Advanced organic chemistry wim dehaen

WIM DEHAEN ADVANCED ORGANIC CHEMISTRY Chapter Concerted reactions During concerted reactions the cleavage of the bonds of the starting materials and the formation of the new bonds of the product happen at the same time (in other words in concert) without the occurrence of discrete intermediates A very important class of concerted reactions is formed by the pericyclic reactions The latter are characterized by a cyclic transition state In the text below we will discuss the different types of pericyclic reactions at length In a second part of the chapter others examples of concerted reactions are given, together with the consequences for the stereochemistry of the products formed 1.1 Pericyclic reactions : properties and types -During the course of the reaction no (high-energy) radical, carbocation or carbanion intermediates are formed In many cases, the activation energy will be rather low as a consequence In general, there are no important solvent effects observed in these reactions because during the reaction no (large) changes in polarity occur -The cyclic transition state implies a large degree of organisation of the reagents, so the reaction entropy will be negative -The pericyclic reactions will in many cases lead to the stereo- and regioselective formation of products even if several isomers would be possible -The reactions are activated by heating (thermally) or by irradiation with UV- or visible light (photochemically) R h + R photochemical [2+2]cycloaddition R Synthesis of cyclopropanes from carbenes + + S O2 thermal Diels-Alder cycloaddition R SO2 transformation of sulfolene to butadiene and SO2 We can distinguish three types of pericyclic reactions: -Cycloadditions: two separate molecules or fragments form a new cyclic system, and during this process two -bonds disappear and two -bonds are formed An example is the photochemical [2+2] dimerisation of alkenes to form cyclobutanes or the thermal [4+2] DielsAlder cycloaddition reaction Cheletropic reactions and the reverse process, the extrusion reactions, form a special case in which the two -bonds are formed (respectively cleaved) at the same atom These [n+1] processes will for instance take place for the addition of carbenes (see later) to alkenes and the formation of butadiene and SO2 from sulfolene -Electrocyclic reactions: within a single, conjugated open chain system with n -bonds a transformation occurs to a cyclic system with (n-1)  bonds and one (1) newly formed bond In function of the reaction circumstances, the reverse reaction (ring opening) may take place The reaction takes place thermally or photochemically cyclobutene butadiene -Sigmatropic rearrangements: during the reaction, a group R migrates over a conjugated system, of which the bonds shift during the migration Thus, the total amount of - or π-bonds does not change during these reactions An example is the Claisen rearrangement, in which an allyl group shifts over an enolate system, resulting in the formation of an unsaturated carbonyl compound This is an example of a [3,3]-sigmatropic rearrangement O O Claisen rearrangement 1.2 Pericyclic reactions : general principles 1.2.1 Molecular orbitals Molecular orbitals are obtained by linear combination of atomic orbitals (LCAO) Atomic orbitals can be seen as wave functions, combining in-phase (bonding interaction) or out-ofphase (antibonding interaction) If two p-orbitals are combined following the long axis, this results in the formation of a bonding -orbital and an antibonding *-orbital The latter has a higher energy and the orbitals with the lowest energy are the first to be filled with electrons These two simple orbitals are symmetric in relation to the bond axis, while in regard to the nodal plane (m, the plane perpendicular to the bond axis) the -orbital is symmetric (S) and the *-orbital antisymmetric (A) In relation to the C2-axis perpendicular to the bond axis this is the same: the -orbital is symmetric (S) and the *-orbital antisymmetric (A) The - and *-orbitals are formed by lateral overlapping (respectively bonding and antibonding) of two p-orbitals These orbitals are both antisymmetric in regard to the bond axis, and in relation to the nodal