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DEGREE PROJECT, IN , SECOND LEVELORGANIC CHEMISTRYSTOCKHOLM, SWEDEN 2015
Synthesis and Application of ChiralCarbocations
ANA ALICIA PALES GRAU
KTH ROYAL INSTITUTE OF TECHNOLOGY
CHE
1
Acknowledgements
I wish to acknowledge my research mentor Prof. Johan Franzén for accepting me in his group
and his mentorship during the whole project. His valuable suggestions were very fruitful for
the completion of the project.
I would also like to thank my research group for their continuous support and valuable inputs.
I am grateful to Organic Chemistry department in KTH for providing me the necessary
facilities and a great laboratory environment.
I must mention my gratitude to my home university Universitat Politècnica de València and
my host university KTH Royal Institute of Technology and Erasmus Plus exchange
programme of EU.
Finally, I would like to thank my family and friends for their continuous encouragements
during this whole period.
2
Abstract
Asymmetric synthesis is most significant method to generate chiral compounds from
prochiral substrates. It usually involves a chiral catalysis, which can be either metal based or
organo-catalysis. Both of these systems have their own advantages and disadvantages. In
recent times, organocatalysts are gathering widespread attention due to their low toxicity and
inexpensive nature. Organocatalysts can replace traditional metal based Lewis acid catalysts
in several useful organic transformations like the Diels-Alder reactions.
Carbocations are compounds with positively charged carbon atoms and they can activate the
substrate by pulling its electrons thus making it more electrophilic. Though carbocations are
well-known in literature, they are not well explored in catalysis despite their tremendous
potential.
The aim of this project is to synthesize new chiral carbocations, derived from different chiral
auxiliaries and substitution on aromatic moiety and to investigate them in asymmetric Diels-
Alder reactions. We envisioned the final product to be enantio-enriched as the carbocations
are chiral in nature.
We have synthesized several chiral secondary and tertiary alcohols as a precursor of
carbenium salts. These alcohols were mainly synthesized by addition of Grignard reagent or
organolithium reagents to the carbonyl compounds. Though, we have synthesized several
chiral alcohols, only three carbocations could be isolated those having methoxy group in the
aromatic ring. The methoxy group was found to be crucial for the stabilization of the
carbocation.
All the isolated carbocations were able to catalyze the Diels-Alder reactions, however it was
found that carbocation 4 with BF4 as a counter ion was better reactive than others.
Unfortunately, we could not get any chiral induction with the use of these catalysts. We
believe that with better tuning in catalysts structure and the reaction conditions these
carbocations might able to produce chiral induction in the product.
3
List of Abbreviations
BINOL 1,1'-Bi-2-naphthol
BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene
ee Enantiomeric excess
TfOH Triflurometahnesulfonic acid
DCM Dichloromethane
Tr Trityl
Cp Cyclopentyl
TBS tert-Butyldimethylsilyl
EWG Electron withdrawing group
LUMO Lowest Unoccupied Molecular Orbital
HOMO Highest Occupied Molecular Orbital
LA Lewis Acid
DMAP Dimethylamino pyridine
TsCl para-Toluene sulfonyl chloride
r.t. Room Temperature
o.n. Over Night
DMF Dimethyl formamide
THF Tetrahydrofuran
DIAD Diisopropylazodicarboxylate
NMR Nuclear Magnetic Resonance
* Chiral Center
w.r.t. with respect to
4
Table of contents
1 Introduction…………………………………………………………………5
1.1 Chirality…………………………………………………………………5
1.2 Chiral Catalysis (Asymmetric catalysis)………………………………..5
1.3 Chiral Lewis Acid Catalysis…………………………………….............6
1.4 Different type of metal free Lewis acid catalysis……………………….7
1.4.1 Silyl cation based catalysts………………………………………..7
1.4.2 Carbocations………………………………………………………9
2 Aim of this Project…………………………………………………………15
3 Results and Discussion……………………………………………………..17
3.1 Design and synthesis of the chiral carbocation 1……………………….17
3.2 Design and attempted synthesis of the chiral carbocation 2……………19
3.3 Design and attempted synthesis of chiral carbocation 3………………..22
3.4 Design and Synthesis of chiral carbocation 4…………………………..24
3.5 Design and attepmted synthesis of carbocation 5………………………26
3.6 Design and attempted synthesis of carbocation 6………………………27
3.7 Catalytic evaluations of carbocations in Diels-Alder and hetero
Diels-Alder reaction…………………………………………………….29
4 Conclusion and outlook……………………………………………………31
5 Experimental part…………………………………………………………..32
6 References…………………………………………………………………45
5
1 Introduction
“The universe is dissymmetrical; for if the whole of the bodies which compose the solar
system were placed before a glass moving with their individual movements, the image in the
glass could not be superimposed on reality……….. Life is dominated by dissymmetrical
actions. I can foresee that all living species are primordially, on their structure, in their
external generates functions of cosmic dissymmetry.”
-Louis Pasteur, 1848[1]
1.1 Chirality
“Chirality is an all-encompassing phenomenon” (Blaser et al. 2012) which is unveiled by
both macroscopic as well as microscopic objects found in nature. In molecular terms
chirality, a geometrical phenomenon outcomes in the “dual existence” (termed as
enantiomers) of a molecule. The two enantiomers have same chemical structure and they are
non-superimposable mirror image to each other. In this context it is not surprising that the
biological and therapeutic activity of a chiral substance depends upon their stereochemistry,
since all highly living organisms are chiral.[2]
The one enantiomer of the racemic mixture
(eutomer) is biologically active whereas the other (distomer) is either fatal or inactive.[3]
This
is the reason behind the fact that more than one third of the marketed drugs are chiral in
nature and the regulator will approve the new drugs with an asymmetric centre only in one
enantiomeric form.[4]
1.2 Chiral Catalysis (Asymmetric catalysis)
Prior to the tragedy caused with the use of racemic thalidomide as a sedative, came into light
in early 60s, only a few synthetic methods for the preparation of chiral compounds were
known. In 1970, the development of the asymmetric synthesis started and now there are
numerous methods to obtain a chiral compound. These methods can be broadly categorized in
three different routes, viz., (i) Resolution of the racemates to provide single enantiomers (ii)
The chiral pool synthetic approach and (iii) Asymmetric synthesis.
6
However, among them asymmetric synthesis, mostly achieved by a chiral catalyst (metal
catalyst or organo-catalyst), is a most general way to obtain optically pure compounds due to
broad substrate scope and flexibility to synthesize any of the desired enantiomer.
A catalyst provides an alternative route for the reaction with lower activation energy (Figure
1). Thus catalysts can enable a reaction which is either very slow or not progressing at all.
