A templated-strategy towards an all-
carbon [2] rotaxane through a clipping
mechanism
A synthetic study using a covalent approach
Inèz C. Koornneef
1
Bachelor Thesis Chemistry
A templated-strategy towards an all-carbon [2] rotaxane
through a clipping mechanism
A synthetic study using a covalent approach
By
Inèz C. Koornneef
July 2
nd, 2018
Student number
11078464
Research Institute
Van 't Hoff Institute for Molecular Sciences
Research Group
Synthetic Organic Chemistry
Supervising Professor
Prof. dr. Jan H. van Maarseveen
Daily Supervisor
Drs. L. Steemers
Second Reviewer
2
Populair wetenschappelijke samenvatting
Machines nemen sinds de industriële revolutie steeds meer werk over van de mens. Voor de mens is namelijk het werk dat de meeste werktuigen uitvoeren, onmogelijk. Denk hierbij aan werktuigen die in de bouw worden toegepast, maar ook kleinere machines zoals robots die het meest precieze werk kunnen uitvoeren. Echter, wat de meeste mensen niet weten is dat er nóg kleinere en inwikkeldere machines bestaan dan de robots en dit zelfs op moleculair niveau kunnen worden ingezet. Deze worden rotaxanen ge-noemd.
Rotaxanen bestaan uit drie hoofdcomponenten: een draad, een ring en een stopper-groep die zich aan beide uiteinden van de draad bevindt (figuur 1). Doordat de ringcomponent heen en weer beweegt om de draad, hebben rotaxanen de potentie om in de toekomst als moleculaire schakelaren/motoren gebruikt te kunnen worden. De stopper-groepen zorgen ervoor dat de ring niet van de draad afglijdt en dat het een geheel blijft.
Een rotaxaan kan samengesteld worden met behulp van een niet-gemoduleerde of een gemoduleerde methode. Bij deze methodes wordt gebruik gemaakt van niet-covalente interacties zoals waterstofbruggen, elektrostatische interacties of een geactiveerd metaal (figuur 1 om voorbeelden hiervan te zien). In dit onderzoek is echter gebruik gemaakt van een andere methode namelijk, de covalente methode. Het verschil tussen de niet-gemoduleerde methoden en de covalente methode is dat bij de laatste methode de ring en draad-helften tijdelijk aan een template verbonden worden met een covalente binding. Door deze in een later stadium te verbreken, door bijvoorbeeld hydrolyse, wordt de rotaxaan gevormd (figuur 2).
Figuur 1: Rotaxaan onderdelen en de bestaande templated-synthese methoden. Het zwarte punt is een geactiveerd overgangsmetaal. Hierbij wordt het metaal gecoördineerd met de ring, gevolgd met de coördinatie van twee draadhelften met daaraan de stoppers. Dit leidt tot een
3
tussenproduct van een rotaxaan. Een zogenaamde reductieve eliminatie zorgt voor de vorming van de covalente binding tussen de draad-helften, wat resulteert in het vormen van een rotaxaan.
Figuur 2: Covalente methode om een rotaxaan samen te stellen, waarbij een template wordt gebruikt om de fragmenten tijdelijk aan elkaar te binden.
In 1967 werd door Harrison & Harrison voor het eerst een rotaxaan gesynthetiseerd met 6% opbrengst, door gebruik te maken van een statistische methode. Dit betekent dat de ring per toeval om de draad heen zou moeten gaan. In 1964 en 1967 werd voor het eerst een gemoduleerde strategie toegepast door Schill & Zollenkopf. Rond de jaren 70 viel het onderzoek stil, totdat de groep van Sauvage & Dietrich-Büchecker een grote doorbraak realiseerde. Zij gebruikten niet-covalente interacties om de rotaxaan componenten te pre-organiseren. Het nadeel hiervan was dat de niet-covalente eenheden steeds in het eindproduct behouden bleven, wat leidde tot weinig variatie in de rotaxanen.
Door in dit onderzoek gebruik te maken van een covalente strategie, kunnen er niet-covalente eenheden voorkomen worden in het eindproduct. Dit zou leiden tot gevarieerdere eindresultaten.
Eerst werden de draadhelften samengesteld, waarna de draad op de broomatomen in de template aangevallen zouden worden. Later bleek dat de ring om de template heen, de aanval van de draadhelften hinderde en niet tot een rotaxaan leidde. Door een joodbenzeen-groep aan de template te binden, werd de template reactiever en makkelijker te bereiken (figuur 3). Echter is tijdens een tussenstap van de ring-synthese, de volledige ringsynthese mislukt. Dit heeft geleid tot zijreacties tijdens de aanval van de draadhelften op de template. Meer onderzoek is nodig om het ringfragment compleet te maken en om uit te vinden of de aanval van de draadhelften dan mogelijk is. Zo zou vastgesteld kunnen worden of de synthese van een rotaxaan met covalente chemie een potentiële strategie is.
4
A templated-strategy towards an all-carbon [2] rotaxane through a
clipping mechanism
Inèz C. Koornneef Villalba, drs. Luuk Steemers and prof. dr. Jan H. van Maarseveen*
Van ‘t Hoff Institute for Molecular Chemistry, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Neth-erlands
Supporting Information is enclosed with this document
ABSTRACT: In this research a template is being used to couple it with the synthesized ring halves through a transesterification
reaction after which a cyclisation reaction results in the macrocycle intermediate. The generated thread fragments, that acted as stopper groups, were supposed to couple with the iodo atoms on the template via a Sonogashira reaction. However, the efforts to hydrogenate the macrocycle intermediate, only generated ca. 50% of the hydrogenated macrocycle. Therefore, coupling the thread fragments with the iodo atoms, to generate an all-carbon [2] rotaxane, caused a mixture of products including Glaser coupling-prod-ucts. Further hydrogenation methods must be applied on the macrocycle, such as diazene utilization or Wilkinson’s catalyst, before the thread fragments can be coupled.