plane m the -orbital is symmetric and the *-orbital antisymmetric In relation to C2 this situation is reversed  Energy       C=C bond lateral overlap C-C bond axial overlap The wave function 1 = c11 + c22 for the bonding - and -orbitals, and the wave function 2 = c11 - c22 for the antibonding *- and *-orbitals The numbers c1 and c2 are the orbital coefficients Visually, these coefficients are shown by the size of the orbital lobes For symmetric compounds (e.g ethene) c1 = c2, in other cases (e.g CH2=O) the two coefficients are different Ethene has both (*)- and (*)-orbitals The energy of the - en *-orbitals is given in theoretical discussions as respectively + and -, in which  is the energy of the original p-orbital and  the energy difference by delocalisation of the electrons over the two atoms of the molecule Both  and  are negative energy values The -orbital is in this case the highest occupied molecular orbital (HOMO), and the *orbital is the lowest unoccupied molecular orbital (LUMO) Both are the frontier orbitals  Energy    LUMO  HOMO  Electronic configuration of ethene In linearly conjugated systems there are several (>2) p-orbitals that simultaneously enter in lateral interaction with each other The electrons of the resulting molecular orbitals are delocalised over all the participating atoms A prerequisite is that the conjugated system is not interrupted by sp3-hybridised atoms Atomic orbitals that are perpendicular (as in allenes or cumulenes) can not overlap and are not conjugated Examples of simple linearly conjugated systems are butadiene (n = 4) and allyl (n =3) (cation, radical or anion) 1,4Pentadiene has two localised double bonds, therefore it is not conjugated isolated double bonds conjugated systems butadiene 1,4-pentadiene CH2 allyl anion H2C C CH2 allene The n different wave functions of a system with n atoms are described according to LCAO for the j-th orbital as: j = c1j1 + c2j2 + c3j3 + + cnj3 The coefficients for polyene systems with n atoms can be theoretically calculated (the socalled Hückel approach) whereby a coefficient crj of the r-th atom orbital in the j-th molecular orbital is given by: crj = (2/n+1)0.5 x sin rj/n+1 Example: the coefficient for the third atomic orbital in the fourth wave function of a four atom system is 0.6 and the energy of a molecular orbital j is given in general by E =  + m in which m = cos(j/n+1) If m = the orbital is non-bonding This approach gives information on the relative contribution of the atomic orbitals in a certain molecular orbital (size of lobes = orbital coefficients) and also shows if the interaction is bonding, antibonding or not-bonding At the same time the amount of knots (electron density = 0), and their position in the molecule, can be determined Application of these formulas on ethene (n =2) leads to m = and c1 = c2 = 0.707 The following system is this with n = 3, the allyl system In this case we have three molecular orbitals 1, (E =  + 1.414), 2 (E = ) and 3 (E =  - 1.414) Thus, the molecular orbital 2 is non-bonding An allyl cation has electron configuration 1220, an allyl radical 1221, and an allyl anion 1222 The allyl group is bent because the central carbon atom has sp2-hybridisation and thus the angle is 120° The orbital coefficient c22 = 0, in other words a knot is localised on the central atom of the second orbital of the allyl system The other two coefficients are c21 = c12= c32 = c23 = 0.707 and c11 = c31 = c13 = c33 = 0.5 The molecular orbital 2 is the LUMO for the allyl cation, and the HOMO for the allyl anion The molecular orbital 1 has no knots, and the molecular orbital 3 has two knots, in between atoms 1-2 and 2-3 In general, a linearly conjugated system in the n-th molecular orbital has n-1 knots Symmetry m Energy    C2  S A A S S A   Molecular orbitals of allyl The most stable conformation of butadiene (n = 4) is a zigzag structure With LCAO four molecular orbitals can be formed, in which four -electrons are accommodated Thus, the HOMO is the 2-orbital (one knot) and the LUMO is the 3-orbital (two knots) The difference in energy between HOMO and LUMO is for butadiene (n = 4) 1.236, this is less than the “HOMO-LUMO-gap” for the allyl cation (n = 3, 1.414) or ethene (n = 