' _computing_structure_solution 'SIR92 (Altomare et al, 1994)' _computing_structure_refinement 'RAELS, (Rae, 1996)' _computing_molecular_graphics 'ORTEP-II, (Johnson, 1976)' _computing_publication_material 'Local programs'
# CHEMICAL DATA
_chemical_name_systematic ? _chemical_formula_moiety 'C16 H18 O10' _chemical_formula_sum 'C16 H18 O10' _chemical_formula_iupac ? _chemical_formula_weight 370.3 _chemical_absolute_configuration ?
# CRYSTAL DATA
_space_group_crystal_system monoclinic _space_group_name_H-M_alt 'P 21/n' loop_ _space_group_symop_id _space_group_symop_operation_xyz 1 x,y,z 2 1/2-x,1/2+y,1/2-z 3 -x,-y,-z 4 1/2+x,1/2-y,1/2+z
_cell_length_a 12.261(6) _cell_length_b 12.555(5) _cell_length_c 12.522(6) _cell_angle_alpha 90 _cell_angle_beta 114.50(2) _cell_angle_gamma 90 _cell_volume 1754(1) _cell_formula_units_Z 4 _cell_measurement_reflns_used 10 _cell_measurement_theta_min 9 _cell_measurement_theta_max 10 _cell_measurement_temperature 294 _exptl_crystal_description block _exptl_crystal_colour colourless _exptl_crystal_size_max 0.20 _exptl_crystal_size_mid 0.20 _exptl_crystal_size_min 0.15 _exptl_crystal_size_rad ? _exptl_crystal_density_diffrn 1.40 _exptl_crystal_density_meas ? _exptl_crystal_density_method 'not measured' _exptl_crystal_F_000 776.0 _exptl_absorpt_coefficient_mu 0.114 _exptl_absorpt_correction_type none _exptl_absorpt_process_details ? _exptl_absorpt_correction_T_min ? _exptl_absorpt_correction_T_max ?
# EXPERIMENTAL DATA
_diffrn_radiation_probe x-ray _diffrn_radiation_type 'Mo K\a' _diffrn_radiation_wavelength 0.71073 _diffrn_measurement_device_type 'Nonius CAD-4' _diffrn_measurement_method \w--2\q _diffrn_reflns_number 2568 _diffrn_reflns_av_R_equivalents 0.021 _diffrn_reflns_theta_max 23 _diffrn_measured_fraction_theta_max 1.00 _diffrn_reflns_theta_full 23 _diffrn_measured_fraction_theta_full 1.00 _diffrn_reflns_limit_h_min -13 _diffrn_reflns_limit_h_max 13 _diffrn_reflns_limit_k_min -13 _diffrn_reflns_limit_k_max 0 _diffrn_reflns_limit_l_min 0 _diffrn_reflns_limit_l_max 13 _diffrn_standards_number 1 _diffrn_standards_interval_time 30 _diffrn_standards_decay_% 0
# REFINEMENT DATA
_refine_special_details
;Thermal motion was refined using five rigid-body parameters, a 12- parameter TL group for each acetyl, with the centre of libration at the attachment atom, and one 15-parameter TLX group for the remainder of the structure. ;
