Chapter 17 — Alkynes: Reactions and the Power of Triple Bonds

"A triple bond is two double bonds in disguise. Add HCl twice, you get a geminal dihalide. Reduce with Lindlar Pd, you get a cis-alkene. Reduce with Na/NH₃, you get a trans-alkene. With one functional group, you have access to alkenes of either geometry — that's the power of alkynes." — paraphrase from a synthesis text

"Acetylide anions are the original carbon nucleophiles. Before Grignard reagents were discovered, acetylene was the way to extend a carbon chain. Their pKa is special — alone in organic chemistry — and their reactivity is unmatched." — Clayden, Greeves, Warren

This chapter covers alkynes — molecules with a C≡C triple bond. The chemistry is similar to alkene chemistry (Ch 15-16) but with two important differences: 1. Two π bonds can be added across, giving stepwise addition products. 2. Terminal alkynes (with C-H attached to C≡C) have a uniquely acidic C-H (pKa ~25), making them deprotonable to give alkynide anions — powerful carbon nucleophiles.

Alkynes are central to: - Selective alkene formation (Lindlar Pd → cis; Na/NH₃ → trans). - C-C bond formation via alkynide nucleophiles. - Modern Pd-catalyzed coupling (Sonogashira; Ch 37). - Pharmaceutical synthesis (the Pill = 17α-ethynyl estradiol; many anticancer drugs). - Click chemistry (Sharpless 2022 second Nobel for CuAAC). - Bioconjugation and biomolecular labeling.

By the end of this chapter you should be able to: - Describe alkyne structure (sp hybridization, linear geometry, pKa of terminal C-H). - Predict alkyne addition products (Markovnikov first, then second). - Recognize that hydration gives ketones (via enol tautomerism). - Use alkynide anions as nucleophiles for C-C bond formation. - Choose Lindlar Pd vs. Na/NH₃ for cis or trans alkene formation. - Recognize the Sonogashira coupling and click chemistry applications. - Apply alkyne chemistry to natural product and drug synthesis.

17.1 Alkyne structure and bonding

An alkyne has a C≡C triple bond: - One σ bond (sp + sp). - Two perpendicular π bonds (formed from p_y and p_z orbitals). - Linear geometry (~180° at each sp carbon).

Both alkyne carbons are sp hybridized: - Two sp hybrid orbitals form two σ bonds (to substituent + to other carbon). - Two unhybridized p orbitals form two π bonds (perpendicular to each other).

Bond properties: - C≡C bond length: ~1.20 Å (shorter than C=C 1.34 Å, shorter than C-C 1.54 Å). - C≡C bond strength: ~200 kcal/mol (vs. C=C 146 kcal/mol; C-C 80 kcal/mol). - The π bonds are weaker individually than the σ but stronger than alkene's π.

sp hybridization in detail

The sp carbon has: - 2 sp orbitals (each 50% s, 50% p). - 2 unhybridized p orbitals (perpendicular to each other and to the sp axis).

The two sp orbitals point in opposite directions (180° apart), giving the linear geometry. Each sp orbital forms a σ bond — to the other sp carbon and to a substituent (H, R).

The two unhybridized p orbitals overlap with the corresponding p orbitals on the other sp carbon to form two π bonds. These π bonds are perpendicular to each other; together they encircle the σ bond.

The result: the C≡C has a cylindrical electron cloud with σ + 2π in three "rings." This is why alkynes are described as having "increased s-character" — 50% s in their bonds vs 33% (sp²) or 25% (sp³).

Terminal vs internal alkynes

• Terminal alkyne: HC≡C-R (one C of the triple bond has an H).
• Internal alkyne: R-C≡C-R' (both Cs have substituents).

Examples: - Acetylene (HC≡CH): the simplest alkyne; gas at room temperature; flammable. - Propyne (HC≡C-CH₃): terminal; gas. - 1-butyne (HC≡C-CH₂-CH₃): terminal. - 2-butyne (CH₃-C≡C-CH₃): internal. - Diphenylacetylene (PhC≡CPh): symmetric internal alkyne.

Linear geometry

Because both alkyne carbons are sp, the geometry is linear (~180° at each carbon). This contrasts with alkenes (~120°). The linear geometry has implications: - Alkynes can fit in narrow molecular environments (less steric bulk than alkenes). - Cyclic alkynes are strained: cyclooctyne is the smallest stable cyclic alkyne (and has ~12 kcal/mol of strain). Smaller cyclic alkynes (cycloheptyne, cyclohexyne) are unstable. - Used as rigid linkers in molecular design (the alkyne acts as a "stick" of fixed length).

Boiling points and physical properties

Alkynes have similar boiling points to alkanes of the same C count, slightly lower than alkenes. Acetylene boils at -84 °C; propyne at -23 °C; 1-butyne at +9 °C; etc. Higher-MW alkynes are liquid at room temperature.

Alkynes are non-polar (or slightly polar for terminal alkynes due to the C-H polarization). Soluble in organic solvents; slightly soluble in water (more soluble than alkenes due to weak H-bonding from terminal C-H).

17.2 Acidity of terminal alkynes

The terminal alkyne C-H has pKa ~25 — uniquely acidic among hydrocarbons.

The progression: more s-character in the C-H bond means the bond is shorter and stronger, but also the conjugate base (carbanion) is more stable because the lone pair is in an sp orbital (more s-character means the electrons are closer to the nucleus, more stabilized).

Why s-character matters

In an sp³ orbital (25% s, 75% p), the electrons spend most of their time in the more-extended p orbital region. In an sp orbital (50% s, 50% p), the electrons spend more time near the nucleus, where the electrostatic stabilization is strongest.

The conjugate base of a terminal alkyne (R-C≡C⁻) places the lone pair in an sp orbital, where it is stabilized by being closer to the carbon nucleus. The conjugate base of an alkane (R-CH₂⁻) places the lone pair in an sp³ orbital, where it is less stabilized.

The pKa difference (25 vs 50) reflects this stabilization: the alkynide anion is much more stable than an alkyl anion.

Acid-base chemistry

The terminal alkyne is acidic enough to be deprotonated by: - NaNH₂ (pKaH ~38): completely deprotonates. - n-BuLi (pKaH ~50): completely deprotonates. - NaH (pKaH ~35): completely deprotonates. - KOtBu: not strong enough.

Not by: - NaOH (pKaH ~16): too weak. - NaOEt (pKaH ~16): too weak. - Et₃N (pKaH ~10): far too weak.

The result: alkynide anion (acetylide) RC≡C⁻ — a strong base AND a strong carbon nucleophile.

Worked example

Worked Problem 17.1: Why is the terminal alkyne C-H more acidic than the alkene C-H?

Solution: Hybridization affects acidity. The sp orbital has more s-character (50%) than sp² (33%) or sp³ (25%). More s-character = electrons are held closer to the nucleus, the bond is more polar, and the conjugate base is more stable (because the negative charge is in an orbital with more s-character, closer to nucleus, lower energy). Therefore, the alkyne C-H is more acidic.