INTRODUCTION
Machines have a significant role in human development, helping the human kind to expand their capacities. Humans are always searching the limits of machines and that is why molec-ular machines have attracted interest and attention over the past decades.1 Molecular interlocked molecules have the potential to be used as motors,1 switches,2 elevators,3 and artificial mus-cles,4 all at a molecular level.One of the most common known molecular interlocked molecules is the rotaxane which is a ring threaded over an axle with stoppers at each end.1,2 A rotaxane can be used as a molecular switch, shuttling between additional stations on the thread. There are several methods to synthesize these molecules, namely, through capping the ends of a thread that is non-covalently bound in a macrocycle, clipping a ring over an already capped thread, or via an active metal template that is coordinated within the ring and induces the coupling of two thread fragments.5 A disadvantage of this method is that non-covalent interactions such as hydrogen bonding,6 crown ether-ammonium interactions,7 or metal-ion interactions,4,8,9 are a prerequisite for the synthesis of these rotaxanes. Even though these non-covalent interactions are the only widely used method to synthesize rotaxanes, the pioneering work in the 1960s was performed using covalent approaches.10,11 Nevertheless, the in-terest in covalent approaches, which are analogous to the
clip-ping and capclip-ping approaches,5 became highly underused since
the strategies with non-covalent interactions arose in 1984. The first synthesis with the non-covalent strategy was by the re-search group of Sauvage & Dietrich-Büchcker where they used a copper(I)-ion for pre-organizing two fragments containing a phenanthroline motif which resulted in an organometallic com-plex.12 This strategy did not remain unnoticed. In 1991 the group of Stoddard reported the use of electrostatic interactions for the synthesis of a rotaxane and in 1995 Vögtle et al. used H-bonding as a non-covalent template strategy.13, 14 The drawback of this non-covalent method is the inherent necessity for certain motifs which remain in the product resulting in small structural diversities. By using covalent approaches, the need of non-co-valent interactions to pre-organize the components are being obviated, hence this strategy prevents the presence of such mo-tifs in rotaxane products. The group of Höger presented the use of a covalent template for the synthesis of an ‘impossible’ ro-taxane by using a terephthalic acid derivative as a template.15 The template keeps the fragments temporary interlocked until the connecting ester bonds are cleaved, releasing the rotaxane. Nevertheless, at higher temperatures the [2] rotaxane was un-stable, resulting in the free thread and ring fragments.
A predecessor in the Synthetic Organic Chemistry (SOC) group, focussed their research on the synthesis of rotaxanes by using a modified terephthalic acid template.16 Here, two bro-mide atoms were introduced on the 2- and 5- positions of the
5
phenyl ring of the template. Based on previous experiments,17they assumed that the template could be coupled to the ring halves to form the di-ester 1 via a transesterification reaction (scheme 1). They envisioned a clipping type cyclization of the ring halves, using the Ring-Closing Metathesis (RCM) reaction, to form the macrocycle 2. After hydrogenation 3, the bromide atoms on the template could react under Sonogashira conditions to form the pre-rotaxane. After cleavage of the ester bonds by a saponification, the all-carbon [2] rotaxane 4 would be liberated (figure 1).
Scheme 1: Results earlier research.
Figure 1: Target molecule earlier research for an all-carbon [2] rotaxane.
Despite the attempts, the full hydrogenation of macrocycle could not be achieved with Pd/C as catalyst, what resulted to a mixture of compounds during the Sonogashira reaction. Due to time deficiency the research had to be stopped. This research project is a follow-up investigation of the last named research and it continues the quest for the preparation of an all-carbon [2] rotaxane.16 The terephthalic acid was, hereby, used again as template which was modified by introducing two p-iodophenyl groups in the 2- and 5 positions of the phenyl ring. After cou-pling the ring halves to the terephthalic acid template via a transesterification reaction 5, the clipping-type cyclization with the Ring-Closing Metathesis reaction could be performed; re-sulting in macrocycle 6; view scheme 2 for the general outline and scheme 3 for the retrosynthesis. After the hydrogenation of the E/Z mixture, the capped thread fragments would then be coupled on the iodophenyl groups under Sonogashira condi-tions. Hydrogenation of the alkyne bonds and saponification of the ester bonds would give the all-carbon [2] rotaxane 7.
RESULTS & DISCUSSION
In the beginning of this research, the same pathway per-formed by the predecessor was carried out to synthesize 13 starting with the synthesis and coupling of the terephthalic acid and the ring halves. First the terephthalic acid was converted into the acid chloride by dissolving 2,5-dibromoterephthalic acid in THF together with (COCl)2. By adding one drop of DMF as catalyst, this yielded 8 (scheme 4). The ring halves were syn-thesised by generating the di-aldehyde 9 in 49% yield by per-forming a Double Duff reaction of 4-t-butylphenol. 9 reacted with 4.5 equiv of the 6-hexenylmagnesiumbromide resulting in the triol 10 in 79% yield which was subsequently reduced giv-ing rgiv-ing half 11 in 73% yield. The couplgiv-ing of the template with the ring halves was achieved by a transesterification reaction to form intermediate 12 in 27% yield. Clipping of the fragments to give macrocycle 13 was performed by an RCM reaction with 20 mol% of Grubbs II catalyst. The product was obtained in 47% yield and was subsequently reduced with PtO2. This re-sulted in the successful hydrogenation of 13 into 14 in quanti-tative yield. The next step was to couple the thread fragments using a Sonogashira reaction. This was tried by reacting 4-pentyn-1-ol with the bromine atoms and PdCl2(PPh3)2 and CuI at 50 °C for 48 hours under N2 atmosphere. 1H NMR revealed no differences in signals, hence no reaction took place and only starting material was observed.
6
Scheme 3: Retrosynthesis of the general approach starting with the target molecule 30 and ending in the three base fragments of a rotaxane: a stopper, thread and ring.
Scheme 4: Synthesis of the ring halves by using the same approach performed by the predecessor in the SOC group.
