Reactions of Alkenes. Alkenes generally react in an addition mechanism (addition two new species add to a molecule and none leave)

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1 eactions of Alkenes Alkenes generally react in an addition mechanism (addition two new species add to a molecule and none leave) X Y X Y ave already observed using a + electrophile ( or +/ 2 ) that a carbocation intermediate is generated which directs the regiochemistry Whenever a free carbocation intermediate is generated there will not be a stereopreference due to the nucleophile being able to react on either lobe of the carbocation (already observed this with S N 1 and E1 reactions) + 3 C C 2 C 3 btain racemic mixture of this regioisomer

2 eactions of Alkenes There are three questions to ask for any addition reaction X Y X Y 1) What is being added? (what is the electrophile?) 2) What is the regiochemistry? (do the reagents add with the X group to the left or right?) 3) What is the stereochemistry? (do both the X and Y groups add to the same side of the double bond or opposite sides?) All of these questions can be answered if the intermediate structure is known

3 eactions of Alkenes Dihalogen compounds can also react as electrophiles in reactions with alkenes Experimentally it is known, however, that rearrangements do nor occur with 2 addition -therefore free carbocations must not be present The large size and polarizability of the halogen can stabilize the unstable carbocation With an unsymmetrical alkene, however, both bonds to the bromine need not be equivalent Called a omonium ion -this structure will direct further reactions Possible partial bond structures!+!+!+ or More stable partial positive charge!+ Does not rearrange, therefore this carbocation must not be present

4 Dihalogen Addition The bromonium ion thus forms a partial bond to the carbon that can best stabilize a positive charge which will then react with the bromide nucleophile!+!+ Due to the 3-centered intermediate, dihalogen additions occur with an anti addition 3 C C 3 3 C C 3 3 C C 3 btained product Not obtained

5 Formation of alohydrins When water is present when a dihalogen is added to a double bond, then water can react as the nucleophile with the halonium (e.g. bromonium) ion!+!+ 2 Favored product While water is a weaker nucleophile than bromide, because it is the solvent there is a much greater concentration present The halonium ion thus directs both the regiochemistry (oxygen adds to the carbon that can best stabilize the partial positive charge) and the stereochemistry (due to the three membered ring the oxygen must add anti to the the bromine already present) D C 3!+!+ C 3 D 2 The halohydrin is named according to which halogen is present (chlorohydrin, bromohydrin, iodohydrin) D C 3

6 alogenation of Alkynes Dihalogen can be added to alkynes in addition to alkenes The reaction is similar to alkenes with the main difference being the presence of two π bonds thus allowing reaction to occur twice for a total of 4 halogens adding to the compound 3 C C 3 3 C C 3 3 C C 3 With one addition, obtain trans vicinal dihalogen Second addition is favored, hard to stop at alkene stage as alkene is more reactive than alkyne Due to difference in reactivity, it is possible to selectively add to an alkene in the presence of an alkyne 1 equiv.

7 xymercuration An alkene can also be hydrated using mercury salts (called oxymercuration) Mercury diacetate [g(ac) 2 ] is a common reagent which loses one acetate to generate an electrophilic source of mercury g g C 3 Ac g!+!+ C 3 The electrophilic mercury reacts with an alkene to form a mercurinium ion which is similar to bromonium ions in that a three membered ring is formed with a partial bond to the carbon that can best handle the partial positive charge Water can then react (which is typically the solvent for these reactions) in an anti addition Ac g!+ C 3!+ 2 NaB Acg 4 C 3 The mercury can subsequently be removed with sodium borohydride to form the alcohol

8 outes to ydrate an Alkene Different routes have been seen to hydrate an alkene, each route though offers different advantages and often an entirely different product C 3 3 C C 3 +/ 2 3 C C 3 C 3 C 3 Markovnikov product Generate free carbocation that rearranges to more stable 3 cation C 3 1) B 3 TF 2) 2 2, Na C 3 Anti-Markovnikov 3 C C 3 3 C C 3 C 3 3 C C 3 1) g(ac) 2, 2 2) NaB 4 C 3 3 C C 3 Markovnikov product Do not generate free carbocation therefore no rearrangements occur

9 Epoxidation To form an epoxide from an alkene, need to generate an electrophilic source of oxygen Previously we have observed oxygen acting as a nucleophile and reacting with carbocation sites A peroxy acid (or peracid) is a source of electrophilic oxygen!-!-!- 3 C 3 C!+!+!+!- Acetic acid Peracetic acid (called peracid or peroxy acid) Due to the high electronegativity for oxygen, typically the oxygen atoms in an organic compound have a partial negative charge (therefore nucleophilic) In a peracid, however, the terminal oxygen is already adjacent to an oxygen with a partial negative charge The terminal oxygen thus has a partial positive charge and thus is electrophilic

10 Epoxidation When an alkene reacts with a peracid, an electrophilic reaction occurs where the π bond reacts with the electrophilic oxygen C 3 C 3 C 3 C 3 C 3 C 3 The reaction forms an epoxide (oxirane) with a carboxylic acid leaving group Due to the cyclic transition state for this reaction, the two new bonds to oxygen form SYN C C 3 3 C 3 C 3 C 3 3 C C 3 C 3 C 3 C 3