17.3 Alkyne addition reactions

Alkynes undergo all the addition reactions of alkenes, but twice (once for each π bond).

HX addition

$$RC≡CR + 2 HX \to RC(X)_2-CHR'$$

But typically stopping at one HX: $$RC≡CR + HX \to RC(X)=CHR' \text{ (Markovnikov vinyl halide; cis or trans depending on mechanism)}$$

A second HX gives the geminal dihalide: $$RC(X)=CHR' + HX \to RCX_2-CH_2R' \text{ (gem-dihalide)}$$

The Markovnikov rule applies: H goes to the C with more H's; X goes to the more-substituted C.

Mechanism

The alkyne addition mechanism is similar to the alkene mechanism (Ch 15) but with the additional π bond: 1. H⁺ adds to the alkyne; cation forms (vinyl cation or bridged). 2. X⁻ attacks; vinyl halide forms. 3. Second HX adds to the vinyl halide; cation; second X⁻ attacks; gem-dihalide.

For terminal alkynes, the Markovnikov direction has -H on the terminal C (the C with more H's) and -X on the internal C. Net: HC≡CR + HX → CH₂=CXR (vinyl halide) → CH₃-CX₂R (gem-dihalide).

The vinyl halide intermediate is sometimes isolable, but more often the reaction proceeds to the gem-dihalide unless conditions are carefully controlled.

Hydration: gives ketones

$$RC≡CR + H_2O \xrightarrow{HgSO_4, H_2SO_4} \text{vinyl alcohol (enol)} \to \text{methyl ketone (keto)}$$

Hydration of an alkyne gives a vinyl alcohol (enol) at first. But enols are unstable; they rapidly tautomerize to the keto form (Ch 27).

For terminal alkynes (RC≡CH): hydration is Markovnikov, so OH goes to the more-substituted (internal) C. The enol → methyl ketone (R-CO-CH₃).

For internal alkynes: hydration gives the more-stable ketone (depends on substituent stabilization). Symmetric internal alkynes give a single ketone product.

Mechanism of hydration

1. H₂SO₄ + H₂O on alkyne → vinyl cation (Markovnikov).
2. Hg²⁺ catalyzes the formation of a mercurinium-like 3-membered ring.
3. Water attacks the more-substituted vinyl C → vinyl alcohol with -HgX still attached.
4. Demercuration → enol.
5. Keto-enol tautomerization: the vinyl alcohol (enol) is in rapid equilibrium with the methyl ketone (keto). At equilibrium, the keto form predominates (much more stable; ~10⁻⁵ enol).

Industrial example: vinyl alcohol (acetaldehyde precursor) was historically made from acetylene + Hg(II) catalysis. Modern industrial production has shifted to alternative routes (less mercury).

Hydroboration-oxidation: gives aldehydes (anti-Markovnikov)

For terminal alkynes: $$RC≡CH + R'_2BH \to RC(BR'_2)=CH-H \text{ (anti-Markovnikov vinyl borane)} \to \text{aldehyde}$$

Step 1 (hydroboration): boron adds to the less-substituted C (anti-Markovnikov). With disiamylborane (or 9-BBN), single hydroboration is achievable. The B-C bond is on the terminal C; the other vinyl H is on the internal C.

Step 2 (oxidation, H₂O₂/NaOH): converts B-C to OH-C. The vinyl alcohol (an enol) tautomerizes to the aldehyde.

Net result: terminal alkyne → aldehyde (RCH₂CHO).

This is an important method for making aldehydes from terminal alkynes — the only way to make a primary aldehyde from a non-aldehyde precursor without going through an alcohol oxidation step.

Why disiamylborane (or 9-BBN) for alkyne hydroboration?

BH₃ is too reactive: it would add twice to the alkyne, giving a gem-diborane. Bulky boranes (disiamylborane, 9-BBN) add only once and stop.

Halogenation (X₂)

$$RC≡CR + Br_2 \to RC(Br)=CR(Br) \text{ (trans-dihalide; anti)}$$

Bromonium-ion-like mechanism (similar to alkene). Anti addition. Stereospecific: the two Br atoms end up on opposite faces.

A second Br₂ gives the tetrahalide: $$RC(Br)=CR(Br) + Br_2 \to RCBr_2-CRBr_2 \text{ (tetrahalide)}$$

Often the reaction stops at one Br₂ if 1 equivalent is used. With excess, the tetrahalide forms.

Catalytic hydrogenation: full reduction

$$RC≡CR + 2 H_2 \xrightarrow{Pd/C} RCH_2-CR_2H \text{ (alkane)}$$

H₂/Pd reduces alkyne fully to alkane. The intermediate alkene is reduced further (H₂/Pd doesn't typically stop at the alkene).

To stop at the cis-alkene: use Lindlar Pd (Section 17.4).

Dissolving metal reduction

$$RC≡CR + Na/NH_3(l) \to RCH=CHR \text{ (trans-alkene)}$$

Sodium dissolved in liquid ammonia generates solvated electrons. These electrons reduce the alkyne in a stepwise (anti) addition: one electron, then proton, then one electron, then proton. The geometry: trans alkene.

This is opposite to Lindlar's cis-selective reduction.

Other addition reactions

• HCN addition (with metal catalysis): gives an α,β-unsaturated nitrile (after tautomerization).
• Si-H addition (hydrosilylation): adds Si and H across the alkyne; useful for organosilane synthesis.
• CO + H₂ (hydroformylation): gives α,β-unsaturated aldehydes.

These specialized additions extend the alkyne toolkit; we won't cover them in detail here.

17.4 Selective reduction: cis vs trans alkene

A key synthetic application: starting with an alkyne, you can choose the geometry of the resulting alkene.

Lindlar Pd: cis alkene

Lindlar catalyst: Pd/CaCO₃ poisoned with Pb (lead) and quinoline. The Pb deactivates the surface enough to slow the reduction; quinoline blocks specific sites.

$$RC≡CR + H_2 \xrightarrow{Lindlar} RCH=CHR \text{ (cis-alkene)}$$

Mechanism: the alkyne adsorbs flat on the Pd surface; both H atoms are delivered from the same face → syn addition. The resulting alkene is too sterically hindered to re-adsorb on the surface, so reduction stops at the alkene.

Stereoselectivity: cis alkene (cis substituents).

How was Lindlar discovered?

Helmut Lindlar (Hoffmann-La Roche, Basel, 1952) was developing the synthesis of vitamin A. The molecule contains a cis double bond that needed to be made selectively from an alkyne intermediate. Lindlar developed the Pb-poisoned Pd catalyst to give clean cis selectivity.

The Lindlar catalyst remains the gold standard for selective alkyne → cis-alkene reduction. Used in the synthesis of: - Vitamin A (the original target). - Natural products with cis alkene geometry. - Insect pheromones (often cis alkenes). - Many pharmaceuticals.