Thereafter, the reaction was attempted by coupling trime-thylsilylacetylene to the template by using the same catalysts but different solvent and reaction conditions, namely NEt3 and stirring it at 80 °C for 20 hours. The 1H NMR showed that again nothing happened. Lastly, it was speculated that using a smaller alkane chain would help the coupling reaction since there would
be less hinderance. However, this was not the case and again there were no new signals observed. From these results it was concluded that the bromine atoms are too sterically hindered by the ring, preventing Sonogashira reactions. Due to this setback, the template was converted into a more reactive and bigger one by adding two 4-iodophenyl groups in the 2- and 5-positions of
7
Scheme 5: Synthesis of a more reactive template.
the phenyl ring. 2,5-dibromoterephthalic acid reacted with 3.0 equiv of CH3I giving di-ester 15 in 80% yield, after which 4-trimethylsilylphenylboronic acid was coupled through a Su-zuki reaction to yield the corresponding template intermediate
16 (scheme 5). This product was obtained in 107% yield after
flash column chromatography. Therefore, it probably still con-tained some inorganic impurities such as Pd, because the 1H NMR revealed a pure compound. The next step was to convert the TMS groups to an iodide atom, which was performed by an ipso substitution with ICl resulting in intermediate 17 in 77% yield. To convert the carboxylic acid into the final Pfp-ester on the template, the methyl esters were saponified with KOH giv-ing 18 in quantitative yield. This was then converted to an acyl chloride intermediate 19, using oxalylchloride, after which this was transformed to the final template 20 by quenching with pentafluorophenol. Recrystallization of compound 20 in pure EtOAc, resulted in a quantitative yield.
Formation of the macrocycle was performed by coupling the terephthalic acid template 20 with the ring halves 11 through a transesterification reaction which formed intermediate 21 in 76% yield (scheme 6). Next, a RCM reaction was performed resulting in the clipping of the ring halves over the template to form 22 in 88% yield. 1H NMR revealed the correct signals and MS showed that the main peak was correlated to the correct m/z
ratio of 1162 g/mol. The 13C NMR of this compound was not correct which was probably due to the presence of the Z- and E-isomers formed in the ring. To complete the fully hydrogenated macrocycle a hydrogenation was carried out by using PtO2 as catalyst and by performing the reaction at RT. 1H NMR re-vealed that ca. 50% was converted into the final macrocycle 23. The same reaction was repeated at 50 °C, giving the same result on 1H NMR, the olefinic signals were still presence in ca. 50%. Higher temperatures were not tried, since this might lead to elimination of the iodine atoms on the template.
Although the hydrogenation was not completed and due to time deficiency reasons, the mixture of 22 and 23 was used to react in the Sonogashira reaction with the thread fragments. These thread fragments, that would act as stopper group, were generated through a Suzuki reaction of 3,5-dibromobenzalde-hyde and 4-tert-butylbenzeneboronic acid together with Na2CO3 and Pd(PPh3)4 at 100 °C in a mixture of H2 O/EtOH/Tol-uene (1:1:2). This gave the stopper group 24 in 105% crude yield (scheme 7). The excess of the product could be some im-purities that were considered negligible based on 1H NMR. The linker was added by an addition reaction with lithiated 4-pentyn-1-ol which reacted with the stopper group giving pro-pargyl alcohol 25 in 86% yield. The alkyne bond and alcohol were reduced using Pd/C catalyst resulting in 26 in 48% yield.
8
Scheme 7: Generation of the thread fragments.
The yield of 26 is, compared to the other yields in this path-way, remarkably low while a hydrogenation reaction usually has a higher yield. There were multiple spots visible on the TLC there, which is why there could be concluded that this hydro-genation reaction is not a clean one. A plausible reason for this could be that Pd inserts, after the first hydrogenation, with the secondary alcohol, since this is a better leaving group. This re-sults in possible side reactions by the terminal alcohol and so producing numerous by-products. This hypothesis could be tested by repeating the hydrogenation reaction after protection of the terminal alcohol with a protecting group such as TMS. However, a drawback of this possible solution would be the two extra steps in the synthesis, protection and deprotection. The next step was the conversion of the remaining alcohol group on the stopper to a bromide using an Appel reaction, giving 27 in 91% yield. Because the aim of this investigation was to perform a Sonogashira reaction to obtain the rotaxane, the thread frag-ments needed to contain an alkyne bond at the terminus. There-fore, the bromide atom at the end of the thread was substituted with lithiated TMS-acetylene, using HMPA as co-solvent. This led to 28 in 80% yield. Deprotection of the TMS group with K2CO3 gave rise to the final thread fragment 29 in 82%. Now, the macrocycle mixture of 22 and 23 could react in a So-nogashira reaction with 29 to give the covalently coupled pre-rotaxane 30 (scheme 8).
After perfoming a Sonogashira reaction at RT and doing a column chromatography (PE/EtOAc, 100:0 → 99:1) it was con-cluded based on 1H NMR spectra, that a Glaser coupling had occurred on the alkynes and that a complex mixture of products was obtained (figure 2). The first fractions of the purification revealed the Glaser coupling-product 31 due to the presence of the same signals in the aromatic- and aliphatic region as 29. However, there was no signal of the terminal alkyne. Glaser coupling reactions are side reactions of Sonogashira reactions that are induced by presence of O2 in the reaction. The other fractions obtained by column chromatography showed a mix-ture of products which could be produced due to competing Heck reactions, in which the residual olefins in the macrocycle are coupled to the phenyl ring of the template either intra-, or intermolecularly. Since there was time deficiency, other
coupling reactions of the thread to the template could not be attempted. The results obtained thus far reveal the same conclu-sion as in previous research, namely, that the full hydrogenation of 22 into 23 is a significant factor before the thread fragments can be installed using a Sonogashira reaction. In other words, the alkene lead to problems and must be removed before other reactions could be attempted.
Scheme 8: Protaxane formation via a Sonogashira coupling re-action.