Asymmetric catalysis on the other hand work by lowering the activation energy differently
from one enantiomer to other enantiomer, which is done by asymmetric induction, involves
substrate, reagent, catalyst or environment.
Figure 1. Kinetic profile of a catalyzed reaction.
1.3 Chiral Lewis Acid Catalysis
Lewis acids are electrophilic compounds, which mean they are capable of accepting a pair of
electrons. The Lewis acidic compounds can act as a catalyst due to their ability to activate the
substrates by pulling away electrons making them more electrophilic. In general Lewis acid
catalysis is metal based. Main group metals such as aluminum, boron, silicon, and tin, as well
as many early (titanium, zirconium) and late (iron, copper, zinc) d-block metals can attract
electron from electronegative atom in the substrate, such as oxygen (both sp2 or sp
3),
nitrogen, sulfur, and halogens. Hence, classical carbon-carbon or carbon-heteroatom bond
formation reactions such as Diels-Alder, Ene-reaction or Friedel-Crafts reaction can be
catalyzed by metal based Lewis acid catalysts. The asymmetric versions of these reactions are
also well explored where a chiral ligand scaffold (such as BINOL, BINAP, bis-oxazolines
7
etc.) that is coordinated to the Lewis acidic metal centers provided the necessary chiral
induction.
Though the term Lewis acid catalysis is mostly generalized to metal based catalysts however,
organic compounds like carbenium, silyl, phosphonoum cations or hypervalent compounds
based on silicon or phosphorous also exhibit Lewis acidic activity. The advantages with metal
free Lewis acid catalysts are that they are simple organic molecules and thus any
contamination due to metal source during the synthesis of biologically or pharmaceutically
active compounds can be avoided. [5]
1.4 Different type of metal free Lewis acid catalysis
In this section some selective examples of metal free Lewis acidic catalysis particularly in
asymmetric synthesis have been discussed.
1.4.1 Silyl cation based catalysts
Silicon based Lewis acid catalysis are of particular importance due their ability to catalyze a
broad variety of reactions and also compatible with many carbon nucleophiles like silyl enol
ethers, allyl organometallic reagents and cuprates. Lewis acidic silyl based catalysts can be
divided in two categories based on the strength of the counter anion which is not discussed in
details here.
The first use of silicon based Lewis acid in asymmetric Diels-Alder reaction was reported by
the groups of Jørgensen and Helmchen which involves the use of cationic silyl salt a. A good
reactivity (>95% yield) with high endoselectivity (>95%) was obtained at -40 °C in 1 h.
However a poor enantioselectivity of 10% was achieved (Scheme 1).[6]
8
Scheme 1. First use of silyl cation in asymmetric Diels-Alder reaction.
Following this initial report, Ghosez et al. reported a number of enantiopure cycloalkylsilyl
triflimides (b-e) as active catalyst for enantioselective Diels-Alder reactions to obtain a
maximum endo selectivity of 96% and a maximum enantioselectivity of 59% (Scheme 2).[7]
Scheme 2. Chiral cycloalkylsilyl triflimides in Diels-Alder reaction.
The strong influence of counter ion in silyl based Lewis acid catalysis was investigated by
Sawamura et al. in achiral Mukaiyama aldol reaction by an insitu generated salt f to get the
product in 97% yield in 1h (Scheme 3). However when instead of f, the use of Me3SiOTf,
Me3SiNTf2 and Et3SiNTf2 gave 0, 6 and 13% conversion respectively.[8]
9
Scheme 3. Insitu generated silyl cation in Mukiyama aldol reaction.
In summary silyl based Lewis acid catalysts can be a good alternative for traditional metal
based catalytic systems. However there are still room for improvements in terms of
enantioselectivity and the reaction temperature.
1.4.2 Carbocations
The extraordinary instability of such an ‘ion’ accounts for many of the peculiarities of
organic reactions. Frank C. Whitmore, 1932[9]
A carbocation is an ion with positively charged carbon atom. The above statement by
Whitmore was very crucial for chemists to understand the importance of carbocations in
chemical reactions. The discovery of first carbocation can be attributed to Norris, Kehrman
and Wentzel where they have identified the color solutions containing trityl (triphenylmethyl)
cation.[10]
During the period 1901-1940 efforts from various research groups of Gomberg,
Meerwein, Ingold, Whitmore, Hughes and Kimbali confirmed the presence of carbocations as
an intermediate in various synthetic organic transformations.[11]
After these initial
discoveries, till date carbocations are extensively studied both spectroscopically and
computationally.[12]
The chemists working in the field of carbocations received best
recognition in terms of Nobel Prize to George A Olah for his pioneering research involves the
generation and reactivity of carbocations via superacids.[13]
However despite significant development over more than 100 years carbocations are yet to
significantly represent as organocatalysis as compared to their analogues such as silyl salts.
The first successful report of carbocation as an organocatalyst involves the application of
trityl salts (g) (Figure 2) as a catalyst in Mukaiyama aldol type reactions (Scheme 4) and
Michael addition. The reaction involves the attack of silyl enol ethers to activated acetals or
aldehydes under mild reaction condition and short reaction time at -78 oC to give high
selectivity towards syn- or anti- products.[14]
10
Figure 2. Trityl salts used in first Mukaiyama aldol type reactions and Michael addition.
Scheme 4. The Mukaiyama aldol reaction catalyzed by trityl carbocation.
After this initial report, several other trityl ion catalyzed organic transformations have been
reported. Some of these organic transformations are listed in the flowchart given in scheme 5.
Scheme 5. Trityl carbocation catalyzed organic transformations.
11
The mechanism of the Mukaiyama type aldol reaction was not well known however, it was
proposed that the reactions proceed through catalytic activation of the aldehyde by trityl
carbocation followed by interaction with the silyl enol ether producing the intermediate
(Scheme 6).[15]
Scheme 6. Proposed mechanism involving the trityl carbocation.
However two of the mechanistic pathways have been proposed, (i) the release of TMS triflate
salt and its electrophilic attack on the trityl group in the intermediate or (ii) intramolecular
transfer of the TMS group to the aldolate position resulting in the regeneration of the trityl
catalyst and the formation of the product (Scheme 6).
Further insight in the mechanism was provided by Bosnich et al. where they have
investigated several Lewis acids such as [Ti(Cp)2(OTf)2], Ph3CClO4 and Ph3COTf in the
Mukaiyama aldol and the Sakurai alkylation reaction. It was proved that the reaction was
catalyzed by the TMS salt which was generated insitu by the Lewis acid catalyst employed at
the start of the reaction. It was observed that the Me3SiOTF generated under the reaction
conditions used, is the real catalyst and can catalyze the Mukaiyama aldol reaction even in
undetected amount of 10-7
mol.[16]
Chen et al. have investigated the Mukaiyama aldol reaction in presence of a chiral trityl salt h
(Scheme 7) which was found to be a significant step towards clear understanding of the
mechanism. [17]
12
Scheme 7. Chiral carbocation mediated asymmetric Mukaiyama aldol reaction.