Sodium in liquid ammonia: trans alkene

Sodium metal in liquid ammonia (-33 °C) generates solvated electrons. The mechanism is stepwise radical-anion chemistry:

1. Electron + alkyne → radical anion (one electron in the C=C bond).
2. NH₃ (or t-BuOH) protonates the radical anion → vinyl radical.
3. Another electron → vinyl carbanion.
4. NH₃ protonates → trans alkene.

The geometry results from the more-stable trans vinyl radical/carbanion intermediates. Trans alkene preferred because it minimizes steric strain.

Stereoselectivity: trans alkene.

When to choose which

Need cis-alkene? Use Lindlar Pd. Need trans-alkene? Use Na/NH₃.

This is one of the most useful selectivity tools in synthesis. Many natural products have specific alkene geometries; the synthesis often converts an alkyne to the right alkene geometry.

Worked Problem 17.2: Predict the products: (a) 2-pentyne + H₂/Lindlar → ? (b) 2-pentyne + Na/NH₃ → ?

Solution: (a) cis-2-pentene (the cis isomer; Lindlar selectivity). (b) trans-2-pentene (the trans isomer; Na/NH₃ selectivity).

Industrial alkyne-to-alkene reduction

The vitamin A synthesis (Hoffmann-La Roche, 1947+) was a landmark: a 30+ step synthesis with multiple alkyne-to-cis-alkene reductions. The yearly demand for vitamin A (added to milk, margarine, cereals; supplements) is ~10,000 tons; produced industrially using Lindlar-style chemistry.

17.5 Alkynide anion: the carbon nucleophile

Deprotonation of a terminal alkyne with NaNH₂ (or n-BuLi) gives the alkynide anion:

$$RC≡CH + NaNH_2 \to RC≡C^-Na^+ + NH_3$$

The alkynide anion is a strong base AND a strong carbon nucleophile. Two main reactions:

Alkylation: SN2 on alkyl halide

$$RC≡C^- + R'X \to RC≡C-R' + X^-$$

The alkynide attacks the alkyl halide via SN2. The new C-C bond forms; X⁻ leaves.

Limitations: - Works for primary alkyl halides (good SN2 substrates). - Doesn't work well for secondary or tertiary halides (SN1/E2 competition). - Doesn't work with halides that have β-H (E2 elimination predominates).

This is one of the first C-C bond-forming reactions in our toolkit. It extends carbon chains.

Mechanism Map 17.1: Alkynide alkylation. 1. NaNH₂ + RC≡CH → RC≡C⁻Na⁺ + NH₃ (deprotonation). 2. RC≡C⁻ + R'X → RC≡C-R' + X⁻ (SN2; new C-C bond). Net: HC≡CR + R'X (with NaNH₂ + workup) → RC≡C-R' (extended carbon chain).

Addition to carbonyls

$$RC≡C^- + R'COR'' \to RC≡C-CR'R''-O^- \to \text{after workup, alcohol}$$

The alkynide attacks the carbonyl C (electrophilic, Ch 25 preview). The new C-C bond forms; the carbonyl becomes an alkoxide. After aqueous workup, you get a propargyl alcohol (an alcohol adjacent to a triple bond).

This is alkynide as a Grignard-like nucleophile. The product is a propargyl alcohol with two new substituents on the central C.

Examples: - Acetylide + acetone → 2-methyl-3-butyn-2-ol (a tertiary propargyl alcohol). - Propynide + benzaldehyde → 1-phenyl-2-butyn-1-ol (a secondary propargyl alcohol).

Combining in synthesis

Use sequential alkynide alkylation + addition: 1. Acetylene + NaNH₂ → HC≡C⁻. 2. + R₁-Br → HC≡C-R₁ (a longer alkyne). 3. + NaNH₂ → ⁻C≡C-R₁. 4. + R₂-Br → R₂-C≡C-R₁ (a still longer alkyne, now internal).

Each step extends the carbon chain by one new C-C bond. This is the classical "alkyne synthesis" of long-chain alkynes.

Alkynides in pharmaceutical synthesis

A classic example: 17α-ethynyl-estradiol (the active ingredient of "the Pill"). The synthesis includes an alkynide addition to a steroid ketone:

1. Estrone (a C17 ketone in the steroid scaffold).
2. • HC≡C-Li (or similar acetylide) → 17α-ethynyl-estradiol (with new -C≡CH substituent and -OH on C17).

The 17α-ethynyl group makes the molecule more orally bioavailable (resistant to Phase I metabolism). This was the breakthrough that made the Pill an oral medication; 17α-ethynyl-estradiol has been the active estrogen in oral contraceptives since 1960.

This single alkynide addition reaction enabled a billion-dollar pharmaceutical category.

17.6 Sonogashira coupling: modern Pd-catalyzed alkyne coupling

A modern alternative to alkynide alkylation: Sonogashira coupling (Ch 37).

$$ArX + HC≡CR + Pd + CuI + amine \to ArC≡CR + amine \cdot HX$$

The terminal alkyne is deprotonated by Cu (forming Cu-acetylide); Pd does the cross-coupling with the aryl halide.

Advantages over alkynide alkylation: - Works with aryl halides (which alkynide-SN2 cannot easily handle). - Mild conditions (room temperature, not strong base). - Tolerates many functional groups (amines, alcohols, carbonyls).

Disadvantages: - Pd catalyst (expensive); needs to be recovered. - Requires Cu co-catalyst. - Some functional group restrictions (no acidic protons that interfere with Cu).

Used widely in pharmaceutical synthesis where aryl-alkyne bonds are needed. Many drugs containing aryl-alkynyl fragments are made by Sonogashira.

Examples in drug synthesis

• Imatinib (Gleevec): contains an aryl-alkyne fragment; some analogues made by Sonogashira.
• Erlotinib (Tarceva, EGFR inhibitor): contains a terminal alkyne installed by Sonogashira.
• Topotecan (cancer drug): alkyne synthesis step.
• Many EGFR/HER2 inhibitors: alkyne is a key pharmacophore element.

17.7 Click chemistry: CuAAC and SPAAC

Click chemistry is a class of fast, reliable reactions developed by Sharpless (Nobel 2022 for click). The flagship reaction:

CuAAC (Cu-catalyzed azide-alkyne cycloaddition)

$$RC≡CH + R'-N_3 \xrightarrow{Cu(I)} \text{1,4-substituted 1,2,3-triazole}$$

A terminal alkyne + an organic azide + a Cu(I) catalyst → a 1,2,3-triazole ring (a 5-membered N-N-N-C-C aromatic ring).

The reaction: - Forms a single regioisomer (1,4-substituted; not 1,5). - Works in water, biological media. - Tolerates almost all functional groups. - Goes essentially to completion. - Is "click" — fast, irreversible, high yield.