_reflns_number_total 2441 _reflns_number_gt 1097 _reflns_threshold_expression I>2\s(I) _refine_ls_structure_factor_coef F _refine_ls_R_factor_gt 0.047 _refine_ls_wR_factor_ref 0.055 _refine_ls_abs_structure_Flack ? _refine_ls_hydrogen_treatment noref _refine_ls_number_reflns 1097 _refine_ls_number_parameters 142 _refine_ls_goodness_of_fit_ref 1.67 _refine_ls_weighting_scheme calc _refine_ls_weighting_details 'w = 1/[\s^2^(F) + 0.0004F^2^]' _refine_ls_shift/su_max 0.001 _refine_diff_density_max 0.68 _refine_diff_density_min -0.62 _refine_ls_extinction_method none _refine_ls_extinction_coef ? _atom_type_scat_source 'International Tables for X-ray Crystallography, Vol. IV'
# ATOMIC COORDINATES AND DISPLACEMENT PARAMETERS loop_ _atom_site_label _atom_site_fract_x _atom_site_fract_y _atom_site_fract_z _atom_site_U_iso_or_equiv _atom_site_adp_type _atom_site_type_symbol _atom_site_occupancy O1 0.4150(3) 0.8259(3) 0.6501(3) 0.056(2) Uani O 1.0 O2 0.4543(3) 0.4364(3) 0.3321(3) 0.047(2) Uani O 1.0 O3 0.5926(3) 0.9167(3) 0.6119(3) 0.068(1) Uani O 1.0 O4 0.6236(3) 0.8568(3) 0.4573(3) 0.059(1) Uani O 1.0 O5 0.1274(4) 0.6831(3) 0.5422(4) 0.092(2) Uani O 1.0 O6 0.1427(3) 0.8168(3) 0.4332(3) 0.066(2) Uani O 1.0 O7 0.2429(3) 0.3757(3) 0.3231(3) 0.055(1) Uani O 1.0 O8 0.1311(3) 0.5021(3) 0.3584(3) 0.053(1) Uani O 1.0 O9 0.5148(3) 0.6534(3) 0.2022(3) 0.069(2) Uani O 1.0 O10 0.6785(3) 0.6094(4) 0.3594(3) 0.080(2) Uani O 1.0 C1 0.4182(4) 0.7182(4) 0.3800(4) 0.0341(9) Uani C 1.0 C2 0.4610(4) 0.7897(4) 0.4856(4) 0.039(1) Uani C 1.0 C3 0.3976(4) 0.7765(4) 0.5498(4) 0.043(1) Uani C 1.0 C4 0.3020(4) 0.6936(4) 0.5025(4) 0.042(2) Uani C 1.0 C5 0.3009(4) 0.6682(4) 0.3805(4) 0.0358(8) Uani C 1.0 C6 0.3118(4) 0.5528(4) 0.3566(4) 0.038(1) Uani C 1.0 C7 0.4181(4) 0.5314(4) 0.3547(4) 0.037(1) Uani C 1.0 C8 0.5026(4) 0.6240(4) 0.3857(4) 0.035(1) Uani C 1.0 C9 0.5635(4) 0.8600(4) 0.5250(5) 0.047(1) Uani C 1.0 C10 0.7318(5) 0.9202(6) 0.4966(6) 0.091(2) Uani C 1.0 C11 0.1822(5) 0.7278(5) 0.4976(5) 0.049(2) Uani C 1.0 C12 0.0275(5) 0.8565(5) 0.4213(6) 0.081(3) Uani C 1.0 C13 0.2263(4) 0.4680(4) 0.3422(4) 0.041(1) Uani C 1.0 C14 0.0458(5) 0.4218(5) 0.3567(6) 0.073(2) Uani C 1.0 C15 0.5635(5) 0.6325(4) 0.3031(5) 0.046(2) Uani C 1.0 C16 0.7468(6) 0.6140(8) 0.2890(7) 0.130(4) Uani C 1.0 H1O1 0.4845 0.8758 0.6719 0.061 Uani H 1.0 H1O2 0.3911 0.3818 0.3211 0.054 Uani H 1.0 HC1 0.3990 0.7609 0.3070 0.039 Uani H 1.0 HC4 0.3289 0.6286 0.5529 0.045 Uani H 1.0 HC5 0.2284 0.6999 0.3164 0.041 Uani H 1.0 HC8 0.5645 0.6156 0.4680 0.039 Uani H 1.0 H1C10 0.7696 0.9122 0.4400 0.114 Uani H 1.0 H2C10 0.7114 0.9968 0.5008 0.105 Uani H 1.0 H3C10 0.7890 0.8955 0.5760 0.102 Uani H 1.0 H1C12 0.0071 0.9225 0.3721 0.126 Uani H 1.0 H2C12 -0.0352 0.8011 0.3828 