As chiral induction was obtained in the product (ee 50%) hence, carbenium-mediated
catalysis cannot be discarded. The enantioselectivity was found to be significantly influenced
by the nature of the silyl substituent, counter ion of the trityl salt and the reaction time. For
instance, it was found that with increase in reaction time enantiomeric excess in the product is
decreasing with increase in yield, which suggests dominance of the silyl mediated reaction
pathway with increasing reaction time. Further, when reaction conditions that suppressed the
silyl mediated pathway were employed, those were found to be very crucial in order to get
higher chiral induction in the product. From this study it could be concluded that the rigid
conformation and the enhanced reactivity of the carbocation may be the key requirement for
the productive enantioselective carbenium catalysis in the aldol-type additions.
Carbocations can be useful catalysts for non-chiral and chiral version of Diels-Alder reaction.
Diels-Alder reactions can be performed even without the use of a catalyst. However use of a
Lewis acidic catalysts can significantly enhance the rate of the reaction as well as the
regioselectivity of the product. The catalyst is functioning by binding to the EWG of the
dienophile, thus lowering its LUMO further (Scheme 8).
13
Scheme 8. Role of Lewis acid catalyst in Diels-Alder reaction.
But tradition Lewis acids often have to use in stoichiometric ratio and there still room for
improvement in terms of catalytic activity and selectivity. In this area development of
carbocations as Lewis acid catalysts for both chiral and non-chiral Diels-Alder reaction can
be an interesting approach.
The asymmetric version of the Diels-Alder reaction was first discovered in 1948 but the
Lewis acid catalyzed version was first known in 1963. Besides metal based catalytic system
chiral organocatalysts such as chiral amines, heterocyclic carbenes and chiral guanidines have
also been reported for the asymmetric version. However there are only few reports which
involve carbocations as a catalyst in either chiral or non-chiral Diels-Alder reaction.
Kagan et al. designed o-substituted ferrocenyl scaffold i that allowed to avoid the placement
of two aryl groups on the carbocation and provided the stabilization and asymmetry and
utilized them in Diels-Alder reaction in DCM at -35 oC in presence of 4Å molecular sieves to
get predominantly the exo-product (Scheme 9).[18]
14
Scheme 9. Ortho substituted ferrocenyl cation in Diels-Alder reaction.
Mechanistic study by the group of Sammakia et al. has showed that the reaction is actually
catalyzed by the protic acid TfOH which is generated in situ either by the hydrolysis of the
carbenium salt or by the nucleophilic attack of the diene on the cation center.[19]
The carbocations can be interesting candidate for the potential Lewis acidic catalysis
(Scheme 10) due to the flexibility in tuning the electronic and steric features of the positively
charged sp2 carbon depending on the nature of the reaction. Again the nature of the counter
ion can also significantly affect the stability and reactivity of the carbocation. One added
advantage of exploitation of carbocation as Lewis acid catalysts is that they do not possess
the toxicity that might arise from metal based catalysis. Also by incorporation the chirality in
the carbocations in suitable position will make them ideal choice in asymmetric Lewis acid
catalyzed reactions.
Scheme 10. Carbocations as a catalyst in Diels-Alder reaction.
15
2 Aim of this Project
The aim of this project was to synthesize, characterize and evaluate new chiral carbenium
salts as a catalyst in different asymmetric organic transformations like Diels-Alder or hetero
Diels-Alder reactions.
The tertiary or secondary carbocations (Figure 3) were to be synthesized starting from
enantiopure chiral alcohols such as (R)-2-methyl-2-butanol, (S)-(-)-α-Methyl-2-
naphthalenemethanol and (S)-1-phenyl ethanol etc (Figure 4). As the starting alcohols are
optically pure in nature so the resultant carbocations are also chiral and expected to induce
chirality in the product in Diels-Alder or similar type of Lewis acid catalyzed reactions.
Figure 3. Structure of carbocations attempted in this thesis.
16
Figure 4. Enantiopure alcohols as auxiliaries in the synthesis of chiral carbocations.
Further to stabilize the carbocation the effect of the electron donating group in the aromatic
moiety and the role of the counter ions were also to be considered during the synthesis of the
new carbenium salts.
17
3 Results and Discussion
3.1 Design and synthesis of the chiral carbocation 1
In search of suitable chiral carbocation catalyst for several asymmetric organic
transformations our investigation started with the synthesis of compound 1 (Figure 5).
Figure 5. Structure of Carbocation 1
To get the target compound 1, at first tosylation of a commercially available optically pure
(R)-2-methylbutanol 1a was carried out following the reaction conditions mentioned in
scheme 11 to obtain compound 1b.
Scheme 11. Reaction conditions for the synthesis of compound 1b
Next tosylated product 1b which was synthesized in the previous step, was reacted with 2-
bromophenol 1c in presence of cesium carbonate as a base in order to get compound 1d
(Scheme 12).
18
Scheme 12. Reaction conditions for synthesis of compound 1d
The brominated compound 1d was treated with activated magnesium turnings to form insitu
the aryl magnesium bromide 1e (Grignard reagent), which on further reaction with 4-
Methoxy benzophenone 1f gave the tertiary alcohol 1g (Scheme 13) which acts as the
precursor of carbenium salt 1.
Scheme 13. Grignard reaction conditions for synthesis of compound 1g.
The electrophile for the Grignard i.e., the ketone in this case was judiciously chosen keeping
the stability factor of the carbocation in mind. A methoxy group in the ortho or para position
of the benzene ring of ketone, would expected to stabilize the resultant carbocation due to its
ability to donate a pair of non-bonded electrons and thus participating in a resonating
structure (Scheme 14).
Scheme 14. Synthesis of the carbocation and its resonance stabilization.
19
During the Grignard addition to the ketone, there is generation of a new chiral center in the
product, which will lead to the mixture of two diastereomers for the alcohol 1g (Figure 6).
However, in the next step during the synthesis of the carbocation the chiral center is
destroyed again resulting in formation of the same carbocation from both the diastereomeric
alcohols.
Figure 6. Two possible diastereomers of the alcohol 1g.
The desired carbocation 1 was synthesized from the tertiary alcohol 1g (mixture of both
diastereomers) following the procedure reported by Mayr et. al.[20]
In this procedure the
alcohol was dissolved in Et2O, propionic anhydride and HBF4.OEt2 was added to the reaction
mixture to obtain the carbocation as dark red color precipitate.
3.2 Design and attempted synthesis of the chiral carbocation 2
Once our previously synthesized carbocation could not induce any chirality in Diels-Alder
and hetero Diels-Alder reaction, we have designed a second type of carbocation scaffold 2
(Figure 7) based on another chiral auxiliary i.e. (S)-(-)-α-Methyl-2-naphthalenemethanol 2a.