Applications

• Bioconjugation: linking proteins, antibodies, drugs together.
• Drug discovery: combinatorial libraries built by CuAAC.
• Materials science: cross-linking polymers.
• Surface chemistry: functionalizing surfaces with biomolecules.
• In-vivo imaging: making fluorescent probes.

The 2022 Nobel Prize in Chemistry was awarded to Sharpless, Bertozzi, and Meldal for click chemistry. Sharpless's second Chemistry Nobel (the first was 2001 for asymmetric synthesis).

SPAAC (strain-promoted azide-alkyne cycloaddition)

Cu-catalyzed click requires Cu, which can be toxic to cells. SPAAC uses strained cyclooctyne instead of a Cu catalyst:

$$\text{cyclooctyne} + R-N_3 \to \text{1,2,3-triazole}$$

Cyclooctyne has ~12 kcal/mol of ring strain; this strain is released in the cycloaddition, so no Cu catalyst is needed. SPAAC works in living cells with no toxicity.

Carolyn Bertozzi (Stanford, Nobel 2022) developed SPAAC and demonstrated it in cells. This enables labeling biomolecules in living organisms — a revolution in chemical biology.

17.8 Industrial alkyne chemistry

Acetylene (HC≡CH) was historically an important industrial chemical: - Calcium carbide (CaC₂) + water → acetylene + Ca(OH)₂. - Reppe chemistry (1928+): used acetylene + CO + alcohol/water to make various organics.

Reppe chemistry

Walter Reppe (BASF, 1920s-1940s) developed industrial methods using acetylene:

1. Vinylation: HC≡CH + ROH → CH₂=CHOR (vinyl ether).
2. Ethynylation: HC≡CH + RCHO → HC≡C-CHOH-R (propargyl alcohol).
3. Carbonylation: HC≡CH + CO + ROH → CH₂=CHCOOR (acrylate).
4. Cyclization: 4 HC≡CH → cyclooctatetraene; or 3 HC≡CH → benzene (Reppe synthesis of benzene).

These reactions were the basis of significant industrial chemistry from the 1930s through the 1960s. The German chemical industry (BASF, Hoechst) was particularly productive.

Modern industrial chemistry

Modern industrial chemistry has shifted to alkene-based feedstocks (cheaper, safer). Acetylene is still used for some specialty applications: - Welding (oxyacetylene torch; ~3000 °C flame). - Vitamin A synthesis (via Lindlar reduction of alkyne intermediate). - Specialty pharmaceutical syntheses. - Polyacetylene (a conductive polymer; Nobel 2000 to Heeger, MacDiarmid, Shirakawa).

17.9 Spectroscopy of alkynes

Alkynes have characteristic spectroscopy:

IR

• C≡C stretch: 2100-2260 cm⁻¹ (variable intensity; weaker than C=C).
• Terminal ≡C-H stretch: 3300 cm⁻¹ (sharp peak, characteristic).

For symmetric internal alkynes (e.g., 2-butyne): the C≡C stretch is IR-silent (no dipole change). Use Raman for these.

¹H NMR

• Terminal ≡C-H: δ 1.7-3.1 ppm (less deshielded than expected; due to the magnetic anisotropy of the C≡C).
• α-CH next to ≡C: δ 2.0-3.0.

The "less deshielded than expected" is because the linear C≡C produces a magnetic field that opposes the external field at the terminal H position; partly cancels the deshielding effect of the sp C.

¹³C NMR

• C≡C carbons: δ 70-90 ppm (much less than alkene C=C at 100-145).
• The shielding is due to the linear geometry and ring current of the C≡C.

MS

• No characteristic alkyne fragments; mass spectra of alkynes look like alkanes/alkenes for the most part.
• Loss of H from terminal alkyne is possible.

Spectroscopy Clue 17.1 — A terminal alkyne is identified by: sharp 3300 cm⁻¹ in IR (≡C-H stretch); a 1H singlet at ~2 ppm in ¹H NMR (the ≡CH); and a ¹³C peak at 70-90. Three independent signals confirm the functional group.

17.10 Alkyne natural products

Many natural products contain alkynes:

Polyacetylenes

Plants (Apiaceae family — carrots, parsley, celery), fungi, and some marine organisms produce polyacetylenes (multiple conjugated C≡C). Examples: - Falcarinol (from carrots): an antifungal polyacetylene with possible cancer-prevention activity. - Nemorosone (from Clusia rosea): polyacetylene with antimalarial activity.

Marine alkynes

Some marine natural products have rare alkynes: - Halichondrin B (from sea sponge): contains an alkyne; precursor to the cancer drug eribulin (Halaven). - Various polyketide alkynes: from sponges, soft corals.

Alkynes in drug design

Alkynes are increasingly used in modern drug design: - Erlotinib (cancer drug): contains a terminal alkyne. - Pemetrexed (cancer drug): contains an alkyne. - Tedizolid (antibiotic): contains an alkyne. - Some HIV drugs: alkynes in structure.

The alkyne provides: - Rigid linker between two functional groups. - A specific binding shape for protein interactions. - Often, metabolic stability (less easily reduced or cleaved than other linkers).

17.11 Worked synthesis problems

Problem A: Synthesize 2-butyne (CH₃C≡CCH₃) from acetylene

Strategy: 1. HC≡CH + NaNH₂ → HC≡C⁻Na⁺. 2. + CH₃Br → HC≡CCH₃ (propyne). 3. + NaNH₂ → ⁻C≡CCH₃. 4. + CH₃Br → CH₃C≡CCH₃ (2-butyne).

Problem B: Synthesize cis-3-hexene from 1-butyne

Strategy: 1. 1-butyne + NaNH₂ → butynide. 2. + CH₃CH₂Br → 3-hexyne. 3. + H₂ + Lindlar → cis-3-hexene (cis selectivity).

Problem C: Synthesize trans-3-hexene from 1-butyne

Strategy: 1. 1-butyne + NaNH₂ → butynide. 2. + CH₃CH₂Br → 3-hexyne. 3. + Na/NH₃ → trans-3-hexene (trans selectivity).

Problem D: Synthesize 2-pentanol from propyne

Strategy: 1. Propyne + NaNH₂ → propynide. 2. + CH₃CH₂Br → 2-pentyne. 3. + H₂/Lindlar → cis-2-pentene. 4. + H₂O/H₂SO₄ → 2-pentanol (Markovnikov hydration).

Problem E: Synthesize 2-pentanone from propyne

Strategy: 1. Propyne + NaNH₂ → propynide. 2. + CH₃CH₂Br → 2-pentyne. 3. + HgSO₄/H₂O → 2-pentanone (Markovnikov hydration of internal alkyne; gives the more-stable ketone).

Problem F: Synthesize hexanal from 1-hexyne

Strategy: 1. 1-hexyne + 9-BBN (one equivalent) → vinyl borane (anti-Markovnikov). 2. + H₂O₂/NaOH → enol → tautomerizes → hexanal.