11 Epoxides Selectivity in Epoxide Formation When synthesizing an epoxide from an alkene with peracid the peracid is acting as a source of an electron deficient oxygen, therefore the most electron rich double bond will react preferentially C 3 1 equivalent More alkyl substituents, therefore more electron rich double bond If more equivalents are added, the remaining double bonds can still react

12 eaction of Epoxides Unlike straight chain ethers, epoxides react readily with good nucleophiles eason is release of ring strain in 3-membered ring (even with poor alkoxide leaving group) C 3 Same reaction would never occur with straight chain ether C 3 No reaction

13 eaction of Epoxides Most GD nucleophiles will react through a basic mechanism where the nucleophile reacts in a S N 2 reaction at the least hindered carbon of the epoxide 3 C C 3 Mg 3 C C 3 All products after work-up Grignard reagents are a source of nucleophilic carbon based anions - 3 C N 3 3 C N 2 Neutral amines also are good nucleophiles 3 C LiAl 4 "LA" "-" Lithium aluminum hydride is a source of - which also reacts in a S N 2 type reaction 3 C

14 eaction of Epoxides Epoxides will also react under acidic conditions The oxygen is first protonated which then allows the positive charge to be placed selectively on the carbon that is most stable with a partial positive charge similar to bromonium or mercurinium ions 3 C + 3 C!+!+ 2 3 C 3 C Vicinal diol (glycol) Can use weaker nucleophiles in this manner since we have a better leaving group Common examples of nucleophiles include water or alcohols

15 eaction of Epoxides Differences in egiochemistry The base catalyzed opening of epoxides goes through a common S N 2 mechanism, therefore the nucleophile attacks the least hindered carbon of the epoxide C 3 Mg In the acid catalyzed opening of epoxides, the reaction first protonates the oxygen This protonated oxygen can equilibrate to an open form that places more partial positive charge on more substituted carbon, therefore the more substituted carbon is the preferred reaction site for the nucleophile + C 3 C 3

16 eaction of Epoxides Grignard and rganolithium compounds are good nucleophiles which can react with an epoxide in a basic mechanism 3 C C 3 Mg 3 C C 3 These reagents can sometimes cause problems due to their very strong base strength -side reactions can occur and also they are very reactive and thus not selective (they will react with any carbonyl present in the compound for example) To overcome these drawbacks organocuprates can also deliver an - source as a nucleophile They will not react, however, with carbonyl compounds C 3 Li CuCN 3 C (C 3 ) 2 Cu(CN)Li 2 3 C C 3

17 Asymmetric Epoxidation Epoxides are thus a very versatile functional group that can react with a variety of nucleophiles to allow synthesis of a wide selection of products When an achiral alkene and an achiral peracid react, however, the epoxide formed would not be chiral Many targeted compounds are chiral and their chirality is critical for the properties A tremendous advantage was obtained when a simple and convenient method was developed to synthesize chiral epoxides Sharpless epoxidation Ti[C(C 3 ) 2 ] 4 Et 2 C C 2 Et (C 3 ) 3 C 3

18 Glycol Formation We have observed glycols (vicinal diols) being formed by reacting epoxides with either basic or acidic water 3 C Na 3 C This reaction generates an ANTI glycol C 3 Na Would need another method to generate a SYN glycol

19 Glycol Formation There are two common reagents for SYN dihydroxy addition to alkenes Both involve transition metals that deliver both oxygens from the same face 3 C C 3 s 3 C 3 C s 2 2 or Na 2 S C C 3 Mn 3 C 3 C Mn 2 Na Contrast this stereochemistry with glycols formed by reacting epoxides C 3 1) C 3 2) Na 3 C

20 Carbonyl Compounds A carbon-oxygen double bond is a common, and useful, functional group in organic chemistry Called a carbonyl group (the carbon is thus called the carbonyl carbon) The type of carbonyl changes depending upon the substituents on the carbonyl carbon N 2 Cl Ketone two groups Aldehyde one, one Amide one, one N Acid one, one Ester one, one Acid chloride one, one Cl Carbonyl compounds can also be synthesized from alkenes

21 zonolysis Instead of reacting the alkene with transition metal reagents to synthesize glycols, other 1,3-dipolar reagents can be used which generate a similar 5-membered ring intermediate When ozone is used ( 3 ) the reaction is called an ozonolysis Mechanism of zonolysis 3 C C 3 Molozonide (primary ozonide) zonide Zn (C 3 SC 3 ) ( 2 /Pd) eductive workup

22 zonolysis With reductive workup, either ketones or aldehydes can be obtained depending upon the substituents on the alkene starting material 3 C C 3 C 3 1) 3 2) C 3 SC 3 3 C C 3 3 C With oxidative workup, however, aldehydes are oxidized to carboxylic acids but ketones are not reactive under these conditions 3 C C 3 C 3 1) 3 2) C C 3 3 C