The present carbocation was believed to be fruitful as it is C2-Symmetric.
20
Figure 7. Structure of the desired carbocation 2.
The attempted synthesis involved a Mitsunobu reaction between the chiral alcohol 2a and 2-
Bromoresorcinol 2b to give the compound 2c (Scheme 15).
Scheme 15. Synthesis of compound 2c.
The Mitsunobu reaction is used to convert primary and secondary alcohol to esters, phenyl
ethers, thioethers and related compounds. One of the key feature is that the reaction proceeds
with clean inversion, which makes the Mitsunobu Reaction with secondary alcohols a
powerful method for the inversion of stereogenic centers in natural product synthesis.
The general mechanism of Mitsunobu reaction between a phenol and an alcohol is depicted
below which justifies the inversion of chirality from 2a to 2c (scheme 16).
21
Scheme 16. Mechanism of the Mitsunobu reaction between a phenol and an alcohol.
The resultant aryl bromide compound 2c was then tested for the generation of Grignard
reagent and its addition to 4,4'-dimethoxybenzophenone. Unfortunately this methodology did
not yield in the tertiary alcohol 2d i.e., the precursor for the desired carbocation (Scheme 17).
Scheme 17. Attempted Grignard addition of compound 2b to 4 4'-dimethoxybenzophenone.
Organolithium reagents are also powerful nucleophile and used for a range of carbon-carbon
bond formation reaction due to the large difference in electronegativity between the carbon
atom and the lithium atom. So, we have visualized insitu generation of the organo-lithium
reagent (also observed from NMR) with compound 2c using both n-butyllithium and tert-
butyllithium and its subsequent addition to 4,4'-dimethoxybenzophenone to obtain the tertiary
22
alcohol (Scheme 18). However, this strategy also failed which we assumed either due to the
bulkier nature of the aryl bromide or less electrophilicity of the ketone due to the presence of
electron donating methoxy groups or a combination of both.
Scheme 18. Attempted synthesis of tertiary alcohol from 2c via organolithium reagent
3.3 Design and attempted synthesis of chiral carbocation 3
We envisioned that one of the reason for the failure of the above strategy to obtain a
carbocation was the bulkiness of the napthyl group in aryl bromide which might be less prone
towards the formation of a Grignard reagent or an organolithium reagent.
Hence design of our next carbocation 3 (Figure 8) was based on a less bulky optically pure
(S)-(-)-1-Phenylethanol 3a which was commercially available.
Figure 8. Structure of desired chiral carbocation 3.
23
A similar Mitsunobu reaction between 3a and 2-Bromoresorcinol 2b provided the aryl
bromide 3b (Scheme 19). This aryl bromide was next then used as a starting material for the
synthesis of the tertiary alcohol 3c according to the reaction procedure described in scheme
19. Nevertheless, similar to the previous case we did not observe any formation of tertiary
alcohol.
Scheme 19. Attempted synthesis of chiral alcohol 3c.
1H-NMR spectra which was recorded of the crude reaction mixture for the synthesis of
tertiary alcohol, suggests that the aryl bromide 3b was able to form organolithium reagents
(detected from shift in peak positions of the starting materials) with both n-BuLi and tert-
BuLi like previous case. However, in both cases the organolithium reagent was unable to
further react with the 4,4’-dimethoxy benzophenone. This observation was crucial for the
design of our next carbocation where we have decided to change the electrophile to an
aldehyde (4-methoxybenzaldehyde) which is higher reactive than a ketone in nucleophilic
addition reaction.
24
3.4 Design and Synthesis of chiral carbocation 4
The next carbocation which was designed and synthesized in the present work is carbocation
4 (Figure 9) which is a secondary carbocation unlike the previous cases as its parent alcohol
is a secondary alcohol.
Figure 9. Structure of carbenium salt 4.
Scheme 20. Synthesis of secondary alcohol 4b.
The synthetic steps for the carbocation 4 is similar to the attempted synthesis of carbocation
3, which involved Mitsunobu reaction of 3a and 2b to give the compound 3b. Organolithium
25
reagent was synthesized insitu from compound 3b by treatment with n-BuLi or tert-BuLi at -
78 oC in dry THF, which then went on to react with 4-methoxybenzaldehyde 4a to procure
the secondary alcohol 4b as a mixture of both the diastereomers (Scheme 20). Incidentally we
were able to separate both the diastereomers (50:50 as suggested from the NMR spectra of
crude reaction mixture) using column chromatography and recorded their NMR.
Once we obtained the secondary alcohol in pure form, we have tried to synthesize the
carbenium salts from both of the diastereomeric alcohols using the procedure reported earlier
for carbenium salt 1, which involved the addition of propionic anhydride and HBF4.OEt2 to a
ethereal solution of the alcohols (Scheme 21). Unlike the case of tertiary alcohol the
carbenium salt from the secondary alcohol did not precipitated out in the reaction medium.
Hence the carbenium fluoroborate salt 4-BF4 was precipitated out in a mixture of hexane and
ether and washed several times with dry hexane to remove trace of HBF4 under nitrogen
atmosphere to finally yield 4-BF4 as a red color solid.
Scheme 21. Synthesis of chiral carbocations 4-BF4 and 4-ClO4.
26
In an alternative method the carbocation 4 was synthesized as perchlorate salt (4-ClO4) using
a procedure described by Wada et al.,[21]
which involved the addition of 70% perchloric acid
to a suspension of the alcohol in isopropanol (Scheme 21). In this method the carbocation
was precipitated out as white solids at -20 oC which was further recrystallized in isopropanol.
In this context it is important to mention that we have synthesized an analogue of the alcohol
4b, which involved the formation of organolithium reagent from the same aryl bromide 3b
and its subsequent addition to benzaldehyde to give the chiral secondary alcohol 4d (Scheme
22).
Scheme 22. Synthesis of secondary alcohol 4d.
Next, we have tried to synthesize the carbenium salts of the chiral secondary alcohol 4d
according to earlier mentioned procedure. However, in both of the cases we could not isolate
the carbocation from the solution which is indicative towards the less stability of the
carbocation generated from this alcohol. This is again justifies the theory that the presence of
a methoxy group in aromatic rings increases the stability of the carbocation via conjugation.
3.5 Design and attempted synthesis of carbocation 5
Once we found that the organolithium reagent derived from aryl bromide 3b is forming
secondary alcohols by reacting with aldehydes, we have decided to test the same protocol for
the aryl bromide 2c which was obtained from (S)-(-)-α-Methyl-2-naphthalenemethanol.