Problem G: Synthesize 1,1-dichloropentane from 1-pentyne

Strategy: 1. 1-pentyne + 2 equiv HCl → 1,1-dichloropentane (Markovnikov; each HCl adds with H to terminal C, Cl to internal C; both Cl on the same C).

These problems illustrate how alkyne chemistry is used in synthesis.

17.12 Key disconnections in retrosynthesis

When designing a synthesis, alkynes are useful disconnection points:

• A cis-alkene can be made from an alkyne by Lindlar reduction.
• A trans-alkene from an alkyne by Na/NH₃.
• A ketone from an internal alkyne by hydration (Markovnikov).
• An aldehyde from a terminal alkyne by hydroboration-oxidation.
• A new C-C bond from an alkynide + alkyl halide (SN2) or carbonyl (addition).
• An aryl-alkyne by Sonogashira coupling.
• A 1,2,3-triazole by click chemistry (CuAAC).

Strategic placement of alkynes allows complex molecules to be assembled from simpler building blocks. This is the value of alkyne chemistry in modern synthesis.

17.13 Common mistakes

Common Mistake 17.1 — Trying to use NaOH or NaOEt to deprotonate a terminal alkyne. The pKa is 25, so you need NaNH₂, n-BuLi, or NaH — not the weaker bases. NaOH (pKaH 16) cannot deprotonate.

Common Mistake 17.2 — Forgetting that HgSO₄/H₂O hydration of a terminal alkyne gives a methyl ketone, not the corresponding alcohol. The enol intermediate tautomerizes to the keto form.

Common Mistake 17.3 — Confusing Lindlar Pd (cis selective) with Na/NH₃ (trans selective). When you need a specific alkene geometry, the choice matters.

Common Mistake 17.4 — Using BH₃·THF (full equivalent) on an alkyne. It would add twice. Use disiamylborane or 9-BBN for clean monohydroboration of an alkyne.

Common Mistake 17.5 — Trying to alkynide-SN2 a tertiary alkyl halide. SN2 doesn't work on 3°; the alkynide either won't react or will eliminate via E2. Use Sonogashira coupling for aryl, or stay with primary alkyl halides.

17.14 Connections to later chapters

• Chapter 18 (radicals): alkyne polymerization is radical-mediated.
• Chapter 19 (Diels-Alder): alkynes can be dienophiles; cyclopentadienone-alkyne cycloadditions.
• Chapter 25 (carbonyl additions): alkynide + carbonyl → propargyl alcohol.
• Chapter 27 (enolates): enol/keto tautomerism is the same chemistry.
• Chapter 31 (retrosynthesis): alkynes as disconnection points.
• Chapter 35 (drug design): alkynes in pharmaceutical structures.
• Chapter 37 (Pd cross-coupling): Sonogashira coupling.
• Chapter 40 (modern synthesis): click chemistry for bioconjugation.

17.15 Mechanism details: deeper looks

Hydration mechanism step by step

For terminal alkyne (HC≡CR) + H₂O/H₂SO₄/HgSO₄:

1. Hg²⁺ binds the alkyne to form a mercurinium-like complex.
2. Water attacks the more-substituted C (Markovnikov; more cation-like).
3. Result: enol with -OH at the more-substituted C, -HgX at the less-substituted C.
4. Protodemercuration: H⁺ replaces -HgX.
5. Tautomerization: the enol (vinyl alcohol) → keto form (methyl ketone).

Why is the keto form so much more stable than the enol? Two reasons: - The C=O bond is stronger (~178 kcal/mol) than the C=C bond (~146 kcal/mol). - The keto form has a C-H bond + C=O; the enol has C=C + O-H. The keto form's bond enthalpies sum is ~10-15 kcal/mol higher.

The equilibrium constant K = [keto]/[enol] is typically ~10⁵-10⁶ for simple ketones. So the enol is ~0.001-0.01% present at equilibrium. (For β-dicarbonyls, the enol is more stable; that's a special case in Ch 27.)

Hydroboration-oxidation mechanism for alkynes

For HC≡CR + 9-BBN:

1. Hydroboration: 9-BBN's B-H adds across the alkyne. B goes to the less-substituted C; H to the more-substituted. The stereochemistry is syn — B and H add to the same face.

The product: a vinyl borane (R-CH=CH-B(9-BBN)) with the B at the less-substituted C and the alkene's geometry as cis (syn addition gives cis substituents on the C=C).

2. Oxidation (H₂O₂/NaOH): the C-B bond is converted to C-OH with retention of configuration. The 9-BBN migrates to make boronate, and the new C-O bond forms.

3. Tautomerization: the resulting vinyl alcohol (enol) tautomerizes rapidly to the aldehyde.

Net: terminal alkyne → primary aldehyde (R-CH₂-CHO).

Lindlar reduction stereochemistry

Why does Lindlar give cis alkene? The mechanism is the same as standard catalytic hydrogenation, but stops at the alkene (because Pb-poisoned surface doesn't readily re-adsorb the alkene).

Both H atoms come from the same Pd surface, so they're on the same face → cis (syn) addition.

The stereochemistry is essentially determined by the hydrogen-Pd surface geometry: the Pd surface acts as a flat substrate, and the alkyne adsorbs flat; H atoms transferred from the surface are on the same face.

Na/NH₃ (Birch-type) reduction stereochemistry

Why does Na/NH₃ give trans alkene? The mechanism involves discrete electron-transfer and protonation steps:

1. e⁻ + RC≡CR → radical anion (one extra electron in the antibonding π*).
2. Protonation by NH₃ → vinyl radical (with the H on one C).
3. e⁻ + vinyl radical → vinyl anion.
4. Protonation by NH₃ → alkene.

The vinyl radical and vinyl anion intermediates have two configurations: cis and trans. The trans is more stable (less steric strain), so the trans is preferentially formed and protonated. Thermodynamic control of stereochemistry.

This is why Na/NH₃ gives trans, while Lindlar gives cis: different mechanisms (radical anion intermediates vs surface delivery) give different stereoselectivities.

17.16 Cyclic alkynes and benzyne

Cyclooctyne — the smallest stable cyclic alkyne

Cyclooctyne (8-membered ring with C≡C) has ~12 kcal/mol of strain because: - The C≡C wants to be linear (180°). - An 8-membered ring forces the C≡C-C angle to be ~155-160°. - This bent alkyne has higher energy than a linear acetylene.

Smaller cyclic alkynes (cycloheptyne, cyclohexyne, cyclopentyne, cyclobutyne) are unstable; they typically dimerize or react with the solvent.

The strain in cyclooctyne is what enables strain-promoted azide-alkyne cycloaddition (SPAAC) without a Cu catalyst. The strain is released when the alkyne reacts.

Benzyne (preview of Ch 23)

A benzyne (or aryne) is a benzene ring with one extra π bond — making it like an alkene + a benzene ring, with the alkene's π bond perpendicular to the aromatic π system. Benzyne is highly strained and reactive.

Benzyne is generated from aryl halides + strong base (Ch 23 SNAr/benzyne mechanism). It's a key intermediate in some aryl substitutions.