2, 2) Thus, the longer is the conjugation, the smaller is the distance between HOMO and LUMO The Hückel calculations predict two orbital coefficients 0.6 and 0.371 In the two frontier orbitals the coefficients on the two outer atoms is larger than those on the central In the different molecular orbitals of butadiene the knots are always located between the carbon atoms, and this is typical for linearly conjugated systems with an even amount of carbon atoms Furthermore, the two occupied molecular orbitals 1 and 2 show respectively a bonding and antibonding interaction between the central atomic orbitals on C-2 and C-3 The relevant coefficients are larger for 1 which makes the interaction more bonding Thus, we can say that the C-2-C-3 bond in butadiene has partial double-bond-character We would like to mention that in simplified representations of the molecular orbitals of conjugated systems often all orbitals are shown with the same coefficients It is important to keep in mind that this does not completely correspond to reality Symmetry Energy     m C2  A S  S A  A S S A  Below are shown the simplified representations (orbitals, energies, symmetry) of the next homologous systems with n = (pentadienyl) and n = (1,3,5-hexatriene), following the same logic The HOMO-LUMO gap is further reduced, respectively to  (n = ) and 0.890 (n = 6) Symmetry   C2 S A A S S A A S S A   Energy m       Symmetry Energy   m C2 A S   S A A S  S A  A S S A       For cyclic conjugated systems other rules apply The Hückel orbital theory describes the energy of planar polycyclic polymethines (CH)n ([n]annulenes) as: E =  + 2 cos 2r/n with n = number of C-atoms ; r = 0, 1, 2, n-1 Mnemotechnically, one can obtain the energy levels by representing the molecule as a regular polygon that is circumscribed by a circle with diameter 4 The lowest atom (situation for r = 0) should always be placed at the bottom of the circle, and the corresponding lowest energy level is  + 2 A difference with the linear polymethines is that molecular orbitals with the same energy (degenerate systems) can occur In the figure below, the Hückel energy levels are given for planar, cyclic conjugated systems of n = to n =                      Carrying out the calculation for a six-membered ring (benzene) shows the occurrence of orbitals with r = 0, , , 3, 4, The Hückel energies are respectively  +2, +, -, -2, - and + Chapter Terpene chemistry Terpenes originally have been named after turpentine, the volatile oil of natural origin that contains mainly -pinene By extension, the term terpene is used for all volatile oils derived from plants Essential oils, derived from plants by distillation and often components of perfumes, also contain terpenes A few examples are camphor (from the camphor tree) used to protect clothes from moths, humulene (from hop) which contributes to the flavour of beer, thujone, one of the ingredients of absinth, patchouli alcohol, Vitamin A, phytol, a degradation product of chlorophyl and friedeline, a component of cork The structures are very diverse A striking general characteristic of these compounds is that they have 5n carbon atoms, mostly a number of methyl groups and/or double bonds Apparently, terpenes are constructed by combination of isoprene units (Mono)terpenes have 10, sesquiterpenes 15, diterpenes 20, and triterpenes 30 carbon atoms Polyterpenes such as natural rubber (cis- double bonds) and gutta-percha (trans) exist of many such 5C units O -pinene camphor C10H16 C10H16O humulene C15H24 HO O thujone C10H16O OH patchouli alcohol Vitamin A C15H26O C20H30O OH H O phytol C20H40O friedeline C30H50O 215 H H In reality, during biosynthesis the terpenes are not constructed from isoprene, but rather from acetate units Mevalonic acid is a C6-unit built from acetates (as CH3COSCoA) and the biosynthesis is stepwise under the influence of specific enzymes, the first step being a Claisen ester condensation, in which acetoacetyl-SCoA is formed The third acetate (as enol) will undergo an aldol condensation with this acetoacetylSCoA The resulting product is non-chiral (prochiral) but by enantioselective hydrolysis of one of the thiolesters, a chiral monoacid can be formed After reduction with NADPH in two