0.107 Uani H 1.0 H3C12 0.0310 0.8734 0.5007 0.079 Uani H 1.0 H1C14 -0.0212 0.4563 0.3697 0.097 Uani H 1.0 H2C14 0.0131 0.3849 0.2789 0.077 Uani H 1.0 H3C14 0.0867 0.3686 0.4203 0.082 Uani H 1.0 H1C16 0.8323 0.5955 0.3388 0.198 Uani H 1.0 H2C16 0.7129 0.5621 0.2228 0.141 Uani H 1.0 H3C16 0.7424 0.6876 0.2569 0.136 Uani H 1.0 loop_ _atom_site_aniso_label _atom_site_aniso_U_11 _atom_site_aniso_U_22 _atom_site_aniso_U_33 _atom_site_aniso_U_12 _atom_site_aniso_U_13 _atom_site_aniso_U_23 _atom_site_aniso_type_symbol O1 0.061(3) 0.064(2) 0.050(2) -0.002(2) 0.030(2) -0.016(1) O O2 0.050(3) 0.038(2) 0.057(2) 0.005(1) 0.026(2) -0.002(1) O O3 0.060(2) 0.072(3) 0.064(3) -0.023(2) 0.018(2) -0.022(2) O O4 0.045(2) 0.071(2) 0.064(2) -0.010(2) 0.024(2) 0.004(2) O O5 0.083(2) 0.080(3) 0.164(4) 0.015(2) 0.101(3) 0.028(2) O O6 0.063(2) 0.074(3) 0.080(3) 0.017(2) 0.048(2) 0.009(2) O O7 0.054(2) 0.040(2) 0.072(3) -0.009(1) 0.028(2) -0.013(2) O O8 0.045(2) 0.055(2) 0.066(3) -0.009(1) 0.031(2) -0.011(2) O O9 0.065(2) 0.104(3) 0.048(2) 0.004(2) 0.033(2) 0.011(2) O O10 0.047(2) 0.135(4) 0.072(2) 0.021(2) 0.038(2) 0.017(2) O C1 0.035(1) 0.035(1) 0.033(2) 0.004(1) 0.0155(9) 0.005(2) C C2 0.039(2) 0.039(1) 0.041(2) 0.001(1) 0.018(1) -0.001(1) C C3 0.045(2) 0.047(1) 0.041(2) 0.002(1) 0.022(1) -0.004(1) C C4 0.042(2) 0.047(2) 0.043(2) 0.002(1) 0.024(2) 0.000(1) C C5 0.033(1) 0.039(1) 0.036(1) 0.004(1) 0.016(1) 0.003(1) C C6 0.037(1) 0.039(2) 0.041(2) 0.000(1) 0.018(1) 0.001(1) C C7 0.038(1) 0.036(1) 0.039(2) 0.004(1) 0.0180(9) 0.002(1) C C8 0.034(2) 0.038(1) 0.035(1) 0.004(1) 0.016(1) 0.003(1) C C9 0.038(2) 0.049(3) 0.046(2) -0.007(2) 0.011(2) 0.000(2) C C10 0.059(2) 0.108(5) 0.110(5) -0.032(3) 0.038(3) -0.001(4) C C11 0.047(2) 0.054(3) 0.063(3) -0.004(2) 0.040(2) -0.009(2) C C12 0.063(2) 0.090(3) 0.101(5) 0.022(3) 0.045(3) -0.001(3) C C13 0.041(2) 0.041(2) 0.042(3) -0.007(1) 0.019(2) -0.008(2) C C14 0.058(2) 0.075(3) 0.100(5) -0.022(2) 0.045(3) -0.011(3) C C15 0.045(2) 0.055(4) 0.048(2) 0.004(2) 0.028(2) 0.002(2) C C16 0.072(2) 0.242(9) 0.110(4) 0.029(4) 0.070(3) 0.025(5) C
# MOLECULAR GEOMETRY loop_ _geom_bond_atom_site_label_1 _geom_bond_atom_site_label_2 _geom_bond_distance _geom_bond_site_symmetry_1 _geom_bond_site_symmetry_2 _geom_bond_publ_flag O1 C3 1.336(5) 1_555 1_555 no O2 C7 1.343(5) 1_555 1_555 no O3 C9 1.224(6) 1_555 1_555 no O4 C9 1.335(6) 1_555 1_555 no O4 C10 1.447(6) 1_555 1_555 no O5 C11 1.178(5) 1_555 1_555 no O6 C11 1.345(6) 1_555 1_555 no O6 C12 1.446(6) 1_555 1_555 no O7 C13 1.217(5) 1_555 1_555 no O8 C13 1.335(6) 1_555 1_555 