Alkynes

Alkynes are molecules that incorporate a C  C triple bond

Alkynes Given the presence of two pi bonds and their associated electron density, alkynes are similar to alkenes in their ability to act as a nucleophile Converting pi bonds to sigma bonds generally makes a molecule more stable.

Alkyne Uses Acetylene is the simplest alkyne It is used in blow torches and as a precursor for the synthesis of more complex alkynes More than 1000 different alkyne natural products have been isolated One example is histrionicotoxin, which can be isolated from South American frogs and is used on poison-tipped arrows by South American tribes

An example of a synthetic alkyne is ethynylestradiol Alkyne Uses Ethynylestradiol is the active ingredient in many birth control pills The presence of the triple bond increases the potency of the drug compared to the natural analog

10.3 Alkyne Acidity Recall that terminal alkynes have a lower pK a than other hydrocarbons Acetylene is 19 pK a units more acidic than ethylene

Alkyne Acidity Because acetylene (pK a =25) is still much weaker than water (pK a =15.7), a strong base is needed to make it react, and water cannot be used as the solvent Negative charge is stabilized in sp hybridized orbital

Alkyne Acidity Use ARIO to rationalize the equilibria below A bases conjugate acid pK a must be greater than 25 for it to be able to deprotonate a terminal alkyne

Preparation of Alkynes Like alkenes, alkynes can also be prepared by elimination

Preparation of Alkynes Such eliminations usually occur via an E2 mechanism Geminal dihalides can be used Vicinal dihalides can also be used E2 requires anti-periplanar geometry

Preparation of Alkynes: Elimination Reactions of Dihalides For geminal dihalides (on C2), can produce either internal or terminal alkyne

Preparation of Alkynes Often, excess equivalents of NaNH 2 are used to shift the equilibrium toward the elimination products NH 2 1- is quite strong, so if a terminal alkyne is produced, it will be deprotonated That equilibrium will greatly favor products

Preparation of Alkynes A proton source is needed to produce the alkyne Predict the products in the example below

Reduction of Alkynes Like alkenes, alkynes can readily undergo hydrogenation Two equivalents of H 2 are consumed for each alkyne  alkane conversion The cis alkene is produced as an intermediate due to mechanism. The addition of the first equivalent of H 2 produces an alkene, which is more reactive than the alkyne so the alkene is not observed

Reduction w/ a Poisoned Catalyst A deactivated or poisoned catalyst can be used to selectively react with the alkyne Lindlar’s catalyst and P-2 (Ni 2 B complex) are common examples of a poisoned catalysts

Reduction w/ a Poisoned Catalyst Is this a syn or anti addition?

Anhydrous ammonia (NH 3 ) is a liquid below –33 ºC – Alkali metals dissolve in liquid ammonia and function as reducing agents Alkynes are reduced to trans alkenes with sodium or lithium in liquid ammonia The reaction involves a radical anion intermediate Conversion of Alkynes to trans-Alkenes (Dissolving Metal Reductions)

Mechanism: Step 1 Dissolving Metal Reductions Note the single-barbed and double-barbed (fishhook) arrows.

Dissolving Metal Reductions Mechanism: Step 1 The radical anion adopts a trans configuration to reduce repulsion

Mechanism: step 2 and 3 Draw the product for step 3 of the mechanism Dissolving Metal Reductions

Mechanism: step 4 Dissolving Metal Reductions

Predict the product(s) for the following reaction 10.5 Dissolving Metal Reductions

Familiarize yourself with the reagents necessary to manipulate alkynes Practice with conceptual checkpoint Summary of Reductions

Addition of HX to Alkynes Involves Markovnikov Products Internal alkynes produce mixture of halogenated alkenes, then Markovnikov product Terminal alkynes produce Markovnikov product The associated mechanisms remain to be elucidated

Peroxides can be used in the hydrohalogenation of alkynes to promote anti-Markovnikov addition just like with alkenes The process proceeds through a free radical mechanism that we will discuss in detail in Chapter 11 Hydrohalogenation of Alkynes

Like alkenes, alkynes can also undergo acid catalyzed Markovnikov hydration The process is generally catalyzed with HgSO 4 to compensate for the slow reaction rate that results from the formation of vinylic carbocation An internal alkyne will generate more than 1 product. Hydration of Alkynes