steps, mevalonic acid is formed, which is in equilibrium with mevalonolactone OH OH CoAS CoAS O O O O OH O CoAS SCoA SCoA SCoA O O OH HO OH HO OH O O NADPH H HO OH O SCoA mevalonic acid OH mevalonolactone O O Although mevalonic acid is the true precursor of the terpenes, a carbon atom needs to be removed from this C6-unit This happens via a concerted fragmentation reaction from the pyrophosphate analog of mevalonic acid, after which isopentenyl pyrophosphate is formed This compound can reversibly isomerise to the dimethylallyl- (prenyl-) pyrophosphate, and thus two types of C5-building blocks are available 216 O OH HO O ATP OH OH HO -H2O OPP OPP -CO2 isopentenyl pyrophosphate mevalonic acid OPP prenyl pyrophosphate Combination of the dimethylallyl pyrophosphate (better electrophile) with the isopentenyl pyrophosphate (better nucleophile, less steric hindrance) affords a C10-fragment, the geranyl pyrophosphate, which acts as the starting point for the biosynthesis of monoterpenes Repeating this reaction gives the farnesyl pyrophosphate, which can be converted to sesquiterpenes OPP OPP OPP OPP H H geranyl pyrophosphate OPP farnesyl pyrophosphate Geranyl pyrophosphate should be difficult to cyclise because the double bond has trans geometry This can be changed by a rearrangement reaction, after which the pyrophosphate goes to the tertiary centre This probably involves an allyl cation and is catalysed by Mg(II) After rearrangement, cyclisation is possible, and the pyrophosphate is released The cation that is generated can lose a proton to form limonene, or cyclise with the remaining double bond after which -pinene is formed (again after proton loss) The latter cation can also first 217 undergo the Wagner-Meerwein rearrangement, and this secondary cation can be converted into camphor after hydroxylation and oxidation OPP OPP OPP -H H limonene O Wagner-Meerwein rearrangement camphor -pinene The sesquiterpenes are derived from farnesyl pyrophosphate Cyclisation of this pyrophosphate can take place with different regioselectivity, giving either the humulyl cation, or the E,E-germacradienyl cation The humulyl cation can lead to the formation of αhumulene after proton loss, or further cyclisation can occur, followed by proton loss to give trans-β-caryophyllene (one of the components of clove oil and other essential oils of spices including pepper, caraway, cinnamon, rosemary, basil, etc…) Sequential rearrangements of the E,E-germacradienyl cation catalysed by the patchoulol synthase enzyme ultimately give patchouli alcohol after hydroxylation of the final cation Earlier loss of protons at several stadia of rearrangement can be seen as sources of α-, β- and γ-patchoulene 218 -OPP- PPO farnesyl pyrophosphate E,E-germacradienyl cation -OPP- -patchoulene humulyl cation -humulene -patchoulene -patchoulene trans--caryophyllene HO = HO patchouli alcohol ((-)-patchoulol) Steroids may be of animal or plant origin Characteristic is the tetracyclic structure, and the rings are called A, B, C, D Examples are cholesterol, testosterone, estradiol, cortisone, cholic acid and -sitosterol Although they belong to the terpene family, the “5n-rule” is not always obeyed Cholesterol for instance has 27 carbon atoms By carrying out experiments with labelled mevalonic acid, it was shown that cholesterol is formed by cyclisation of two molecules of farnesyl pyrophosphate 219 The first step in the biosynthesis is the dimerisation of farnesyl pyrophosphate to presqualene pyrophosphate This is a remarkable reaction that is only possible because the enzyme is holding all reagents in the correct conformations Afterwards the pyrophosphate will be released, a ring expansion to a cyclobutyl cation will occur and the latter will ring open to a squalene cation, which then is reduced by NADPH This is an application of a non-classical cation 220 OPP PPO HH PPO H presqualene pyrophosphate PPO NADPH squalene Enzymatic epoxidation of one the terminal double bonds gives a chiral squalene oxide, which then can cyclise after protonation of the oxirane oxygen After a cascade reaction, a tetracyclic compound is formed This is followed by a series of 1,2-shifts (Wagner-Meerwein rearrangements) after which finally lanosterol