We'll cover benzyne in detail in Ch 23. For now, just notice: benzyne is an aryne (cyclic alkyne in an aromatic ring) and has Ch 17 alkyne reactivity in some respects.

Other cyclic alkynes

Larger cycloalkynes (cyclooctyne, cyclonyne, cyclodecyne) are stable and used in: - SPAAC click chemistry (cyclooctyne). - Materials science (cyclic alkyne polymers). - Synthetic templates (rigid linkers).

17.17 Glaser coupling and alkyne dimerization

The Glaser coupling (1869, Carl Glaser) is the oxidative dimerization of two terminal alkynes:

$$2 RC≡CH + Cu(I) + O_2 \to RC≡C-C≡CR + 2 H^+$$

The reaction: two terminal alkynes are deprotonated by Cu(I); the resulting copper acetylides couple to give a 1,3-diyne (two C≡C in a chain).

Modern variants

• Eglinton coupling: uses Cu(II) acetate; goes faster.
• Hay coupling: uses Cu(I) + amine ligand; gives high yields.

These are important for making polyacetylenes and carbon-rich materials. Recent applications include: - Synthesis of nanographenes. - Carbon allotropes (carbynes, polyynes). - Conductive polymer precursors.

As byproduct in Sonogashira

Glaser coupling can occur as a byproduct in Sonogashira reactions when the Cu co-catalyst gets oxidized. Modern Sonogashira protocols (Cu-free; or with strict O₂ exclusion) minimize this side reaction.

17.18 Drug design with alkynes

Alkynes are common in modern drug design because:

Rigid linker

The linear geometry of an alkyne provides a rigid, well-defined distance between two functional groups. Useful for: - Connecting pharmacophore elements with a fixed geometry. - SAR (structure-activity relationship) studies: replace a variable linker with a rigid alkyne to see if the drug works better. - Conformational restriction: locks the molecule's geometry.

Metabolic stability

Alkynes are often more metabolically stable than alkenes: - Alkenes can be oxidized by P450 enzymes to epoxides (then to diols). - Alkynes are often less easily oxidized; the linear geometry doesn't fit well in P450 active sites.

This stability extends the in vivo half-life of alkyne-containing drugs.

Specific receptor binding

Some receptors have binding pockets that fit only a linear (alkyne) linker, not a flexible (alkane) or kinked (alkene) one. For example: - Erlotinib: the terminal alkyne fits a hydrophobic pocket of EGFR kinase. - Pemetrexed: contains an aryl-alkyne fragment that binds dihydrofolate reductase. - Tubulin-binding drugs: some have alkyne pharmacophores.

Examples in modern drugs

• Erlotinib (Tarceva): EGFR inhibitor for lung cancer; contains a terminal alkyne.
• Pemetrexed (Alimta): antimetabolite for lung cancer; aryl-alkyne core.
• Tedizolid (Sivextro): oxazolidinone antibiotic; contains alkyne linker.
• Selpercatinib (Retsevmo): RET kinase inhibitor; alkyne linker.
• Many propargylic amine drugs: e.g., selegiline (Parkinson's), pargyline (antihypertensive) — both monoamine oxidase inhibitors.

17.19 Radical addition to alkynes

Like alkenes, alkynes undergo radical addition:

Radical HBr addition

$$RC≡CR + HBr + ROOR \to RCH=CHBr \text{ (anti-Markovnikov vinyl halide)}$$

With peroxides or radical initiators, HBr adds to alkynes via a radical mechanism: 1. Radical initiator → Br• radical. 2. Br• + alkyne → vinyl radical (with •-C-C-Br pattern; Br on less-substituted C, radical on more-substituted C). 3. Vinyl radical + HBr → vinyl-H + Br• (chain propagation).

The product: anti-Markovnikov vinyl halide (Br on less-substituted C).

This is the radical equivalent of HBr addition to alkynes. Without peroxides, the polar mechanism gives Markovnikov.

Radical chain reactions of alkynes in industry

Polyacetylene (HC=CH-CH=CH-... polymer) is made by radical-initiated polymerization of acetylene. The 1977 discovery that polyacetylene is conductive when doped led to the 2000 Nobel Prize in Chemistry (Heeger, MacDiarmid, Shirakawa) for conductive polymers.

17.20 Alkyne metathesis

In addition to alkene metathesis (Ch 37), alkynes can undergo alkyne metathesis:

$$2 R-C≡C-R + W \text{ catalyst} \to R-C≡C-R + R-C≡C-R'$$

The R groups exchange between two alkynes via a metallacyclobutadiene intermediate (analogous to the metallacyclobutane in alkene metathesis).

Alkyne metathesis catalysts: - Mortreux/Mauduit Mo or W catalysts: classical, often need elevated temperatures. - Schrock molybdenum alkylidynes: well-defined; high activity. - Modern Mo, W catalysts: improving over time.

Used for synthesis of: - Macrocyclic polyynes (precursors to carbynes). - Rigid polymer backbones. - Some natural product syntheses (Fürstner group).

17.21 Comparison with alkene chemistry

The chemistry of alkynes parallels that of alkenes, but with key differences:

The two hybridizations and bond strengths give alkenes and alkynes their respective "personalities" in synthesis.

17.22 Modern applications of click chemistry

Bertozzi's bioorthogonal chemistry

Carolyn Bertozzi (Stanford, Nobel 2022) coined the term "bioorthogonal chemistry": chemical reactions that work in living systems without disrupting normal biology. Click chemistry is the flagship example.

Key features of bioorthogonal reactions: - Selective: react only with the partner functional group. - Fast: complete in minutes to hours. - Aqueous: work in water or biological buffers. - Mild: room temperature, neutral pH, no toxic catalysts.

SPAAC (cyclooctyne + azide) is the most widely used bioorthogonal reaction. Applications: - Cell surface labeling: introduce an azide on a cell-surface glycan; SPAAC with a fluorescent cyclooctyne to image the cell. - In vivo imaging: inject an azide-labeled probe; image its location with a cyclooctyne-fluorophore. - Activity-based protein profiling: an azide-tagged drug binds its target; visualize binding with SPAAC + fluorescent cyclooctyne. - Antibody-drug conjugates: link a drug to an antibody via a click reaction.

These applications enable real-time imaging of biology at the molecular level.

Click chemistry in drug discovery

Combinatorial libraries built by CuAAC: 1. Pre-make a library of azides. 2. Pre-make a library of terminal alkynes. 3. Click each pair → 1,2,3-triazole library. 4. Screen for biological activity.

This has yielded several drug candidates, including some HIV protease inhibitors and kinase inhibitors.

The 1,2,3-triazole ring itself is bioactive — it can mimic an amide (similar geometry, similar H-bonding), so it serves as a bioisostere in drug design.