9
CONCLUSION
In summary, this research review seems to be promising for synthesizing an all-carbon [2] rotaxane in a way that it could be a potential covalent strategy to generate various all-carbon [2] rotaxanes. The ring halves were generated by using the same synthetic methods in previous research giving 11 in 73% yield. Furthermore, a more reactive template 20 was synthesized, be-cause it was concluded after multiple approaches that the bro-mine atoms on the terephthalic acid were sterically hindered by the ring. The template was obtained in quantitative yield after recrystallisation from pure EtOAc. Through a transesterifica-tion reactransesterifica-tion, followed up by an RCM clipping reactransesterifica-tion, inter-mediate 22 was formed in 88% yield. Hydrogenation of the ole-fins was unsuccessful using PtO2 catalyst, giving a mixture of
22 and 23 in a ratio of ca. 50:50. Other catalyst including a
Wilkingson catalyst could be tried out. Furthermore, ap-proaches such as diazene reduction could also be performed since it selectively reduces alkenes or higher temperatures could be attempted but the elimination of the iodide atoms of the tem-plate would be risked. Thread fragment that act as stopper groups were generated by using a transmetalation reaction whereby lithiated 4-pentyn-1-ol was coupled to 24 giving 25 in 76% yield. The hydrogenation reaction of 25 to 26 was not a clean reaction as usually. It resulted in a yield of 48%. By using TLC, various spots were observed, what showed that this hy-drogenation is not a clean reaction. A hypothesis for this event could be the insertion of Pd on the secondary alcohol, resulting in side reactions and multiple by-products. By protecting the terminal alcohol with a protecting group, this assumption could be tested. The remaining alcohol group was converted into a bromide via an Appel reaction. A terminal alkyne was needed for the final Sonogashira reaction; thus, the bromide atom was substituted into a TMS-group after which it was deprotected with K2CO3 resulting in the final thread fragment 29 in 60% yield. Coupling of the thread fragments with the macrocycle via a Sonogashira reaction resulted in Glaser by-product and a mix-ture of compounds.
Because these are not unsatisfactory results, this could be a potential strategy for managing the production of a variety of all-carbon [2] rotaxanes. The main value of this project was to obtain more knowledge about the synthesis of an all-carbon [2] rotaxane and to show that there is a potential method to generate these molecules via covalent chemistry. More research is needed to come to an optimize this pathway and to conclude for the synthesis of an ‘impossible’ all-carbon [2] rotaxane.
ASSOCIATED CONTENT
Supporting Information
Supporting information is enclosed with this document, and con-tains the general comments, experimental data and spectral data (1H
NMR-, 13C NMR- and Mass spectra).
ACKNOWLEDGMENT
First, I would like to thank prof. dr. Jan van Maarseveen for accept-ing me as an intern in his research group. I have gained a lot of lab experience and I learned how I have do purify a compound by per-forming a perfect column, I have almost become an expert in doing columns (even if I do say so myself). Furthermore, I would like to thank Luuk Steemers a lot for helping me daily with this project and answering my millions of questions, I never would have come so far without him. I also wanted to thank Joost Reek for taking the time reviewing my report and being my second corrector. Fi-nally, I also appreciated the company in the lab and that everyone thought about my project with me.
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Mechanically Interlocked Molecules, Universiteit van Amsterdam, 2017.
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Supporting information
A templated-strategy towards an all-carbon [2] rotaxane through a
clipping mechanism
Inèz C. Koornneef Villalba, drs. Luuk Steemers and prof. dr. Jan H. van Maarseveen
University of Amsterdam Van ’t Hoff Institute of Molecular Sciences, Synthetic Organic Chemistry
Table of Content
I. General Comments ... S2 II. Experimental Data ... S2 II.I Synthesis ring halves and macrocycle 14 ... S2 II.II Template synthesis ... S4 II.III Synthesis macrocycle 23 ... S6 II.IV Thread fragment synthesis that act as stoppers ... S7 III. Spectral Data: 1H NMR spectra & 13C NMR ... S10 IV Spectral data: Mass spectra ... S30
S2
I.
General Comments
Unless stated otherwise, reactions were performed without special precautions like drying or N2/Argon atmosphere. To obtain the dry solvents, DCM and CH3CN, CaH2 was used as drying agent to distill the solvents. Dried THF and Et2O were obtained by distillation with sodium and were stored under N2 atmosphere like DCM and CH3CN. Dry DMF on 4Å molecular sieves was obtained from Sigma Aldrich and stored under N2 atmosphere. Reagents were purchased with the highest purity (mostly >98%) from Sigma Aldrich and Fluorochem and used as received. Grubbs 2nd generation catalyst was purchased from AK Scientific. Reactions were monitored with thin layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F-254). SilaFlash® P60 (particle size 40-63 μm) was used for silica column chromatography. NMR spectra were recorded on Bruker DRX-400 and 300 MHz instruments and calibrated on residual undeuterated solvent signals as internal standard. The 1H-NMR multiplicities were mentioned as followed: s = singlet, d = doublet, t = triplet, q = quarted, quint = quintet, m = multiplet. Melting points were recorded on a Wagner & Munz Polytherm A Melting point apparatus and are uncorrected. IR spectra were recorded on a Bruker Alpha FTIR machine. High resolution mass spectra (HRMS) were recorded on a Mass spectrum collected on a AccuTOF GC v 4g, JMS-T100GCV Mass spectrometer (JEOL, Japan). FD/FI probe equipped with FD Emitter, Carbotec or Linden (Germany), FD 10 μm.
II.
Experimental Data
II.I Synthesis ring halves and macrocycle 14
Compound 8To dissolve the 2,5-dibromoterephtalic acid (1.62 g; 5 mmol; 1 equiv), THF (25 mL) and (COCl)2 (1.72 mL; 20 mmol; 5 equiv) were added to the flask under inert atmosphere. DMF (1 drop) was added to the solution and the reaction was stirred for 3,5 hours at RT. To obtain product 8, the solution was concentrated in vacuo. 1H NMR was not taken on time → acidchloride probably decomposed to
start-material.