23 ydrohalogenation of Alkynes Similar to reactions with alkenes, when alkynes react with hydrohalic acid (e.g. ) the proton reacts with the π bond and the positively charged intermediate is reacted with the halide Unlike alkene reactions, however, the addition of to the first π bond generates a high yield of the trans product (not a mixture of cis and trans as would be expected with a free carbocation) 3 C C 3 3 C!+!+ C 3 3 C C 3 Vinyl cations are very unstable Since there is still a remaining π bond, additional equivalents of will react a second time to generate the geminal (on the same carbon) dihalogen 3 C C 3 3 C C 3

24 ydration of Alkynes To hydrate an alkyne a mercury catalyst is added (in contrast to alkene reactions when acidic water alone is sufficient) Similar to oxymercuration routes with alkenes 3 C C 3 g(ac) C gac C C gac C 3 The last step is a KET-ENL equilibrium 3 C (not resonance) Ketone form is generally more stable C 3 3 C C 3 Due to the positive charge developed after second π bond reacts with acid, do not need to add a reducing agent (NaB 4 ) similar to the alkene oxymercuration

25 Keto-Enol Equilbrium Generally the ketone form is more stable than the enol form (carbon-oxygen double bonds are relatively more stable) 3 C C 3 3 C C 3 - Enol form is thus not the stable form, if an enol is generated in a reaction convert the structure to the keto form

26 ydroboration of Alkynes ydroboration of alkynes can also occur *need bulky reagent to prevent side reactions due to second π bond (Sia is an acronym for sec-isoamyl) B (Sia) 2 B B 2 Notice hydroboration still occurs with syn addition and the regiochemistry is dictated by the stability of the initial carbocation intermediate

27 ydroboration of Alkynes xidation of borane product The borane can be oxidatively removed (analogous to alkene reactions) 2 2 B 2 Na *if a terminal alkyne is used the product of this reaction sequence is an aldehyde after keto-enol equilibrium

28 ydrogenation of π Bonds An alkene can also be reduced to an alkane 2 catalyst A catalyst is required for this process (hydrogen gas alone will not reduce alkenes) eterogeneous catalyst reaction occurs on the metal surface of the catalyst (Pt, Pd, Ni, Pd/C) and thus results in SYN reduction N N (diimide) A nonmetallic reducing agent can also be used, diimide is a common choice and also results in SYN reduction

29 ydrogenation of π Bonds eduction of alkynes With two π bonds important to realize a variety of structures can be obtained depending upon the reducing conditions used 2, Pt If use hydrogen gas with a variety of metal catalysts (Pt, Pd, Ni, Pd/C are common choices) it is hard to stop at the alkene, the alkyne will be fully reduced to the alkane In order to stop at the alkene stage, a weaker catalyst is needed

30 ydrogenation of π Bonds Alkyne to Alkene ne approach is to use a poisoned catalyst (Lindlar s catalyst) the catalyst has impurities added which lower the effectiveness of the metal surface 2 Lindlar s catalyst (Pd/CaC 3 /Pb) *btain cis reduction, because the alkyne must approach the metal surface from one direction, hence both hydrogens are added from the same side

31 ydrogenation of π Bonds Alkyne to trans-alkene To obtain a trans alkene from reduction of alkyne a different mechanism is required Dissolving metal reduction yields the trans product Na N 3 (l) eaction is run at low temperature so that the ammonia is a liquid (acts as solvent) Mechanism involves dissolved electrons reducing the alkyne

32 ydrogenation of π Bonds The mechanism for dissolving metal reductions involve the formation of a solvated electron Na N 3 (l) Na N 3 (l) This solvated electron can add to the LUM of the alkyne to generate a radical/anion N 3 (l) With radical/anion want to sterically place groups apart N 2 An acid base reaction generates a vinyl radical 1) N 3 (l) 2) N 3 The vinyl radical repeats the two steps to add the second hydrogen TANS

33 ther eactions of Alkenes Carbenes A carbene refers to a carbon atom containing only 6 electrons in the outer shell (two covalent bonds and an extra two electrons unlike a carbocation) C ighly reactive This compound will react quickly with alkenes to form a cyclopropane 3 C 3 C C 3 C 3 C 3 C C 3 3 C C 3 Common method to generate cyclopropane structures

34 Carbenes There are a number of ways to generate a carbene 2 C N N C 2 Loss of diazo leaving group C(C 3 ) 3 C 2 Dihalo carbenes (typically dichloro or dibromocarbene) are generated by reacting haloforms with strong base Either of these methods of carbene generation will react with alkenes 2 C N N

35 Carbenes Since with carbenes we have 6 electrons in the outer shell, it depends upon which orbitals the electrons are placed to determine the flavor of the carbene Both electrons in same orbital, must be spin paired and thus this is called a singlet state Electrons in different orbitals, electrons will have the same spin and thus called a triplet state Both states of carbenes can react, but the singlet state is generally more reactive The singlet can react in a concerted manner (both new C-C bonds of cyclopropane are formed at same time) and thus the reaction must be SYN C 3 C 3 3 C C 3 The triple cannot form both bonds at the same time and thus the cyclopropane formed can be either SYN or ANTI in addition (experimentally these reactions are used to differentiate which state is reacting)