27
Therefore, according to earlier procedure aryl bromide 2c was treated with tert-butyl lithium
which was followed by the addition of benzaldehyde. However, in this reaction protocol
though we were able to obtain the secondary alcohol 5a, the yield of the reaction was very
poor (15 % isolated yield) (Scheme 23).
We have tried to convert this alcohol to its corresponding carbenium perchlorate salt, but we
did not observe the formation of carbocation in the solution (Scheme 23).
Scheme 23. Attempted synthesis of chiral carbocation 5.
3.6 Design and attempted synthesis of carbocation 6
The better reactivity of the organolithium reagent obtained from aryl bromide 3b with
aldehydes guided us to try the same reaction using simple benzophenone 6a as an
electrophile. Benzophenone is significantly more electrophilic that 4,4´-dimethoxy
benzaldehyde. So, we envisioned that possibly we could form a tertiary alcohol starting from
3b and 6a following the same reaction procedure described in scheme 24. In concordance
with our expectation we ended up isolating the tertiary alcohol 6b.
28
Scheme 24. Synthesis of chiral carbocation 6.
29
3.7 Catalytic evaluations of carbocations in Diels-Alder and hetero Diels-Alder reaction
The isolated carbocations 1, 4-BF4 and 4-ClO4 were evaluated for their catalytic activity in
Diels-Alder reactions and hetero Diels-Alder reactions according to the reaction schemes 25
and 26.
Scheme 25. Diels-Alder reaction of methacrolein and 2,3-Dimethyl-1,3-butadiene.
Scheme 26. Hetero Diels-Alder reaction between benzaldehyde and 2,3-Dimethyl-1,3-
butadiene.
The results obtained from these catalytic experiments were summarized in Table 1. It was
observed that all the isolated carbenium salts were able to catalyze both the Diels-Alder and
the hetero Diels-Alder reaction. However, carbocation 4 with BF4 was the best among them
in terms of reactivity. Unfortunately, we could not get chiral induction with none of these
catalysts.
30
Table 1: Catalytic evaluation of carbenium salts in Diels Alder (DA) and hetero Diels-Alder
reaction (HDA)a
Catalyst Reaction Conversion (%)b ee (%)
1 DA 80 0
1 HDA 45 0
4-BF4 DA 100 0
4-BF4 HDA 82 0
4-ClO4 DA 91 0
4-ClO4 HDA 60 0
aReaction conditions: Substrate (0.2 mmol), Catalyst (5 mol%), DCM (0.3 mL), r.t.
bConversions were determined by
1H NMR (Figure 10).
Figure 10. Determination of reaction conversion in Diels-Alder reaction from 1H-NMR.
ppm (t1)9.009.5010.00
0
50000000
100000000
9.557
9.456
1.00
10.1
8
31
4. Conclusions and outlook
In this project we have designed and synthesized new chiral carbocations starting from
commercially available chiral alcohols. The carbocations were synthesized from their parent
secondary or tertiary alcohols. We have synthesized various secondary and tertiary alcohols
via addition of Grignard reagent and organo-lithium reagents to the carbonyl compounds. It
was observed that the aryl bromides obtained from (S)-1-phenylethanol were better reactive
than the other derived from (S)-(-)--Methyl-2-naphthalenemethanol. Again, the formation of
the alcohols was also strongly dependent on the reactivity of the carbonyl compounds.
Next we tried to convert these alcohols to carbenium salts, but were able to isolate only three
carbenium salts viz., 1, 4-BF4 and 4-ClO4, those having a methoxy group in the aromatic
moiety. The methoxy group is believed to be beneficial for resonance stabilization of the
carbocation.
The isolated carbenium salts were used as catalysts in asymmetric Diels-Alder and hetero
Diels-Alder reactions. Each of the carbenium salts were able to catalyze the earlier mentioned
reaction, however, carbocation 4 with BF4 was best among them in terms of reactivity. It was
unfortunate that in all of these cases we could not get any chial induction in the product in the
present reaction condition.
It is promising that the carbocations, synthesized in this thesis are able to catalyze the Diels-
Alder reaction. So we believe that with further tuning in the catalyst structure and modifying
the reaction conditions (such as reaction temperature, solvents, catalyst loading etc.), the
chiral induction in the product could be achieved.
32
5. Experimental Part
Methods and Materials
All the chemicals were obtained from Sigma-Aldrich and were used as received. Distilled
solvents were used in all the experiments received from a solvent drying system. 1H NMR
spectra were recorded on a Bruker Advance 400 or a Bruker Advance DMX 500 instrument
in CDCl3 using solvent residual signals as internal standards (e.g. 7.26 ppm for residual
CHCl3 in CDCl3).
Flash chromatography was carried out using Merck silica gel 60 (230-400 mesh size). For
TLC Merck silica gel 60 F254 plates were used and visualization were done by UV light or by
staining with permanganate. For all the moisture sensitive reactions flame dried reaction
vessels were used and the reactions were carried out under positive pressure of nitrogen.
5.1 Synthesis of (R)-2-methylbutyl 4-methylbenzenesulfonate 1b
To a stirred solution of (R)-2-methyl-2-butanol (3.71 mL, 34.04 mmol) in CH2Cl2 (160 mL),
DMAP (0.415 g, 3.40 mmol) and Et3N (9.5 mL, 68.06 mmol) were added. To the mixture, a
solution of tosyl chloride (6.48 g, 34.03 mmol) in CH2Cl2, (160 mL) was added drop wise
over 30 min. The reaction mixture was stirred overnight. The resulting yellowish solution
was washed with water (100 mL) and aqueous NaHCO3 (10%, 2 x 100 mL). The organic
layer was dried over MgSO4. The removal of solvent under reduced pressure afforded a
brownish oil which was purified by column chromatography (SiO2, eluent: Hexane/ CH2Cl2,
3/1) to yield the desired compound as colorless oil.
Yield: 7.26 g (29.95 mmol, 88%).
33
Rf value: 0.2 (Hexane/ CH2Cl2, 3/1).
1H-NMR (Bruker 400 MHz, CDCl3): = 7.79 (d, J=8 Hz, 2H), 7.35 (d, J= 8 Hz, 2H), 3.89
(m, 1H), 3.82 (m, 1H), 2.44 (s, 3H), 1.72 (m, 1H), 1.39 (m, 1H), 1.17 (m, 1H), 0.88 (d, J= 6.8
Hz, 3H), 0.83 (t, J=7.2 Hz, 3H).
5.2 Synthesis of (R)-1-bromo-2-(2-methylbutoxy)benzene 1d
To a degassed solution of 2-bromophenol (0.8 g, 4.62 mmol) in DMF (20 mL), (R)-2-
methylbutyl 4-methylbenzenesulfonate (1.34 g, 5.54 mmol) was added. After 10 min Cs2CO3
(2.25 g, 6.93 mmol) was added and the reaction mixture was allowed to stir overnight at
100ºC. After cooling to room temperature, the mixture was filtered over sintered glass
Buchner funnel. The filtrate was collected and evaporated to dryness under reduced pressure.