is obtained 221 squalene O2, NADPH, epoxidase O squalene oxide H H H HO H O H H H HO H lanosterol These two last steps are interesting and will be discussed in detail The oxirane opens on the most substituted side, as expected, and then the alkenes react every time on the most accessible side, except the third alkene that attacks on the “wrong” side The stereochemistry of the final product is a result of the stereochemistry in the alkene and of the conformations assumed in the transition state A chair conformer leads to a trans-relation between adjacent groups, but the boat conformer results in a cis-relation (Me en H) The migrations are all anti-migrations and the migrating groups are axial and anti-periplanar in relation to the previous one, in such a way that the migrating group will every time carry out a SN2-reaction on the migration terminus with inversion The chain stops because there is a cis-relation between the Me and the H in the B-ring Hydrogen elimination is the only thing that can happen 222 Me H Me Me H O Me R TS cyclisation Me H Me H Me Me H HO Me Me R TS rearrangement Me H Me The rest of the biosynthesis of cholesterol is based on redox reactions and amounts to a shift of the double bond, and the oxidation and decarboxylation of a number of methyl groups of lanosterol R R H H H HO H H H HO lanosterol cholesterol Cholesterol can be prepared in the laboratory in a multistep procedure We mention the Woodward synthesis (JACS 1952, 74, 4223) which starts from a quinone and butadiene.The adduct is epimerized with base, reduced and treated with acid to give an unsaturated ketone The hydroxy group is reductively removed with zinc in acetic anhydride 223 O O Me O Me Me KOH + MeO MeO O O MeO H O H LiAlH4 Me Zn/Ac2O O OH Me O H OH H MeO H OH Me H Claisen condensation and Michael addition leads to a precursor for a Robinson annelation (after “retro-Claisen”) The resulting tricyclic system is hydroxylated and the two hydroxy functions protected with an acetal Selective reduction, Claisen condensation and formation of an enamine are followed by Michael reaction to acrylonitrile, hydrolysis and lactonisation HCOOEt/EtONa 2.EtCOCH=CH2, KtBuO Me CrO3 H Me KOH O Me Me Me acetone Me O Me H H H O H O O H2, Pd HCOOEt/EtONa PhNHMe CN Me O Me H O Me OH Me H O O Me O Me O Me Me H Me PhCH2NMe3 OH Me H Ac2O O AcOH O Me O Me H H Ph N Me CN O Ph N Me This lactone is treated with Grignard reagent and recyclized (Robinson annelation) Periodate cleavage followed by another (regioselective) Robinson annelation gives a tetracyclic aldehyde that is oxidized and esterified Then a catalytic reduction (Pt/H2) is carried out that involves three alkenes and the ketone The isomers are separated at this point and the alcohol reoxidized to the ketone 224 Me Me Me O Me O Me CH3MgI H H O Me O Me O Me H H NaOH O O HIO4 base Me H H H O Me COOMe reduction H Me H Me CHO Me COOMe K2Cr2O7 H H CH2N2 H Me O isomer O separation 3.CrO3 Selective reduction with sodium borohydride gives the β-hydroxy compound The ester is saponified and converted to the acid chloride Reaction with dimethylcadmium and an alkyl Grignard reagent then leads to a tertiary alcohol The latter is dehydrated and reduced, and after saponification cholestanol is obtained, a precursor for cholesterol Me H O Me COOMe NaBH4 OH H H H Ac2O SOCl2 Me COCl Me2Cd H RMgBr Me H AcO Me Me H H HO H OH H H H 1.HOAc Ac2O H2/Pt OH Me Me Me H Me H H H HO HO cholesterol H H H cholestanol Vitamin A and the tetraterpene carotene are prepared from simple building blocks such as acetone and acetylene Condensation in basic medium and reduction gives a tertiary alcohol that is converted to prenyl bromide The latter is used to alkylate ethyl acetoacetate, and hydrolysis gives a ketone 225 Na OH O base, ethyl acetoacetate PBr3 O H Zn-Cu Br This ketone is then combined with an acetylide, and the resulting alcohol is selectively reduced (Lindlar’s catalyst) and the enol ether hydrolysed to citral Citral is converted to ψionone by aldol condensation with acetone Acid cyclization gives β-ionone BrMg OEt H2/Pd-BaSO4 OH OH O OEt OEt H H2SO4 acetone O Ba(OH)2 CHO O citral -ionone -ionone The β-ionone is converted to an aldehyde by Darzens condensation and