no O8 C14 1.447(6) 1_555 1_555 no O9 C15 1.182(5) 1_555 1_555 no O10 C15 1.320(6) 1_555 1_555 no O10 C16 1.447(7) 1_555 1_555 no C1 C2 1.501(6) 1_555 1_555 no C1 C5 1.571(6) 1_555 1_555 no C1 C8 1.554(6) 1_555 1_555 no C2 C3 1.340(6) 1_555 1_555 no C2 C9 1.444(7) 1_555 1_555 no C3 C4 1.494(6) 1_555 1_555 no C4 C5 1.555(6) 1_555 1_555 no C4 C11 1.507(6) 1_555 1_555 no C5 C6 1.497(6) 1_555 1_555 no C6 C7 1.341(6) 1_555 1_555 no C6 C13 1.452(7) 1_555 1_555 no C7 C8 1.497(6) 1_555 1_555 no C8 C15 1.510(6) 1_555 1_555 no loop_ _geom_angle_atom_site_label_1 _geom_angle_atom_site_label_2 _geom_angle_atom_site_label_3 _geom_angle _geom_angle_site_symmetry_1 _geom_angle_site_symmetry_2 _geom_angle_site_symmetry_3 _geom_angle_publ_flag C9 O4 C10 115.9(5) 1_555 1_555 1_555 no C11 O6 C12 116.2(4) 1_555 1_555 1_555 no C13 O8 C14 116.5(4) 1_555 1_555 1_555 no C15 O10 C16 115.2(5) 1_555 1_555 1_555 no C2 C1 C5 102.8(4) 1_555 1_555 1_555 no C2 C1 C8 115.6(4) 1_555 1_555 1_555 no C5 C1 C8 106.8(4) 1_555 1_555 1_555 no C1 C2 C3 112.0(5) 1_555 1_555 1_555 no C1 C2 C9 127.1(4) 1_555 1_555 1_555 no C3 C2 C9 120.7(5) 1_555 1_555 1_555 no O1 C3 C2 126.9(5) 1_555 1_555 1_555 no O1 C3 C4 119.2(4) 1_555 1_555 1_555 no C2 C3 C4 113.8(5) 1_555 1_555 1_555 no C3 C4 C5 102.6(4) 1_555 1_555 1_555 no C3 C4 C11 114.2(4) 1_555 1_555 1_555 no C5 C4 C11 114.0(4) 1_555 1_555 1_555 no C1 C5 C4 106.6(4) 1_555 1_555 1_555 no C1 C5 C6 103.2(4) 1_555 1_555 1_555 no C4 C5 C6 115.4(4) 1_555 1_555 1_555 no C5 C6 C7 111.4(4) 1_555 1_555 1_555 no C5 C6 C13 127.9(4) 1_555 1_555 1_555 no C7 C6 C13 120.6(5) 1_555 1_555 1_555 no O2 C7 C6 126.1(5) 1_555 1_555 1_555 no O2 C7 C8 119.4(4) 1_555 1_555 1_555 no C6 C7 C8 114.4(4) 1_555 1_555 1_555 no C1 C8 C7 101.7(4) 1_555 1_555 1_555 no C1 C8 C15 115.1(4) 1_555 1_555 1_555 no C7 C8 C15 111.3(4) 1_555 1_555 1_555 no O3 C9 O4 123.3(5) 1_555 1_555 1_555 no O3 C9 C2 123.4(5) 1_555 1_555 1_555 no O4 C9 C2 113.3(5) 1_555 1_555 1_555 no O5 C11 O6 123.0(5) 1_555 1_555 1_555 no O5 C11 C4 125.7(6) 1_555 1_555 1_555 no O6 C11 C4 111.3(4) 1_555 1_555 1_555 no O7 C13 O8 124.3(5) 1_555 1_555 1_555 no O7 C13 C6 123.5(5) 1_555 1_555 1_555 no O8 C13 C6 112.2(5) 1_555 1_555 1_555 no O9 C15 O10 125.0(5) 1_555 1_555 1_555 no O9 C15 C8 125.0(5) 1_555 1_555 1_555 no O10 C15 C8 109.9(5) 1_555 1_555 1_555 no data_drb277 _audit_creation_method 'RAELSPUB and manual entry'
# SUBMISSION DETAILS
_publ_contact_author_name ? _publ_contact_author_address ? _publ_contact_author_email ? _publ_contact_letter ? _publ_requested_journal ? _publ_requested_category ?