Materials and surface chemistry

Click chemistry is used in: - Polymer cross-linking: connecting polymer chains via CuAAC. - Surface functionalization: attaching biomolecules to surfaces (gold, silica, glass). - Nano-particle decoration: putting fluorophores or drugs on nanoparticles. - Hydrogel formation: cross-linking via click reactions.

17.23 Polyacetylenes and conductive polymers

The 2000 Nobel Prize in Chemistry went to Heeger, MacDiarmid, and Shirakawa for the discovery and development of conductive polymers. The flagship: polyacetylene (HC=CH-CH=CH-...).

Discovery story

In 1977, Hideki Shirakawa (Tsukuba, Japan) and a graduate student were trying to make a polyacetylene film by Ziegler-Natta polymerization of acetylene. The student accidentally used 1000-fold more catalyst than the recipe specified. Instead of the usual brown powder, they got a shimmery silver film.

When tested for conductivity, the film conducted electricity poorly (semi-insulating). But when the researchers added iodine (a dopant), the conductivity increased ~10⁹ fold — to nearly metallic levels.

This discovery launched the field of conductive organic polymers. Subsequent work by Heeger and MacDiarmid (UPenn) developed many other conductive polymer systems.

Applications

Conductive polymers are used in: - OLEDs (organic LEDs): in displays for phones and TVs. - Solar cells (organic photovoltaics): thin-film, flexible solar cells. - Antistatic coatings. - Smart windows (electrochromic devices). - Bioelectronic interfaces. - Conductive textiles.

The chemistry: polyacetylene's conjugated π system allows electrons to move along the polymer backbone. Doping (adding electron donors or acceptors) creates charge carriers (holes or electrons) that conduct.

This is alkyne chemistry (acetylene as the monomer) extended to materials science.

17.24 The chemistry of cumulated alkenes (allenes)

A close relative of alkynes: allenes, R₂C=C=CR'₂, with two consecutive C=C bonds sharing a central sp carbon.

Structure of allenes

The central carbon of an allene is sp hybridized (like an alkyne). The two C=C bonds are perpendicular to each other; the substituents on each terminal sp² carbon are in perpendicular planes.

This means allenes can be chiral — even with no traditional stereocenter (no sp³ C with 4 different groups). The chirality comes from the perpendicular arrangement of the two terminal alkenes.

Allene: H₂C=C=CH₂ (achiral). 2,3-pentadiene: CH₃HC=C=CHCH₃ (chiral if substituents are different).

Allene chemistry

Allenes undergo addition reactions similar to alkenes but typically: - HX adds across the more-substituted C=C. - The other C=C can also react under more aggressive conditions. - Many allene reactions go through allyl cation intermediates.

Allenes are present in some natural products (mycomycin, an antibiotic; some terpenoid pheromones).

Cumulenes

If three or more C=C are cumulated: cumulenes (R₂C=C=C=CR'₂; etc.). These are unusual; only a few stable cumulenes exist (e.g., [3]-cumulene). Most cumulenes are reactive and rare.

17.25 Total synthesis featuring alkynes

Some classical total syntheses heavily feature alkyne chemistry:

Vitamin A (retinol) — Hoffmann-La Roche, 1947

A 30+ step industrial synthesis featuring multiple alkyne-to-cis-alkene reductions (Lindlar). The final compound has 5 conjugated double bonds (a polyene). The synthesis was a triumph of industrial process chemistry.

Annual production: ~10,000 tons/year of vitamin A; supplements millions of people who would otherwise have vitamin A deficiency.

Erythromycin — Woodward, Corey, et al.

The complex 14-membered macrolide antibiotic erythromycin has been synthesized many ways, including via alkyne-containing intermediates. Lindlar reduction of an alkyne intermediate gives a cis-alkene that's part of the macrolide ring's flexibility.

Discodermolide

A marine natural product (anticancer activity); total synthesis (Smith, Schreiber, Paterson) included alkyne-to-alkene reductions to install specific double bond geometries.

Erlotinib (Tarceva)

The EGFR inhibitor (lung cancer drug) is synthesized using a Sonogashira coupling for the aryl-alkyne C-C bond, followed by other functional group manipulations.

These are examples of how alkyne chemistry is integrated into the synthesis of useful drugs and natural products.

17.26 Practical lab considerations

Working with terminal alkynes

• Storage: stable in solution; often stored in the freezer to slow polymerization.
• Reactivity with Cu: terminal alkynes form Cu-acetylides spontaneously; can clog tubing and contaminate equipment with insoluble residues. Avoid Cu vessels for terminal alkyne work.
• Acetylene gas: highly flammable and explosive at high concentrations; must be handled carefully (welding gas suppliers store acetylene dissolved in acetone in pressurized tanks).
• Calcium carbide: a solid source of acetylene; reacts with water to release the gas. Useful for laboratory generation of small amounts.

Hydroboration of alkynes

• 9-BBN is preferred for clean monohydroboration (stops at the vinyl borane).
• BH₃ would add twice; gives gem-diborane.
• Reaction is faster than alkene hydroboration (alkynes have more accessible π electrons).

Lindlar reduction tips

• Catalyst loading: 5-10 wt% Pd-Lindlar relative to substrate.
• Solvent: pyridine, ethyl acetate, methanol, or toluene.
• Conditions: 1 atm H₂; room temperature; reaction usually complete in hours.
• Monitoring: TLC for substrate consumption; GC for cis/trans selectivity.
• Quinoline addition: sometimes needed to enhance selectivity (especially for sensitive substrates).

Na/NH₃ tips

• Liquid NH₃: needs a cold trap (-33 °C boiling point at 1 atm).
• Na metal: handle under inert atmosphere; reacts violently with water.
• Adding alcohol (t-BuOH): provides protons for the radical anion intermediate.
• Workup: quench cold with NH₄Cl; warm to room temperature to evaporate NH₃.

Sonogashira coupling tips

• Pd source: Pd(PPh₃)₂Cl₂ is the classical; modern alternatives include Pd(PPh₃)₄ and Pd(OAc)₂ + ligand.
• Cu co-catalyst: CuI; a few mol%.
• Amine base: triethylamine or diisopropylamine; the amine deprotonates the terminal alkyne via Cu.
• Solvent: typically THF, DMF, or amine itself.
• Aryl halide order: ArI > ArBr > ArCl in reactivity.

17.27 Hydrohalogenation regiochemistry — special cases

For the simple terminal alkyne HC≡CR + HBr: - Markovnikov: -CH₂CR(Br)= (then second HBr → CH₃CR(Br)₂). - Anti-Markovnikov (with peroxides): -CH(Br)=CR (then second HBr → CH₂(Br)CHR(Br)).

But for conjugated alkynes (e.g., HC≡C-CH=CH₂ or HC≡C-Ar), the regioselectivity is more nuanced because of conjugation effects.

For alkynes adjacent to electron-withdrawing groups (HC≡C-CO₂Me, HC≡C-CN), the Markovnikov direction is reversed (HC₂ adds at the EWG-bearing C; OH at the terminal C). This is the same as Michael addition (Ch 29) — the EWG-stabilized carbanion intermediate determines regiochemistry.