hydrolysis Another sequence of alkyne addition/selective reduction yields an alcohol that is acetylated, dehydrated (with iodine as weak Lewis acid) and hydrolysed to Vitamin A O ClCH2COOEt/NaOEt H CHO BrMg OMgBr H2, Pd-BaSO4 CH2OH Ac2O I2 CH2OH hydrolysis Vitamin A 226 OH The synthesis of β-carotene uses the same β-ionone intermediate and oct-4-ene-2,7-dione in successive alkyne condensation reactions Selective reduction and dehydration simply gives the β-carotene In the same way, the ψ-ionone can be converted to the tetraterpene lycopene (a coloring agent in tomatoes) Br O OMgBr MgBr eq EtMgBr MgBr O O OH -carotene H2, Pd-BaSO4 OH TsOH lycopene O 227 OH HO Exercises chapter Mevalonic acid was marked with 13C and infused into a plant that produced camphor and αterpene Where the 13C labels end up in the terpene products? OH OH 13 O O CH2OH mevalonic acid + -pinene camphor Explain what happens in the following transformation : Me Me Me O Me O Me H H O Me CH3MgI O Me O Me H H NaOH O O HIO4 base Me CHO Me H H O Explains what happens in the following transformation and add a crucial ester reagent : O "ester"/NaOEt H CHO Find pathways to humulene and patchouli alcohol starting from farnesyl pyrophosphate assuming that the necessary enzymes are present for oxidation, rearrangement and/or addition reactions HO farnesyl pyrophoshate humulene 228 patchouli alcohol Contents Chapter Concerted reactions Excercises Chapter 39 Chapter Neutral intermediates 43 Exercises Chapter 81 Chapter Negatively charged intermediates 84 Exercises Chapter 143 Chapter Positively charged intermediates 149 Exercises Chapter 170 Chapter Rearrangements 173 Exercises chapter 201 Chapter Fragmentation reactions 204 Exercises chapter 212 Chapter Terpene chemistry 215 Exercises chapter 228 229 [...]... nonsymmetrical, the reaction itself loses it symmetry This reaction stays concerted but in de transition state the formation of the bond between the termini with the larger orbital coefficients is much further advanced in comparison with the other σ-bond This is an explanation of the unexpected regioselectivity, forming the 1,2disubstituted product with the most steric hindrance The two remaining termini can... carbonyl ene reaction of (R)-citronellal, a terpene compound This reaction is catalysed by the Lewis acid ZnBr2, which affords isopulegol, that by reduction can be transformed into (-)-menthol The stereochemistry of the carbonyl ene reaction is explained by the occurrence of a trans-decaline transition state, in which the larger substituents (methyl, hydroxy, isopropenyl) assume an equatorial position... are well known and the Claisen- and Coperearrangements belong to this class The transition state is a six-membered ring with a chair conformation as in cyclohexane This allows us to determine the stereochemistry in relevant cases The Claisen-rearrangement is a general synthetic method of ,-unsaturated carbonyl compounds If the enol ether is part of an aromatic system, an allylphenol is formed after... other words, the -bond opens along lobes with opposite sign (antarafacially), and the separated orbitals turn in the same sense This is a conrotatory ring opening and will have an effect on the stereochemistry of substituted butadienes / cyclobutenes For instance, starting from cis (or Z-)-3,4-dimethylcyclobutene the E,Z-hexa-2,4-diene will be formed (in two possible ways) On the other hand, starting... CH3 H H Z,E-hexa-2,4-diene H CH3 CH3 H CH3 H 175°C H CH3 + H H CH3 CH3 CH3 E,E-hexa-2,4-diene H Z,Z-hexa-2,4-diene (minor isomer) The corresponding photochemical reaction takes place with another stereochemistry because now this is a 2s + 2s process The ring opening is disrotatory Note that although the two lobes (same sign) are turning to the same side (up or down), one movement will be clockwise... Vitamin D2 Me Me Me Me Me H Me Me H H electrocyclic reaction h, conrotatory HO Me CH2 Me H Me Me HO Me provitamin D2 ergosterol Me Me Me Me CH2 1,7-H-shift (thermal, antarafacial) H HO Vitamin D2 2 Stereochemistry in concerted addition-, substitution- and elimination reactions The Woodward-Hoffmann-rules can also provide insight in the stereospecificity of other concerted reactions (other than pericyclic)