# TITLE AND AUTHOR LIST
_publ_section_title ? _publ_section_title_footnote ? loop_ _publ_author_name _publ_author_footnote _publ_author_address ? ? ?
# TEXT
_publ_section_abstract ? _publ_section_comment ? _publ_section_acknowledgements ? _publ_section_references
; Altomare, A., Burla, M.C., Camalli, M., Cascarano, G.,Giacovazzo, C., Guagliardi, A., Polidori, G., J. Appl. Cryst., 1994, 27, 435.
Ibers, J.A. and Hamilton, W.C., (Eds) International Tables for X-Ray Crystallography Vol. 4 , Kynoch Press, Birmingham, 1974.
Johnson, C.K.,'ORTEP-II', Oak Ridge National Laboratory, Tennessee, U.S.A., 1976.
Rae, A.D., RAELS. A comprehensive Constrained Least Squares Refinement Program, University of New South Wales, 1996.
Schagen, J.D., Straver, L., van Meurs, F., Williams, G., CAD4 Version 5.0, Delft Instruments X-ray Diffraction, 1989. ;
_publ_section_figure_captions ? _publ_section_exptl_prep ? _publ_section_exptl_refinement ? _computing_data_collection 'CAD4 Version 5.0, (Schagen et al, 1989)' _computing_cell_refinement 'CAD4 Version 5.0, (Schagen et al, 1989)' _computing_data_reduction 'Local program' _computing_structure_solution 'SIR92 (Altomare et al, 1994)' _computing_structure_refinement 'RAELS, (Rae, 1996)' _computing_molecular_graphics 'ORTEP-II, (Johnson, 1976)' _computing_publication_material 'Local programs'
# CHEMICAL DATA
_chemical_name_systematic ? _chemical_formula_moiety 'C22 H18 N2 2+, H7 O12 P3 2-' _chemical_formula_sum 'C22 H25 N2 O12 P3' _chemical_formula_iupac ? _chemical_formula_weight 602.4 _chemical_absolute_configuration ?
# CRYSTAL DATA
_space_group_crystal_system monoclinic _space_group_name_H-M_alt 'P 2/c' loop_ _space_group_symop_id _space_group_symop_operation_xyz 1 x,y,z 2 -x,y,1/2-z 3 -x,-y,-z 4 x,-y,1/2+z
_cell_length_a 11.843(6) _cell_length_b 7.327(1) _cell_length_c 16.835(7) _cell_angle_alpha 90 _cell_angle_beta 124.54(2) _cell_angle_gamma 90 _cell_volume 1203(1) _cell_formula_units_Z 2 _cell_measurement_reflns_used 11 _cell_measurement_theta_min 11 _cell_measurement_theta_max 12 _cell_measurement_temperature 294 _exptl_crystal_description irregular _exptl_crystal_colour colourless _exptl_crystal_size_max ? _exptl_crystal_size_mid ? _exptl_crystal_size_min ? _exptl_crystal_size_rad 0.12 _exptl_crystal_density_diffrn 1.66 _exptl_crystal_density_meas ? _exptl_crystal_density_method 'not measured' _exptl_crystal_F_000 624.0 _exptl_absorpt_coefficient_mu 0.314 _exptl_absorpt_correction_type none _exptl_absorpt_process_details ? _exptl_absorpt_correction_T_min ? _exptl_absorpt_correction_T_max ?