The residue was purified by column chromatography (SiO2, Eluent: Hexane/ CH2Cl2, 4/1) to
yield the desired compound.
Yield: 0.930 g (3.82 mmol, 83%).
Rf value: 0.2 (Hexane/ CH2Cl2, 4/1).
1H-NMR (Bruker 400 MHz, CDCl3): = 7.54 (dd, J=6.8, 1.2 Hz, 1H), 7.24 (dd, J= 6.8, 1.2
Hz, 1H), 6.88 (d, J= 8 Hz, 1 H), 6.83 (td, J= 6.8, 0.8 Hz, 1H), 3.90 (q, J= 6 Hz, 1H), 3.81 (q,
J= 6.4 Hz, 1H), 1.96 (m, 1H), 1.65 (q, 1H), 1.36 (m, 1H), 1.07 (d, J= 6.8 Hz, 3H), 0.99 (t, J=
7.6 Hz, 3H).
34
5.3 Synthesis of (4-methoxyphenyl)(2-((R)-2-methylbutoxy)phenyl)(phenyl)methanol 1g
Mg turnings (0.140 g, 5.76 mmol) were treated with diluted HCl and washed with H2O. After
transferring into a 10 mL two-necked round bottom flask equipped with septum, stopper,
condenser and magnetic stirring bar the equipment was heated for 10 minutes with a heat gun
while vacuum was applied. After flushing with N2, dry THF (4mL) was added followed by
addition of the (R)-1-bromo-2-(2-methylbutoxy) benzene (1g, 4.11 mmol) under stirring. The
reaction mixture was heated to reflux for 2 hours. After cooling to 0 ºC with an ice bath a
solution of 4-Methoxybenzophenone (0.872 g, 4.11 mmol) in dry THF (2mL) was added drop
wise and the solution was stirred at room temperature. To this solution, H2O and 2M HCl
were added until the formed precipitate had dissolved completely. The aqueous phase was
extracted with Et2O (3 x 30 mL). The combined organic layers were washed with saturated
NaHCO3 solution, H2O, dried over NaSO4 and concentrated under reduced pressure. The
crude product was purified by column chromatography with n-pentane/ diethyl ether (6/1).
Yield: 0.95 g (2.52 mmol, 60%).
Rf value: 0.4 (pentane/diethyl ether, 6/1).
1H-NMR (Bruker 400 MHz, CDCl3): = 7.35 (m, 8H), 6.96 (d, J= 8 Hz, 1 H), 6.96 (d, J= 8.8
Hz, 2H), 6.84 (t, J= 7.6 Hz, 1H), 6.61 (d, J= 7.7 Hz, 1H), 5.37 (s, 1H), 3.78 (s, 3H), 3.75 (m,
2H), 1.58 (m, 1H), 1.14 (m, 1H), 1.00 (m, 1H), 0.80 (t, J= 7.2 Hz, 3H), 0.74 (d, J= 6.8 Hz,
3H).
13C-NMR: (Bruker 100 MHz, CDCl3): = 158.7, 156.8, 147.3, 139.0, 135.6, 126.9, 120.3,
113.1, 112.1, 81.9, 72.8, 55.2, 34.6, 25.8, 16.4, 16.3, 11.4 ppm.
35
5.4 Synthesis of (R)-(4-methoxyphenyl)(2-(2-methylbutoxy)phenyl)methylium
tetrafluoroborate 1
The triarylmethanol 1g (0.688 g, 1.830 mmol) was dissolved in Et2O (20 mL) and cooled to
0ºC with an ice bath. Propionic anhydride (1.2 mL, 9.16 mmol) was added followed by
addition of HBF4·OEt2 (0.62 mL, 4.57 mmol) over 10 minutes while stirring vigorously. An
intense red colored precipitated was formed after the first drop of HBF4·OEt2. The slurry was
stirred for 2 hours at 0ºC. After trituration with Et2O the precipitate was dried in vacuum.
Yield: 0.49 g (1.1 mmol, 60 %).
36
5.5 Synthesis of 2,2’-((1R,1’R)-((2-bromo-1,3-phenylene)bis(oxy)bis(ethane-1,1-diyl))
dinaphthalene 2c
2-Bromoresolcinol (0.3 g, 1.58 mmol) and (S)-(-)-α-Methyl-2-naphthalenemethanol (0.6 g,
3.491 mmol) where placed in THF (10 ml) with triphenylphospine (1.24 g, 4.76mmol), and
the system was cooled to 0 ºC. DIAD (0.93 mL, 4.76 mmol) was added portion-wise over 30
minutes. The resulting solution was warmed to room temperature and stirred for about 16
hours. The reaction mixture was then diluted with ether and water was added. The mixture
was washed with 5N NaOH, extracted with ether and concentrate. The residue was purified
by column chromatography (heptane/CH2Cl2, 4/1).
Yield: 0.278 g (0.56 mmol, 35%).
Rf value: 0.2 (heptane/CH2Cl2, 4/1).
1H-NMR (Bruker 400 MHz, CDCl3): = 7.83 (t, J=8.4 Hz, 8H), 7.54 (d, J= 9.6 Hz, 2H), 7.46
(m, 4H), 6.79 (t, J=8.4 Hz, 1H), 6.47 (d, J=15.6 Hz, 2H), 5.48 (q, J= 6.4 Hz, 2H), 1.76 (d, J=
6.4 Hz, 6H).
37
5.6 Synthesis of ((1R,1’R)-((2-bromo-1,3-phenylene)bis(oxy))bis(ethane-1,1-
diyl))dibenzene 3b
The 2-Bromoresolcinol (1 g, 5.29 mmol) and (S)-1-phenylethanol (1.41 mL, 11.63 mmol)
where placed in THF (10 mL) with triphenylphospine (4.16 g, 15.87 mmol) and the resulting
mass was cooled to 0ºC. DIAD (3.13Ml, 15.87mmol) was added portion-wise over 30
minutes. The mixture was warmed to room temperature and stirred for about 16 hours and
then diluted with ether and water. The resulting solution was further washed with 5N NaOH
and extracted with ether. The organic portions were combined, dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The residue was purified by column
chromatography with n-pentane/CH2Cl2, 9/1.
Yield: 1.47 g (3.7 mmol, 70 %).
Rf value: 0.35 (n-pentane/CH2Cl2, 9/1).
1H-NMR (Bruker 400 MHz, CDCl3): = 7.41 (d, J= 7.2 Hz, 4H), 7.34 (t, J= 7.6 Hz, 4H),
6.88 (t, J= 8 Hz, 1H), 6.34(d, J= 8.4 Hz, 2H), 5.36 (q, J= 6.4 Hz, 2H), 1.69 (d, J= 6.4 Hz,
6H).