Compound 9
4-(tert-butyl)-phenol (7.39 g; 49.2 mmol; 1 equiv) and hexamine (15.39 g; 109.8 mmol; 2.2 equiv) were by mistake dissolved in THF. This was concentrated in vacuo to regain the compounds after which they were dissolved in TFA (100 mL) and refluxed at 130 °C for two days under N2 atmosphere. The solution was turned brown. This was mixed with 1M HCl (150 mL) and let stir vigorously for 45 minutes. The product was obtained by extracting it with DCM (2 x 150 mL) whereby the combined organic layers were extracted with 1M HCl (2 x 200 mL) and subsequently with water (200 mL). The water layer was washed with DCM, due to presence of a foam, to remove any residual product. The combined organic layers were dried over MgSO4 after which the solvent was removed in vacuo to give a yellow/orange solid/oil. The product was purified by column chromatography in pure DCM and collected in vacuo. TLC revealed the presence of the monoaldehyde and dialdehyde, this is why recrystallization was performed by dissolving the yellow solid in warm cyclohexane (90 mL) and was let cooled till crystals arise. The crystals were collected by vacuum filtra-tion. The precise yield could not be determined due to spillage of the filtrate which contained dissolved crystals. Recrystalli-sation gave light yellow needles of compound 9 (4.969 g; 24.09 mmol; 49%). 1H NMR (400 MHz; CDCl
3; 293 K): δ 11.47
(1H, s); 10.24 (2H, s); 7.98 (2H, s); 1.35 (9H, s). Compound 10
Mg (2.6424 g; 4.5 equiv) was added to a three necked flask with a drop-ping funnel and a condenser. The glassware with the Mg was flame dried and put under vacuum/N2 flow. To the dropping funnel, 6-bromohexene (14.5 mL; 4.5 equiv) was added and diluted in dry THF (109 mL). The dilution was added dropwise whereby the reaction coloured grey and started to boil. This reaction was performed under N2 atmosphere and was refluxed for two hours. A two necked flask was flame dried and put under N2 atmosphere. Due to the following of a wrong procedure, the Grignard was cooled to 0 °C, a precipitation was observed. Compound 2 (4.969 g; 24.04 mmol; 1 equiv) was added to the flask and dry THF (100 mL) was also added. The reaction coloured yellow/grey and the precipitation dissolved. The reaction was stirred at 50 °C overnight under N2 atmosphere. The reaction was cooled to 0 °C and quenched with H2O (15 mL). A precipitation of Mg salts became visible. The solvent was evaporated, and the product was dissolved in Et2O (100 mL) and H2O (100 mL). The water layer was extracted with Et2O (2 x 20 mL) and the combined organic layers were washed with H2O (2 x 20 mL) and brine (2 x 20 mL), dried over Na2SO4, after which the solvent was removed in vacuo to give product 10 (7.10 g; 18.95 mmol;
S3
78.7 %). The product was purified by column chromatography (PE/EtOAc 8:1 → 6:1 → 4:1). 1H NMR (400 MHz, CDCl3,
293 K): δ 8.49 (1H, d); 6.98 (2H, d); 5.80 (2H, m); 5.02 (4H, m); 4.96 (2H, m); 4.79 (2H, d); 2.05 (4H, m); 1.8 -1.79 (4H, m);
1.42 (2H, m); 1.24 (9H, s). Compound 11
Glassware was flame dried and put under N2 atmosphere. Et3SiH (12 mL; 4 equiv), 10 (7.10 g; 18.75 mmol; 1 equiv) and dry DCM (150 mL) were added to the flask and cooled to -78 °C. BF3·Et2O (9.3 mL; 4 equiv) was added dropwise and stirred for an hour at -78 °C and then let warm up to RT in two hours. The reaction was quenched with H2O (50 mL) and the organic layer was dried over MgSO4. Product 11 (4.73 g; 13.66 mmol; 72.9 %) was concentrated by Kogelrohn distillation (180-200 °C; 0.026 bar). 1H NMR (400 MHz, CDCl
3, 293 K): δ 7.00 (2H, s); 5.85 (2H, m);
5.00 (4H, m); 4.50 (1H, s); 2.60 (4H, t); 2.08 (4H, q); 1.64 (4H, quint); 1.44 (8H, m); 1.31 (9H, s). Compound 12
Compound 2 (1.77 g; 5.17 mmol; 2.07 equiv) and NEt3 (0.75 mL; 5.4 mmol; 2,16 equiv) were dissolved in THF (22.4 mL) under inert atmosphere. This mixture was cooled to 0 °C and compound 8 (0.889 g; 2.49 mmol; 1 equiv) was added portion wise. The reaction was stirred for 1 hour at 0 °C and stirred overnight at RT. The mix-ture was diluted with EtOAc (20 mL) and 1M HCl (20 mL), washed with water (2 x 20 mL) and EtOAc (2 x 20 mL). The organic layers were collected and washed with brine, dried over MgSO4 and con-centrated in vacuo. The residue was purified by column chromatog-raphy (PE/EtOAc 99:1 → 98:2 → 96:4) and the yellow product 12 (664 mg; 0.68 mmol; 27.3 %) was obtained. 1H NMR not saved.
Compound 13
Compound 12 (664 mg; 0.68 mmol; 1 equiv) was dissolved in DCM (215 mL) under an inert atmosphere whereby the Grubbs II (76.74 mg; 0.09 mmol; 0.13 equiv) catalyst was added. The reaction was stirred overnight at 40 °C. Product 13 was collected via in vacuo and was purified by column chromatography (PE/EtOAc 99:1 → 98:2 → 96:4) with a yield of 46.7% (2.86 g; 7,7 mmol). Due to the presence of the starting materials visible in the 1H NMR spectrum, trituration of the product was performed with EtOAc. NMR analysis showed that the starting materials were still presence after purification. To eliminate these starting materials from the product, trituration was performed with EtOAc. 1H NMR (400
MHz, CDCl3, 293 K): δ 8.56 (2H, s); 7.16 (4H, s); 5.24 (4H, s); 2.51 (8H, m); 1.88 (8H,
S4
Compound 1413 (226 mg; 0.246 mmol; 1 equiv) was added to a two-necked round bottom flask containing
THF (56 mL) and PtO2 (19.1 mg; 0.084 mmol; 0.3 equiv). The solution was stirred under H2 atmosphere overnight. When the H2 stream was added, the solution obtained a black vague. The white powder product 14 was collected by saving the filtrate of the vacuum filtration over Celite, washing it with EtOAc and concentrating it in vacuo (221 mg; 0.239 mmol; 97.55%). 1H NMR (400 MHz, CDCl
3, 293 K): δ 8.60 (2H, s); 7.14 (4H, s); 2.51
(8H, m); 1.64 (8H, m); 1.57 (18H, s); 1.36 (32H, s).