# EXPERIMENTAL DATA
_diffrn_radiation_probe x-ray _diffrn_radiation_type 'Mo K\a' _diffrn_radiation_wavelength 0.71073 _diffrn_measurement_device_type 'Nonius CAD-4' _diffrn_measurement_method \w--2\q _diffrn_reflns_number 1743 _diffrn_reflns_av_R_equivalents 0.042 _diffrn_reflns_theta_max 23 _diffrn_measured_fraction_theta_max 1.00 _diffrn_reflns_theta_full 23 _diffrn_measured_fraction_theta_full 1.00 _diffrn_reflns_limit_h_min -13 _diffrn_reflns_limit_h_max 13 _diffrn_reflns_limit_k_min 0 _diffrn_reflns_limit_k_max 8 _diffrn_reflns_limit_l_min 0 _diffrn_reflns_limit_l_max 18 _diffrn_standards_number 1 _diffrn_standards_interval_time 30 _diffrn_standards_decay_% 0
# REFINEMENT DATA
_refine_special_details ? _reflns_number_total 1674 _reflns_number_gt 1508 _reflns_threshold_expression I>2\s(I) _refine_ls_structure_factor_coef F _refine_ls_R_factor_gt 0.052 _refine_ls_wR_factor_ref 0.084 _refine_ls_abs_structure_Flack ? _refine_ls_hydrogen_treatment noref _refine_ls_number_reflns 1508 _refine_ls_number_parameters 155 _refine_ls_goodness_of_fit_ref 1.85 _refine_ls_weighting_scheme calc _refine_ls_weighting_details 'w = 1/[\s^2^(F) + 0.0004F^2^]' _refine_ls_shift/su_max 0.004 _refine_diff_density_max 0.52 _refine_diff_density_min -0.43 _refine_ls_extinction_method none _refine_ls_extinction_coef ? _atom_type_scat_source 'International Tables for X-ray Crystallography, Vol. IV'
# ATOMIC COORDINATES AND DISPLACEMENT PARAMETERS loop_ _atom_site_label _atom_site_fract_x _atom_site_fract_y _atom_site_fract_z _atom_site_U_iso_or_equiv _atom_site_adp_type _atom_site_type_symbol _atom_site_occupancy N1 0.3593(3) 0.2445(4) 0.3667(2) 0.0248(8) Uani N 1.0 C1 0.5721(3) 0.4519(5) 0.2999(2) 0.0282(9) Uani C 1.0 C2 0.5449(3) 0.3768(5) 0.3699(2) 0.0247(8) Uani C 1.0 C3 0.4090(4) 0.3151(5) 0.3210(2) 0.0247(8) Uani C 1.0 C4 0.3307(4) 0.3371(6) 0.2135(2) 0.033(1) Uani C 1.0 C5 0.6285(4) 0.3620(5) 0.4683(3) 0.0271(9) Uani C 1.0 C6 0.5757(4) 0.2861(5) 0.5179(2) 0.0259(8) Uani C 1.0 C7 0.6572(4) 0.2654(5) 0.6198(3) 0.0312(9) Uani C 1.0 C8 0.6016(4) 0.1898(5) 0.6643(3) 0.034(1) Uani C 1.0 C9 0.4621(4) 0.1372(5) 0.6104(3) 0.0336(9) Uani C 1.0 C10 0.3810(4) 0.1553(5) 0.5120(3) 0.0295(9) Uani C 1.0 C11 0.4382(4) 0.2292(5) 0.4660(2) 0.0249(9) Uani C 1.0 P1A 0.0000 0.2556(2) 0.2500 0.0242(6) Uani P 1.0 O1A 0.1036(2) 0.1466(3) 