38
5.7 Synthesis of (R)/(S)-(2,6-bis((R)-1-phenylethoxy)phenyl)(4 methoxyphenyl)methanol
4b
The reaction vessel was charged with aryl bromides (0.5 g, 1.26 mmol) and dry THF (1 mL).
The solution was cooled to -78 ºC, and tert-butyllithium (1.483 mL, 2.522 mmol) was added
drop-wise. The resulting mixture was then stirred at -78ºC for 1 hour, which was followed by
the addition of 4-methoxybenzaldehyde (153.3 µL, 1.26 mmol) in one portion under nitrogen.
After stirring for another 30 minutes at -78 ºC, the vessel was allowed to warm to r.t for 16
hours. The reaction content was poured into a saturated aqueous NH4Cl-ice mixture (5 mL).
The aqueous layer was separated and extracted with ether (3 x 30 mL). The combined organic
extracts were dried (Na2SO4), filtered, and evaporated. The yellowish solid was purified by
column chromatography (petroleum ether/ EtOAc, 93/7).
Yield: 0.400 g (0.88 mmol, 70 %).
1H-NMR (Bruker 400 MHz, CDCl3): = 7.39 (m, 21H), 7.04 (d, J= 1.6 Hz, 3H), 6.89 (m,
6H), 6.57 (dd, J= 12, 12 Hz, 2H), 6.34 (dd, J= 8.4, 13.2 Hz, 4H), 5.36 (q, J=6.4 Hz, 2H), 5.27
(q, J=6 Hz, 2H), 4.44(dd, J= 2.8, 8.8 Hz, 2H), 3.84 (d, J= 8 Hz, 6H), 1.59 (d, J= 6.4 Hz, 6H),
1.44 (d, J= 6.4 Hz, 6H).
13C-NMR (Bruker 125 MHz, CDCl3): = 158.4, 158.4, 156.3, 155.8, 142.9, 142.5, 137.6,
128.7, 120.8, 113.3, 107.0, 106.4, 77.0, 55.3, 24.6, 24.2 ppm.
39
5.8 Synthesis of (R)-(S)-(2,6-bis((R)-1-phenylethoxy)phenyl)(phenyl)methanol 4d
The vessel was charged with aryl bromides (0.31 g, 0.79 mmol) and dry THF (1 mL). The
solution was cooled to -78 ºC, and tert-butyllithium (929.41 µl, 1.58 mmol) was added drop-
wise. The resulting mixture was then stirred -78 ºC for 1 hour, which was followed by the
addition of benzaldehyde (79.8µL, 0.79 mmol) in one portion under nitrogen. After stirring
for another 30 minutes at -78 ºC, the vessel was allowed to warm to r.t for 16 hours. The
reaction content was poured into a saturated aqueous NH4Cl-ice mixture (5 mL). The aqueous
layer was separated and extracted with ether (3 x 30 mL). The combined organic extracts
were dried (Na2SO4), filtered, and evaporated. The yellowish solid was purified by column
chromatography (petroleum ether/ EtOAc, 98/2)
Yield: 0.17 g (0.41 mmol, 52 %).
Rf value: 0.25 (petroleum ether/ EtOAc, 98/2).
1H-NMR (Bruker 400 MHz, CDCl3): = 7.52 (m, 25H), 7.02 (d, J= 6.8 Hz, 3H), 6.94 (m,
2H), 6.66 (dd, J= 12, 13.6 Hz, 2H), 6.38 (dd, J= 8.4, 18.8 Hz, 4H), 5.37 (q, J=6 Hz, 4H), 5.26
(q, J=6.8 Hz, 4H) 4.43(m, 2H), 1.62 (d, J= 6.4 Hz, 6H), 1.44 (d, J= 6 Hz, 6H).
13C-NMR (Bruker 125 MHz, CDCl3): = 156.3, 155.7, 145.4, 142.5, 128.7, 125.8, 125.4,
121.0, 120.8, 107.0, 106.8, 106.4, 75.9, 68.6, 68.3, 40.9, 24.6, 24.6, 24.1, 23.9, 20.8, 17.5,
17.3, 14.7 ppm.
40
5.9 Synthesis of (2,6-bis((R)-1-phenylethoxy)phenyl)(4-methoxyphenyl)methylium
perchlorate 4-CLO4
To a suspension of 4b (0.051 g, 0.114 mmol) in 2-propanol (250 µL) was added 70%
perchloric acid (14 µL, 0.136 mmol). The resultant black suspension was stirred at room
temperature for 2 hours. The resulting solution was then cooled at -20 ºC to afford colorless
crystals which was further dissolved in 2-proapnol and recrystallized from air.
Yield: 0.035 g (0.065 mmol, 57 %).
41
5.10 Synthesis of (2,6-bis((R)-1-phenylethoxy)phenyl)(4-methoxyphenyl)methylium
fluoroborate 4-BF4
The diarylmethanol 4b (0.100 g, 0.22 mmol) was dissolved in Et2O (2 mL) and cooled to 0
ºC with an ice bath. Propionic anhydride (0.144 mL, 1.1 mmol) was added followed by
addition of HBF4·OEt2 (0.06 mL, 0.45 mmol) over 10 minutes while stirring vigorously. An
intense red colored precipitated was formed after the first drop of HBF4·OEt2. The slurry was
stirred for 2 hours at 0 ºC. After trituration with Et2O the carbocation was precipitated in dry
hexane and dried in vacuum.
Yield: 0.048 g (0.092 mmol, 42 %).
42
5.11 Synthesis of (R)/(S)-(2,6-bis((R)-1(naphthalene-2-
yl)ethoxy)phenyl)(phenyl)methanol 5a
The reaction vessel was charged with aryl bromides (0.094 g, 0.189 mmol) and dry THF (1
mL). The solution was cooled to -78 ºC, and tert-butyllithium (222.35µl, 2.522 mmol) was
added to it drop wise. The resulting solution was stirred at -78 ºC for 1 hour and then
benzaldehyde (153.3µL, 0.378 mmol) was added in one portion under nitrogen. After stirring
for another 30 minutes at -78 ºC, the vessel was allowed to warm to r.t. for 16 hours. The
reaction content was poured into a saturated aqueous NH4Cl-ice mixture (4 mL). The aqueous
layer was separated and extracted with ether (3 x 30 mL). The combined organic extracts
were dried (over Na2SO4), filtered and evaporated. The yellowish solid was purified by
column chromatography (petroleum ether/ EtOAc, 96/4).
Yield: 0.069 g (0.132 mmol, 70 %).
Rf value: 0.2 (petroleum ether/ EtOAc, 96/4).