II.II Template synthesis
Compound 15Glassware was put in an oven to dry for an hour. The compounds, 2,5-dibromoterephtalic acid (3.248 g; 10.02 mmol; 1 equiv), CH3I (1.9 mL; 30.52 mmol; 3 equiv) and K2CO3 (4.174 g; 30.2 mmol; 3 equiv) were dissolved in dry DMF (30 mL) and the reaction was stirred overnight at 80 °C. The reaction was diluted with EtOAc (50 mL) and H2O (50 mL). Next, it was extracted with EtOAc (3 x 30 mL), washed with H2O (3 x 30 mL) and brine (2 x 40 mL) and dried over MgSO4. The product was collected in vacuo giving yellow needles after which were white needles after recrystallizing the product with MeOH. The filtrate of the recrystallization was concentrated in vacuo and recrystallized a second time to obtain more residual product which resulted in compound 15 (2.809 g;7.98 mmol; 79.8%). 1H NMR (300 MHz,
CDCl3, 293 K): δ 8.09 (2H, s); 3.99 (6H, s).
Compound 16
15 (3.00 g; 8.5 mmol; 1 equiv), 4-trimethylsilyl phenyl boronic acid (4.13 g; 21.28
mmol; 2.5 equiv), Na2CO3 (2.29 g; 21.61 mmol; 2.5 equiv) were dissolved in H2O/EtOH/Toluene (1:1:2 80 mL) under N2 atmosphere. Next, Pd(PPh3)4 (994.6 mg; 10 mol%), was added and stirred for 48 hours at 98 °C. The reaction was di-luted with EtOAc (50 mL) and the water layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with 1M HCl (2 x 50 mL), H2O (2 x 50 mL) and brine (2 x 50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (PE/EtOAc 20:1 → 10:1 → 8:1 → 4:1 → 2:1 → 1:2) to give 16 (4.47 g; 9.1 mmol; 107%) as a red/pink solid compound. Melting-point: 155-182 °C. 1H NMR
(400 MHz, CDCl3, 293 K): δ 7.84 (2H, s); 7.61 (4H, d); 7.39 (4H, d); 3.70 (6H, s); 0.34 (18H, s). 13C NMR (CDCl3, 300
MHz): δ 168.31; 141.30; 140.31; 139.91; 133.34; 133.16; 132.30; 127.77; 52.37; 0.94. IR (cm-1): 2953; 2924; 1724.
1:2 ratio was too polar what caused that the column coloured black (the Pd probably flushed with the eluent). 107% → probably some inorganic compound presence (like Pd) due to the too polar eluent used.
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Compound 17Glassware was flame dried and put under N2 atmosphere. 16 (4.37 g; 8.90 mmol; 1 equiv) was dissolved in dry DCM (90 mL) and ICl (1.4 mL; 26.70 mmol; 3 equiv) was slowly added whereby the solution turned deep purple (due to the colour of compound 16). This was stirred over the weekend at RT, after which the reaction was diluted with DCM (20 mL) and was washed with 0.1M sodium thiosulphate (2 x 150 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo resulting in a brown solid. The residue was recrystallized whereby the brown solid was dissolved in boiling EtOAc and PE was slowly added till a small fraction was precipitated. When a precipitation was visible, the flask was put in an ice bath. This yielded 17 (4.19 g, 7 mmol; 77%). Melting-point: 226-239 °C. 1H NMR (400 MHz,
CDCl3, 293 K): δ 7.82 (2H, s); 7.79 (4H, d); 7.12 (4H, d); 3.72 (6H, s). 13C NMR (CDCl3, 300 MHz): δ 167.74; 139.43;
137.50; 133.05; 132.29; 130.29; 93.95; 52.55. IR (cm-1): 3024; 2841; 1724.
Compound 18
17 (4.19 g; 7.00 mmol; 1 equiv) was dissolved in a THF (60 mL)/ MeOH (42.5 mL)/ H2O (17.5 mL) mixture. Thereby, KOH (1.70 g; 30.3 mmol; 4.3 equiv) was added to the mixture. Since the starting material was not fully dissolved, the reaction was heated up to 80 °C after which the mixture was clear after 30 minutes. This was stirred overnight at 80 °C. The reaction was allowed to cool to RT and was then concentrated in vacuo till the MeOH and THF were evaporated. The residue and H2O layer were acidified with concentrated HCl (37%, 30 mL), where a white precipitation and fume arise, and this was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with H2O (2 x 100 mL) and brine (2 x 100 mL), dried over MgSO4 and concentrated in vacuo to give 18 (3.98 g; 6.9 mmol; 99%) as a white powder.
Melting-point: <300 °C. 1H NMR (400 MHz, DMSO, 293 K): δ 13.20 (1H, s); 7.83 (2H, d); 7.71 (1H, s); 7.23 (2H, d). 13C
NMR (DMSO, 300 MHz): δ 168.30; 139.11; 139.03; 137.02; 134.01; 131.09; 130.52; 94.21. IR (cm-1): 3438; 1662.