0.2464(2) 0.0319(9) Uani O 1.0 O3A 0.0870(3) 0.3824(4) 0.3405(2) 0.0443(5) Uani O 1.0 P1B 0.01723(10) 0.77577(14) 0.07948(6) 0.0300(8) Uani P 1.0 O1B 0.1373(3) 0.8414(4) 0.0780(2) 0.0530(6) Uani O 1.0 O2B 0.0023(3) 0.5673(4) 0.0688(2) 0.051(1) Uani O 1.0 O3B 0.0496(3) 0.8080(4) 0.1814(2) 0.052(1) Uani O 1.0 O4B -0.1150(3) 0.8705(4) 0.0045(2) 0.051(1) Uani O 1.0 HN1 0.2621 0.2009 0.3288 0.025 Uani H 1.0 HC1 0.6074 0.5796 0.3183 0.028 Uani H 1.0 H1C4 0.2422 0.4027 0.1874 0.033 Uani H 1.0 H2C4 0.3118 0.2159 0.1809 0.033 Uani H 1.0 HC5 0.7259 0.4044 0.5045 0.027 Uani H 1.0 HC7 0.7550 0.3061 0.6587 0.031 Uani H 1.0 HC8 0.6601 0.1713 0.7358 0.034 Uani H 1.0 HC9 0.4222 0.0861 0.6444 0.034 Uani H 1.0 HC10 0.2827 0.1164 0.4740 0.030 Uani H 1.0 loop_ _atom_site_aniso_label _atom_site_aniso_U_11 _atom_site_aniso_U_22 _atom_site_aniso_U_33 _atom_site_aniso_U_12 _atom_site_aniso_U_13 _atom_site_aniso_U_23 _atom_site_aniso_type_symbol N1 0.024(2) 0.022(2) 0.025(2) 0.001(1) 0.012(1) -0.001(1) N C1 0.024(2) 0.032(2) 0.022(2) -0.002(2) 0.009(2) -0.002(2) C C2 0.023(2) 0.023(2) 0.025(2) 0.001(1) 0.011(2) -0.003(1) C C3 0.026(2) 0.019(2) 0.024(2) 0.001(2) 0.012(2) -0.003(1) C C4 0.025(2) 0.050(3) 0.020(2) -0.002(2) 0.009(2) 0.000(2) C C5 0.024(2) 0.024(2) 0.026(2) 0.002(2) 0.010(2) -0.004(2) C C6 0.030(2) 0.018(2) 0.025(2) 0.004(2) 0.013(2) 0.000(2) C C7 0.034(2) 0.028(2) 0.022(2) 0.002(2) 0.010(2) -0.003(2) C C8 0.044(2) 0.028(2) 0.027(2) 0.006(2) 0.018(2) 0.002(2) C C9 0.046(2) 0.025(2) 0.034(2) 0.007(2) 0.025(2) 0.004(2) C C10 0.034(2) 0.021(2) 0.033(2) 0.003(2) 0.019(2) 0.001(2) C C11 0.027(2) 0.017(2) 0.024(2) 0.005(1) 0.011(2) -0.001(1) C P1A 0.0219(7) 0.0197(7) 0.025(1) 0.0000 0.0097(6) 0.0000 P O1A 0.0251(8) 0.031(1) 0.035(2) 0.0013(5) 0.0144(9) -0.0046(6) O O3A 0.031(1) 0.043(1) 0.047(1) -0.0065(9) 0.0146(9) -0.023(1) O P1B 0.039(1) 0.0241(8) 0.024(1) -0.0027(5) 0.016(1) -0.0016(5) P O1B 0.050(1) 0.046(1) 0.071(2) 0.0076(9) 0.040(1) 0.022(1) O O2B 0.089(2) 0.0243(9) 0.049(2) -0.0060(5) 0.045(2) -0.0040(6) O O3B 0.091(2) 0.035(1) 0.031(2) -0.006(1) 0.036(1) -0.0027(8) O O4B 0.040(2) 0.049(1) 0.046(1) -0.0003(8) 0.014(1) 0.017(1) O
# MOLECULAR GEOMETRY loop_ _geom_bond_atom_site_label_1 _geom_bond_atom_site_label_2 _geom_bond_distance _geom_bond_site_symmetry_1 _geom_bond_site_symmetry_2 _geom_bond_publ_flag