1H-NMR (Bruker 500 MHz, CDCl3): = 7.83 (m, 6H), 7.72 (s, 1H), 7.52 (m, 9H), 7.33 (t, J=
7 Hz, 1H), 7.20 (s, 1H), 7.12 (s, 1H), 7.07 (s, 1H), 6.85 (t, J= 8.5 Hz, 1H), 6.67 (d, J= 12 Hz,
1H), 6.39 (d, J= 8.5 Hz, 1H), 5.40 (q, J=6.5 Hz, 2H), 4.48 (d, J= 12 Hz, 1H), 1.50 (d, J= 6.5
Hz, 6H).
43
5.12 Synthesis of (2, 6-bis((R)-1-phenylethoxy)phenyl)diphenylmethanol 6b
The vessel was charged with aryl bromides (0.187 g, 0.472 mmol) and dry THF (1.5 mL).
The solution was cooled to -78 ºC, and the tert-butyllithium 1.7M in pentane (555 µL, 0.944
mmol) was added drop-wise. It was stirred at -78ºC for 1 hour and then benzophenone (0.086
g, 0.472 mmol) was added in one portion under nitrogen. After another 30 minutes at -78 ºC,
the vessel was allowed to warm to r.t for 16 hours. The reaction content was poured into a
saturated aqueous NH4Cl-ice mixture (4mL). The aqueous layer was separated and extracted
with ether (3 x 30 mL). The combined organic extracts were dried (Na2SO4), filtered, and
evaporated. The yellowish solid was purified by column chromatography (petroleum ether/
EtOAc, 97/3).
Yield: 0.035 g (0.07 mmol, 15 %).
Rf value: 0.3 (petroleum ether/ EtOAc, 95/5).
1H-NMR (Bruker 400 MHz, CDCl3): = 7.50 (t, J= 8 Hz, 4H), 7.42 (m, 12 H), 7.00 (d, J=
6.4 Hz, 4H), 6.90 (t, J= 8.4 Hz, 4H), 6.73 (s, 1H), 6.32 (d, J= 8.4 Hz, 2H), 5.14 (q, J= 6.4 Hz,
2H), 1.15 (d, J= 6 Hz, 6H).
44
5.13 General procedure for Diels-Alder reaction
The carbenium salts (10 mol%) are introduced in a flame dried reaction vial and dry DCM
(300 µl) was added to it under nitrogen atmosphere. To this solution 2,3-dimethyl-1,3-
butadiene (0.1 mmol) and methacrolein (0.1 mmol) was added and the reaction mixture was
allowed to stir at room temperature under nitrogen. The progress of the reaction was
monitored from NMR study by taking an aliquot at regular interval. After completion of the
reaction the reaction mixture was passed through a plug of silica using ether as an eluent to
separate the catalyst. The etheral solution was analyzed on chiral GC for detection of
enantioselectivity.
5.14 General procedure for hetero Diels-Alder reaction
The carbenium salts (10 mol%) are introduced in a flame dried reaction vial and dry DCM
(300 µl) was added to it under nitrogen atmosphere. To this solution 2,3-dimethyl-1,3-
butadiene (0.1 mmol) and benzaldehyde (0.1 mmol) was added and the reaction mixture was
allowed to stir at room temperature under nitrogen. The progress of the reaction was
monitored from NMR study by taking an aliquot at regular interval. After completion of the
reaction the reaction mixture was passed through a plug of silica using ether as an eluent to
separate the catalyst. The etheral solution was analyzed on chiral GC for detection of
enantioselectivity.
45
6. References
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47
Appendix
ppm (t1)0.01.02.03.04.05.06.07.08.0
-100000000
0
100000000
200000000
300000000
400000000
500000000
600000000
7.4
17
7.3
95
7.3
79
7.3
58
7.3
40
7.3
21
7.3
00
7.2
85
7.2
66
7.2
58
7.2
43
7.2
25
7.2
10
7.1
92
7.1
87
7.1
76
7.0
70
7.0
67
7.0
51
6.9
41
6.9
19
6.9
08
6.8
86
6.8
76
6.8
68
6.8
47
6.8
26
6.5
96
6.5
66
6.5
35
6.5
06
6.3
72
6.3
51
6.3
19
6.2
98
5.3
50
5.3
35
5.3
22
5.2
70
5.2
55
5.2
39
5.2
23
4.4
68
4.4
60
4.4
38
4.4
30
3.8
68
3.8
61
3.8
48
1.6
16
1.6
00
1.5
86
1.5
79
1.5
69
1.5
38
1.5
22
1.4
70
1.4
54
1.2
88
1.2
45
1.1
95
1.1
70
0.9
76
0.9
58
0.9
44
0.9
26
0.9
12
0.8
93
ppm (t1)0.01.02.03.04.05.06.07.08.0
0
100000000
200000000
300000000
400000000
7.9
05
7.8
87
7.8
60
7.8
41
7.1
89
7.1
53
7.1
46
7.1
44
7.1
34
7.1
30
7.1
06
7.1
01
7.0
90
7.0
86
7.0
68
7.0
51
6.7
35
6.7
24
6.7
14
6.1
86
6.1
67
6.1
43
5.2
39
5.2
37
5.2
27
5.2
26
5.2
09
5.2
06
5.1
97
5.1
95
5.1
85
5.1
80
5.1
50
5.1
45
5.1
42
5.1
34
5.1
33
5.1
17
5.1
11
5.1
09
5.1
02
5.1
00
5.0
91
5.0
88
5.0
85
5.0
83
5.0
74
5.0
69
5.0
65
4.0
12
3.9
90
3.9
75
3.9
59
3.9
44
3.7
36
3.7
11
2.5
45
1.5
37
1.5
22
1.4
10
1.3
95
1.1
87
1.1
49
1.1
34
0.8
11
48
ppm (t1)0.01.02.03.04.05.06.07.08.0
0
50000000
100000000
150000000
200000000
250000000
300000000
7.7
39
7.7
32
7.7
22
7.6
99
7.6
94
7.6
81
7.6
34
7.4
28
7.4
12
7.3
99
7.3
95
7.3
88
7.3
80
7.3
76
7.3
66
7.3
21
7.3
18
7.3
01
7.2
85
7.2
41
7.2
26
7.1
83
7.1
07
7.0
28
6.7
65
6.7
48
6.7
31
6.5
80
6.5
56
6.3
05
6.2
88
5.2
95
5.2
82
4.3
87
4.3
63
1.5
02
1.4
86
1.4
74
1.4
59
1.4
41
1.4
08
1.3
95
1.2
87
1.2
69
1.1
83
1.1
58
1.1
43
1.0
93
1.0
68
0.8
70
0.8
56
0.8
39
0.8
25
0.8
10
0.7
95
0.7
81
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