Compounds 19 and 20
To synthesize 20, 18 was converted into an acid chloride 19 by drying the glassware and putting it under N2 atmosphere. 18 (571 mg; 1.00 mmol; 1 equiv) was dissolved in dry THF (10 mL) and oxalylchloride (0.75 mL; 4.00 mmol; 4 equiv) was added. Then, DMF (5 μL) was added as catalyst. Hereby, a gas arose, and the starting material started to dissolve. The reaction was stirred overnight at RT. In the morning, the reaction had a yellow colour. The mixture was concentrated in vacuo to give 19 (615 mg; 1.00 mmol; 100.8%) which was added to mixture of Pfp (524 mg; 2.8 mmol; 2.8 equiv), Et3N (0.42 mL; 3.00 mmol; 3 equiv) and dry THF (10 mL) at 0 °C. By adding 19, a precipitation (Et3N salts) arose and the mixture became white. The reaction was stirred for two hours at RT and was then diluted with EtOAc (50 mL). The organic layer was washed with 1M HCl (2 x 20 mL), NaHCO3 (2 x 25 mL) and brine (2 x 25 mL). Because there was still a presence of a precipitation, concentrated HCl (37%, 5 mL) was added to wash the organic layer. Since NaHCO3 was presence, a gas arose. The organic layer was dried over MgSO4 and concentrated in vacuo which yielded 20 (952 mg; 1.05 mmol; 106%). Recrystallisation was performed to purify the compound and give 13 in quantitative yield as white needles. Melting-point: 224-277 °C. 1H NMR (400 MHz, CDCl
3, 293 K): δ 8.14 (2H, s); 7.85 (4H, d); 7.23 (4H, d). 13C
S6
II.III Synthesis macrocycle 23
Compound 21
Glassware was flame dried and put under N2 atmosphere. Dry CH3CN (12 mL) was added, after which 11 (723.5 mg; 2.1 mmol; 2.1 equiv), Cs2CO3 (801.1 mg; 2.5 mmol; 2.5 equiv), a little spoon of MgSO4 and 20 (890.3 mg; 0.986 mmol; 1 equiv) were added. By adding Cs2CO3, the mixture became deep pink/purple. This was stirred over the weekend at 60 °C. A brown precipitation was visi-ble after the weekend. The reaction was diluted with EtOAc, till all the precipitation was dissolved, after which silica was added and the flask was concentrated in vacuo. The dried silica was loaded on a column (PE/EtOAc, 100:0 → 98:2) to purify the compound and give 21 (0.915 g; 0.75 mmol; 76%) as a salmon pink solid. In the 1H NMR spectrum, starting material was visible, that is why recrys-tallisation was carried out in pure EtOH. This yielded 21 (530 mg; 0.43 mmol; 44%) as white needles. Melting-point: 131-142°C. 1H
NMR (400 MHz, CDCl3, 293 K): δ 8.12 (2H, s); 7.78 (4H, d); 7.21 (4H, d); 7.07 (4H, s); 5.78 (4H, m); 4.97 (8H, t); 2.39 (8H, t); 2.01 (8H, q); 1.57 (8H, m); 1.53 (8H, m); 1.38 (8H, m); 1.30 (18H, s). 13C NMR (CDCl 3, 300 MHz): δ 164.81; 148.99; 144.93; 142.19; 139.29; 139.01; 137.50; 133.63; 133.13; 132.52; 130.66; 124.92; 114.54; 94.22; 34.54; 33.84; 31.50; 30.91; 30.15; 29.30; 28.89. IR (cm-1): 2926; 2856; 1743. Compound 22
Glassware was flame dried. 21 (470.2 mg; 0.38 mmol; 1 equiv) was dissolved in dry DCM (4 mL). Grubbs II (26.9 mg; 0.031 mmol) was added after which the reaction was stirred overnight at 40 °C. A spoon of silica was added to the mixture, which was concentrated in
vacuo. The silica was loaded on a column (PE/EtOAc, 100:0 → 99:1 → 98:2 → 96:4 →
9:1) to purify product 22 (398.4 mg; 0.33 mmol; 88%) as a white solid/foam. Melting-point: 133-137 °C. 1H NMR (400 MHz, CDCl
3, 293 K): δ 8.24 (2H, s); 7.76 (4H, d); 7.20 (4H,
d); 7.06 (4H, s); 5.31 (4H, m); 2.38 (8H, m); 1.90 (8H, m); 1.48 (8H, m); 1.33 (18H, s).
HRMS (FD) calcd for C64H76I2O4 [M+]: 1163.12, found 1162.38. IR (cm-1): 2926; 2855; 2253; 1740; 1597.
S7
Compound 2322 (336.9 mg; 0.289 mmol; 1 equiv) was dissolved in dry THF (5 mL) and PtO2 (21.2 mg; 0.093 mmol; 0.3 equiv) was added. Vacuum/H2 cycles were carried out, after which the reaction was stirred overnight at 50 °C. The mixture was filtered over a plug of Celite, which was flushed with EtOAc and concentrated in vacuo to give 23 as a foamy solid. The 1H NMR showed that only ca. 50% of 22 was converted into 23.
II.IV Thread fragment synthesis that act as stoppers
Compound 243,5-dibromobenzaldehyde (2.667 g; 5.88 mmol; 1 equiv) was added in a flask with 4-tert-bu-tylbenzeneboronic acid (4.425 g; 16.77 mmol; 2.9 equiv), Na2PO3 (4.315 g) and dissolved in a PhMe/H2O/EtOH (50:25:25 mL) mixture. The solution was put under N2/Ag atmosphere whereby Pd(PPh3)4 (1.135 g; 0.1 mmol; 0.017 equiv) was added; the reaction was stirred over-night at 40 °C. To obtain product 6 the solution was washed with H2O (2 x 20 mL) and Et2O (2 x 20 mL). The organic layers were washed with brine, dried over MgSO4 and purified by column chromatography (PE/DCM 5:1 → 3:1 → 2:1). White crystals were obtained of com-pound 24 (2.798 g; 7.55 mmol; 105 %). 1H NMR (400 MHz, CDCl
3, 293 K): δ 10.16 (1H, s);
8.09 (1H, s); 8.08 (2H, s); 7.65 (4H, d); 7.55 (4H, d); 1.41 (18H, s).