Alkynes do not react with aqueous protic acids Mercuric ion (as the sulfate) is a Lewis acid catalyst that promotes addition of water with Markovnikov orientation The immediate product is a vinylic alcohol, or enol, which spontaneously transforms to a ketone or to an aldehyde in the event that acetylene is employed. Hydration of Alkynes

The enol/ketone tautomerization generally cannot be prevented and favors the ketone greatly Tautomers are constitutional isomers that rapidly interconvert. Hydration of Alkynes

Addition of Hg(II) to alkyne gives a vinylic cation Water adds and loses a proton A proton from aqueous acid replaces Hg(II) Mechanism of Mercury(II)- Catalyzed Hydration of Alkynes

Hydroboration-oxidation for alkynes proceeds through the same mechanism as for alkenes giving the anti- Markovnikov product It also produces an enol that will quickly tautomerize In this case, the tautomerization is catalyzed by the base (OH - ) rather than by an acid Hydroboration-Oxidation

In general, we can conclude that a C=O double bond is more stable than a C=C double bond. Hydroboration-Oxidation

After the –BH 2 and –H groups have been added across the C=C double bond, in some cases, an undesired second addition can take place To block out the second unit of BH 3 from reacting with the intermediate, bulky borane reagents are often used Hydroboration-Oxidation

Some bulky borane reagents are shown below Hydroboration-Oxidation

Predict products for the following reaction Draw the alkyne reactant and reagents that could be used to synthesize the following molecule Hydroboration-Oxidation

Markovnikov hydration leads to a ketone Anti-Markovnikov hydration leads to an aldehyde Hydration Regioselectivity

Initial addition gives trans intermediate as the major product Product with excess reagent is tetrahalide The mechanism for alkyne halogenation is not fully elucidated Alkyne Halogenation (Br or Cl)

Strong oxidizing reagents (O 3 or KMnO 4 ) cleave internal alkynes and terminal alkynes; alkyne carbons are fully oxidized Neither process is useful in modern synthesis Oxidative Cleavage of Alkynes

Predict the product(s) for the following reaction Alkyne Ozonolysis

Terminal alkynes are weak Brønsted acids (alkenes and alkanes are much less acidic (pK a ~ 25. See Table 9.1 for comparisons)) Reaction of strong anhydrous bases (e.g., sodium amide) with a terminal alkyne produces an acetylide ion The sp-hydbridization at carbon holds negative charge relatively close to the positive nucleus (Figure 9.5 in text) Acetylide anion is a good nucleophile Alkyne Acidity: Formation of Acetylide Anions

Acetylide ions can react as nucleophiles as well as bases Reaction with a primary alkyl halide produces a hydrocarbon that contains carbons from both partners, providing a general route to larger alkynes Alkylation of Acetylide Anions

Reactions only are efficient with 1º alkyl bromides and alkyl iodides Acetylide anions can behave as bases as well as nucelophiles Reactions with 2º and 3º alkyl halides gives dehydrohalogenation, converting alkyl halide to alkene Limitations of Alkyation of Acetylide Ions

Acetylene can be used to perform a double alkylation This would involve two separate 2-step reactions Complex target molecules can be made by building a carbon skeleton and converting functional groups Alkylation of Terminal Alkynes

Organic synthesis creates molecules by design Synthesis can produce new molecules that are needed as drugs or materials Syntheses can be designed and tested to improve efficiency and safety for making known molecules Highly advanced synthesis is used to test ideas and methods, answering challenges Chemists who engage in synthesis may see some work as elegant or beautiful when it uses novel ideas or combinations of steps – this is very subjective and not part of an introductory course An Introduction to Organic Synthesis

In order to propose a synthesis you must be familiar with reactions – What they begin with – What they lead to – How they are accomplished – What the limitations are A synthesis combines a series of proposed steps to go from a defined set of reactants to a specified product – Questions related to synthesis can include partial information about a reaction of series that the student completes Synthesis as a Tool for Learning Organic Chemistry

Compare the target and the starting material Consider reactions that efficiently produce the outcome. Look at the product and think of what can lead to it Read the practice problems in the text Strategies for Synthesis

Give necessary reaction conditions for the multi-step conversions below Synthetic Strategies

Graded HW #1: Synthesis Problems Give 2 sets of reagents that could be used to synthesize 1-pentyne through elimination reactions. Determine necessary reagents to complete the synthesis below.