N1 C3 1.312(4) 1_555 1_555 no N1 C11 1.381(4) 1_555 1_555 no C1 C1 1.577(6) 1_555 2_655 no C1 C2 1.491(5) 1_555 1_555 no C1 C4 1.542(5) 1_555 2_655 no C2 C3 1.404(5) 1_555 1_555 no C2 C5 1.370(5) 1_555 1_555 no C3 C4 1.503(4) 1_555 1_555 no C4 C1 1.542(5) 1_555 2_655 no C5 C6 1.412(5) 1_555 1_555 no C6 C7 1.420(5) 1_555 1_555 no C6 C11 1.406(5) 1_555 1_555 no C7 C8 1.365(5) 1_555 1_555 no C8 C9 1.415(6) 1_555 1_555 no C9 C10 1.370(5) 1_555 1_555 no C10 C11 1.396(5) 1_555 1_555 no P1A O1A 1.493(2) 1_555 1_555 no P1A O1A 1.494(2) 1_555 2_555 no P1A O3A 1.571(3) 1_555 1_555 no P1A O3A 1.571(3) 1_555 2_555 no P1B O1B 1.515(3) 1_555 1_555 no P1B O2B 1.537(3) 1_555 1_555 no P1B O3B 1.549(3) 1_555 1_555 no P1B O4B 1.512(3) 1_555 1_555 no loop_ _geom_angle_atom_site_label_1 _geom_angle_atom_site_label_2 _geom_angle_atom_site_label_3 _geom_angle _geom_angle_site_symmetry_1 _geom_angle_site_symmetry_2 _geom_angle_site_symmetry_3 _geom_angle_publ_flag C3 N1 C11 121.4(3) 1_555 1_555 1_555 no C1 C1 C2 104.7(3) 2_655 1_555 1_555 no C1 C1 C4 107.0(3) 2_655 1_555 2_655 no C2 C1 C4 115.3(3) 1_555 1_555 2_655 no C1 C2 C3 110.2(3) 1_555 1_555 1_555 no C1 C2 C5 130.7(3) 1_555 1_555 1_555 no C3 C2 C5 119.1(3) 1_555 1_555 1_555 no N1 C3 C2 122.0(3) 1_555 1_555 1_555 no N1 C3 C4 124.9(3) 1_555 1_555 1_555 no C2 C3 C4 113.1(3) 1_555 1_555 1_555 no C1 C4 C3 103.4(3) 2_655 1_555 1_555 no C2 C5 C6 119.2(3) 1_555 1_555 1_555 no C5 C6 C7 122.1(3) 1_555 1_555 1_555 no C5 C6 C11 119.6(3) 1_555 1_555 1_555 no C7 C6 C11 118.3(3) 1_555 1_555 1_555 no C6 C7 C8 119.8(4) 1_555 1_555 1_555 no C7 C8 C9 120.6(3) 1_555 1_555 1_555 no C8 C9 C10 120.9(4) 1_555 1_555 1_555 no C9 C10 C11 118.7(4) 1_555 1_555 1_555 no N1 C11 C6 118.7(3) 1_555 1_555 1_555 no N1 C11 C10 119.7(3) 1_555 1_555 1_555 no C6 C11 C10 121.7(3) 1_555 1_555 1_555 no O1A P1A O1A 115.4(2) 1_555 1_555 2_555 no O1A P1A O3A 104.7(1) 1_555 1_555 1_555 no O1A P1A O3A 112.3(1) 1_555 1_555 2_555 no O1A P1A O3A 112.3(1) 2_555 1_555 1_555 no O1A P1A O3A 104.7(1) 2_555 1_555 2_555 no O3A P1A O3A 107.4(2) 1_555 1_555 2_555 no O1B P1B O2B 111.2(2) 1_555 1_555 1_555 no O1B P1B O3B 108.9(2) 1_555 1_555 1_555 no O1B P1B O4B 112.2(2) 1_555 1_555 1_555 no O2B P1B O3B 102.8(2) 1_555 1_555 1_555 no O2B P1B O4B 111.3(2) 1_555 1_555 1_555 no O3B P1B O4B 110.1(2) 1_555 1_555 1_555 no