Compound 25
This reaction was performed in flame dried glassware under inert atmosphere. 4-pentyn-1-ol (1.1 mL; 11.3 mmol; 1.5 equiv) was dissolved in THF (75 mL) and after cooling the solution to -78 °C, 2.5 M of BuLi (9.0 mL; 22.6 mmol; 3 equiv) and stirred for an hour at that temperature. Next, 24 (2.791 g; 7.53 mmol; 1 equiv) was added, after which the mixture was allowed to warm up to RT and the solution was stirred for another hour. The reaction was quenched with sat. NH4Cl (56 mL), extracted with Et2O (2 x 20 mL) and the organic layers were washed with brine and dried over MgSO4. Product 25 (2.917 g; 6.42 mmol; 85.8 %) was obtained by concentrating the organic lay-ers in vacuo and the obtained yellow oily product was purified by column chromatography (PE/EtOAc 2:1 → 1:1). 1H NMR (400 MHz, CDCl
3, 293
K): δ 7.78 (1H, s); 7.74 (2H, s); 7.60 (4H, d); 7.53 (4H, d); 5.58 (1H, s); 3.80
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Compound 2625 (2.19 g; 4.81 mmol; 1 equiv) was dissolved in EtOH (50 mL) and Pd/C
(53.2 mg; 10% w/w; 0.49 mmol; 0.5 equiv) was added to the solution. H2 was bubbled through the mixture for an hour after which the reaction was stirred overnight under H2 atmosphere. The mixture was filtered over Celite, which was flushed with EtOAc and concentrated in vacuo.
A TLC (PE/EtOAc 10:1) showed many impurities that is why a column chro-matography (PE/EtOAc 10:1 → 8:1 → 6:1) was performed to purify the product. Product 26 (1.026 g; 2.32 mmol; 48 %) was obtained in vacuo as a transparent sticky oil. 1H NMR (400 MHz, CDCl
3, 293 K): δ 7.65 (1H, s);
7.60 (4H, d); 7.50 (4H, d); 7.38 (2H, s); 4.15 (1H, s); 3.67 (2H, t); 2.75 (2H, t); 1.75 (2H, m); 1.59 (2H, m); 1.38 (18H, s).
Compound 27
26 (355 mg; 0.8 mmol; 1 equiv) was dissolved in dry DCM (12 mL) and PPh3 (271.5 mg; 1.03 mmol; 1.3 equiv) was added. This was cooled to 0 °C and NBS (176.2 mg; 0.98 mmol; 1.2 equiv) was added portionwise to the reaction. After the ice in the ice bath was melted, the reaction was stirred for 20h at RT after which the solution was concentrated in vacuo on silica. The silica was loaded on the column (PE/EtOAc 100:0 → 99:1 → 99:2) to give 27 (367 mg; 0.73 mmol; 90.7%) as a colourless oil.Melting-point: °C. 1H NMR (400
MHz, CDCl3, 293 K): δ 7.65 (1H, s); 7.60 (4H, d); 7.50 (4H, d); 7.38 (2H, d); 3.44 (2H, t); 2.76 (2H, t); 1.90 (2H, m); 1.75 (2H, m); 1.52 (2H, m); 1.41 (18H, s); 0.88 (2H, m). 13C NMR (CDCl 3, 300 MHz): δ 150.42; 143.45; 141.70; 138.68; 127.05; 126.14; 125.83; 123.61; 36.16; 34.70; 34.09; 32.88; 31.54; 31.44; 28.61; 28.22. IR (cm-1): 3028; 2959; 2931; 1776. Compound 28
Trimethylsilylacetylene (55 μL, 0.40 mmol; 4 equiv) was added in a flame dried flask with dry THF (1 mL) under N2 atmosphere. 1.6 M nBuLi (0.25 mL; 0.4 mmol, 4 equiv) was added dropwise and stirred for 1 hour at -78 °C. A mixture of 27 (52.0 mg; 0.1 mmol; 1 equiv), HMPA (70 μL, 0.4 mmol; 4 equiv) and dry THF (1 mL) was added dropwise to the reaction. The mixture was stirred for 1 hour at -78 °C followed by 24 hours stirring at 50 °C. The reaction was deep orange which was quenched with sat. NH4Cl (2 mL) at 0 °C and di-luted with H2O (2 mL) and EtOAc (2 mL). After separation of the two layers, the water layer was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with H2O (2 x 10 mL) and brine (2 x 10 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (PE) to give 28 (41.2 mg; 0.08 mmol; 80%) as a colourless oil. 1H NMR (400 MHz, CDCl
3, 293 K): δ 7.66 (1H, s); 7.62 (4H, d); 7.52 (4H,
d); 7.41 (2H, s); 2.78 (2H, t); 2.24 (2H, m); 1.76 (2H, m); 1.59 (2H, m); 1.53 (2H, m); 1.49 (2H, m); 1.42 (18H, m); 1.27 (2H, m); 0.90 (2H, m); 0.19 (9H, s).
S9
Compound 2928 (150 mg; 0.287 mmol; 1 equiv) was dissolved in a mixture of
MeOH/THF (1:1, 5 mL) under N2 atmosphere, after which K2CO3 (48.1 mg; 0.35 mmol; 1.2 equiv) was added. This was stirred over the weekend at RT. The reaction was evaporated, and the residue was extracted with Et2O and H2O. The water layer was extracted twice with Et2O (2 x 20 mL) and the organic layer was washed twice with H2O (2 x 20 mL) and brine (2 x 20 mL), dried over MgSO4 and concentrated in vacuo to give
29 (106 mg; 0.24 mmol; 82%) as a white solid. 1H NMR (400 MHz,
CDCl3, 293 K): δ 7.66 (1H, s); 7.62 ((4H, d); 7.52 (4H, d); 7.40 (2H, s); 2.77 (2H, t); 2.24 (dt, 2H); 1.96 (1H, t); 1.76 (2H, m); 1.56 (2H, m); 1.47 (2H, m); 1.41 (18H, s); 1.33 (2H, m). 13C NMR (CDCl 3, 300 MHz): δ 150.36; 143.60; 141.66; 138.71; 127.05; 126.15; 125.80; 123.55; 84.80; 68.32; 36.22; 34.67; 31.54; 31.51; 28.96; 28.75; 28.54; 18.54. IR (cm -1): 3309; 2960; 2117; 1777; 1596.