For alkynes adjacent to electron-donating groups (HC≡C-NR₂; ynamines), the alkyne behaves differently — protonation generates a keto-imine; addition follows different rules.

These edge cases illustrate the subtleties of alkyne regiochemistry. For most textbook problems, the simple Markovnikov rule applies.

17.28 Comparison of stereoselective alkene-forming reactions

For making a specific alkene geometry (cis or trans), the alkyne approach is one of several:

The alkyne-to-alkene approach is one of the most reliable for controlling alkene geometry; it's used routinely in natural product synthesis.

17.29 Cyclic alkyne synthesis — additional methods

Beyond cyclooctyne, larger cyclic alkynes (cyclonyne, cyclodecyne, etc.) are accessible by: - Alkyne metathesis: ring-closing alkyne metathesis (RCAM) using Mo or W catalysts. - Macrocyclic Sonogashira: intramolecular Sonogashira with an aryl halide and terminal alkyne in the same molecule. - Glaser coupling intramolecularly: oxidative dimerization of two terminal alkynes.

These methods are used for synthesis of: - Macrocyclic natural products (some have C≡C in the ring). - Carbon-rich molecules (rotaxanes, cages, nanoscale architectures). - Conformationally constrained drugs.

Bergman cyclization

A spectacular alkyne reaction: 1,5-hexadiyne with conjugated alkynes (enediyne) undergoes thermal [4+2] cyclization to give a benzene-1,4-diyl (a benzene di-radical):

The result: an aromatic diradical that is highly reactive and can abstract hydrogen atoms from nearby molecules.

This is the mechanism by which enediyne natural products (e.g., calicheamicin, dynemicin, esperamicin) cleave DNA. The drug binds to DNA, gets activated, and the enediyne cyclizes to a diradical that abstracts hydrogens from DNA — cleaving the DNA backbone.

These enediyne natural products are extraordinarily potent (femtomolar activity); synthetic analogues have been explored as anticancer drugs but are too toxic for human use (cleave normal DNA too).

The chemistry: alkyne reactivity at the most extreme end. Enediyne diradicals are alkyne chemistry at its most dramatic.

17.30 Computational chemistry of alkynes

Modern computational methods can study alkynes and their reactions in detail:

• DFT calculations of alkyne π-MO geometries, π-MO energies.
• TS optimization for hydroboration of alkynes; helps understand regiochemistry.
• Hydration mechanism computed: bridges Markovnikov and anti-Markovnikov direction.
• Cyclooctyne strain energy calculated computationally; matches experiment.
• Click chemistry transition states computed; explain regiochemistry.

Computational Exercise 17.1 — In Avogadro, build acetylene (HC≡CH). Optimize. Note the linear C≡C-H geometry. Now build cyclooctyne (8-membered ring with C≡C). Optimize. Note the bent C≡C-C angle (~155°), reflecting strain.

Computational Exercise 17.2 — Build the alkynide anion HC≡C⁻. Visualize the HOMO. The lone pair sits in an sp orbital pointing along the C-C axis (away from the C≡C). This is the "lone pair in sp" arrangement that explains the high stability of acetylide anions.

17.31 The take-home message

Alkynes are versatile starting materials for synthesis. They give: - Stereoselective alkenes (Lindlar → cis; Na/NH₃ → trans). - Carbonyls (hydration → ketone; hydroboration-oxidation → aldehyde). - C-C bonds (alkynide nucleophile + alkyl halide; or Sonogashira; or click). - Triazoles (CuAAC; bioconjugation). - Aldehydes (anti-Markovnikov; hydroboration-oxidation). - Polymers and materials (polyacetylene; carbon-rich architectures).

The terminal C-H acidity (pKa 25) is the unique feature of alkynes — it's what enables alkynide nucleophilic chemistry. Combined with stereoselective reduction methods, alkyne chemistry gives synthetic chemists powerful tools for building carbon-carbon bonds and controlling alkene geometry.

In the era of click chemistry, alkynes have become central to chemical biology and drug development. The 2022 Nobel Prize to Sharpless and Bertozzi underscored the importance of alkyne reactions in modern science.

17.32 Summary

1. Alkynes have C≡C triple bonds: 1 σ + 2 π. sp hybridization; linear geometry (~180°).
2. Terminal alkyne C-H has pKa ~25 (uniquely acidic among hydrocarbons; sp orbital character explains it).
3. Alkynide anion (acetylide): deprotonation by NaNH₂ or n-BuLi gives RC≡C⁻, a strong base and strong carbon nucleophile.
4. Alkyne addition reactions: similar to alkenes but can go twice.
5. HX addition: Markovnikov first; second HX gives gem-dihalide.
6. Hydration: HgSO₄/H₂SO₄/H₂O gives Markovnikov enol → methyl ketone (terminal alkyne).
7. Hydroboration-oxidation: anti-Markovnikov enol → aldehyde (terminal alkyne); use disiamylborane or 9-BBN.
8. Halogenation (Br₂): trans-dihalide (anti); second Br₂ gives tetrahalide.
9. Hydrogenation H₂/Pd: full reduction to alkane.
10. Lindlar Pd: alkyne → cis-alkene (selective).
11. Na in liquid NH₃: alkyne → trans-alkene (selective).
12. Alkynide as nucleophile:
    • SN2 alkylation: RC≡C⁻ + R'X → RC≡C-R' (new C-C bond).
    • Carbonyl addition: RC≡C⁻ + R'COR'' → propargyl alcohol.
13. Sonogashira coupling: Pd-catalyzed alternative; works with aryl halides.
14. Click chemistry (CuAAC, SPAAC): alkyne + azide → 1,2,3-triazole. Sharpless's second Nobel (2022).
15. Linear geometry of alkynes makes them useful as rigid linkers in molecular design.
16. Industrial alkyne chemistry: largely shifted to alkene-based feedstocks; acetylene still used for specialty applications (Reppe chemistry, vitamin A synthesis, welding, specialty pharma).
17. Pharmaceutical alkynes: 17α-ethynyl-estradiol (the Pill); erlotinib, pemetrexed, tedizolid (drugs with terminal alkynes); SPAAC for in-cell biolabeling.
18. Spectroscopy: ≡C-H at 3300 cm⁻¹ (sharp); ≡C-H at 2 ppm in ¹H NMR; C≡C at 70-90 ppm in ¹³C NMR.
19. Mechanism-first principle: alkyne reactions follow the same patterns as alkene reactions (cation, cyclic 3-mem, concerted), just with the option to add twice.
20. Mastery of Chapter 17 gives you: stereoselective alkene synthesis (Lindlar/Na-NH₃), C-C bond formation (alkynide nucleophile), and click chemistry capabilities.

Chapter 18 turns to radical reactions — the alternative mechanism for alkene addition (especially anti-Markovnikov HBr) and other radical chemistry.