1. The document summarizes key concepts about alcohols from Chapter 9 including their structure, nomenclature, physical properties, preparation from alkenes, and common reactions.
2. Alcohols can be prepared through acid-catalyzed hydration of alkenes or hydroboration-oxidation, and they undergo important reactions like dehydration back to alkenes, and conversion to alkyl halides and alkyl sulfonates.
3. Carbocation intermediates play a key role in the mechanisms of alcohol reactions like dehydration and conversion to halides, and carbocation rearrangements must sometimes be considered.
1. The document summarizes key concepts about alcohols from Chapter 9 including their structure, nomenclature, physical properties, preparation from alkenes, and common reactions.
2. Alcohols can be prepared through acid-catalyzed hydration of alkenes or hydroboration-oxidation, and they undergo important reactions like dehydration back to alkenes, and conversion to alkyl halides and alkyl sulfonates.
3. Carbocation intermediates play a key role in the mechanisms of alcohol reactions like dehydration and conversion to halides, and carbocation rearrangements must sometimes be considered.
1. The document summarizes key concepts about alcohols from Chapter 9 including their structure, nomenclature, physical properties, preparation from alkenes, and common reactions.
2. Alcohols can be prepared through acid-catalyzed hydration of alkenes or hydroboration-oxidation, and they undergo important reactions like dehydration back to alkenes, and conversion to alkyl halides and alkyl sulfonates.
3. Carbocation intermediates play a key role in the mechanisms of alcohol reactions like dehydration and conversion to halides, and carbocation rearrangements must sometimes be considered.
preparation (9.6 & review of chemistry from Ch. 10 [alkene reactions]) (A) acid-catalyzed hydration of C=C's (10.12) (B) hydroboration-oxidation of C=C's (10.16) reactions (9.7A) (A) dehydration to afford C=Cs (9.8, 9.9, 9.10) (B) conversion to alkyl halides (9.11, 9.12) & alkyl sulfonates (9.13) R = alkyl, aryl (refer to textbook) common abbrev. = ROH 2 primary secondary tertiary OH this hydroxyl is part of a hemiacetal FG, described in aldehyde & ketone chapter Note that hydroxyl groups can be part of larger FGs (e.g., as in carboxylic acids) Classify the alcohols indicated below Chap. 9 phenol FG; NOT ROH FG 3 Chap. 9 4 very weak acids very strong acids Chap. 9 5 Write the balanced equation for this reaction and provide a correct mechanism balanced equation a correct mechanism: Chap. 9 IN ORGANIC RXN MECHANISMS YOUVE SEEN THUS FAR, CARBOCATION INTERMEDIATES CAN FORM FROM C=C, R-X, R-OH: carbocations (formation) - mini review Clearly show three reactions that lead to formation of this carbocation mechanistic intermediate:
one from a C=C one from an R-X one from an R-OH IN ORGANIC RXN MECHANISMS, CARBOCATION INTERMEDIATES HAVE THREE POSSIBLE FATES: (1) REACTION WITH A NUCLEOPHILE: anionic (:X - ) or neutral (e.g., H 2 O:) (2) LOSS OF AN a-PROTON TO FORM A C=C (3) REARRANGEMENT TO ANOTHER CARBOCATION OF SIMILAR OR GREATER STABILITY :
unsymm. substituted C=C 2 o carbocation 3 o carbocation (favored!) hydride/alkyl migration (shift) to form another cation of equal or greater (not lesser) stability a different 3 o carbocation =
=
overall: an alkene migration (1) (2) (3) (1) (2) (3) and/or and/or X X carbocations (reactions) - mini review 8 ALCOHOLS preparation: (a) acid-catalyzed hydration of ALKENES (b) hydroboration-oxidation of ALKENES Markovnikov regioselectivity non-Markovnikov regioselectivity complementary methods sample reactions overall transformation = HYDRATION elements of water added to C=C What exactly is hydration... and how does it differ from hydrolysis I always get those two confused! (2 reactions; chap. 10) Chap. 9 NOTE: appreciate the difference between the terms hydration & hydrolysis Hydration = combining with the elements of H 2 O (an addition rxn): Hydrolysis = cleavage by H 2 O, w/the elements of H 2 O shared between the fragments (a substitution rxn): H and OH DONT literally need to come from a single molecule of H-O-H; they often come from different sources (e.g., as youll see when examining rxn mechanisms)
In alkene hydration, the overall transformation is addition of the elements of water (H & OH) to C=C In hydrolysis, the overall transformation involves the substitution of the elements of water (H & OH) Youll encounter many examples of hydrolysis reactions in orgo II 9 Note: 10 ALCOHOLS preparation: (a) acid-catalyzed hydration of ALKENES (b) hydroboration-oxidation of ALKENES Markovnikov regioselectivity non-Markovnikov regioselectivity complementary methods sample reactions overall transformation = HYDRATION elements of water added to C=C H + (E + ) In both cases, electrophile ends up on least substituted carbon alcohol regioisomers ( E + ) (2 reactions; chap 10) Chap. 9 (review) mechanistic explanation of regioselectivity: 11 ALCOHOLS reactions: (a) dehydration to ALKENES
(b) conversion to ALKYL HALIDES & ALKYL SULFONATES (a) acid-catalyzed dehydration The mechanism of alcohol DEHYDRATION is the exact reverse of the mechanism of alkene HYDRATION - same mechanistic intermediates but arrows flow in opposite direction!...this is true for equilibrium reactions; e.g.: Typical acids used for alcohol dehydration are H 2 SO 4 or p-toluenesulfonic acid (TsOH) Use Le Chteliers principle to drive equilibrium to left or right; e.g., remove alkene by distillation as it is formed, thus driving the equilibrium to the right (1 reaction) (4 reactions) Chap. 9 12 Often, a less stable carbocation will be converted into either a more stable or equally stable carbocation by a shift of a hydrogen or an alkyl group (called a rearrangement)
Because the migrating group in a 1,2-shift moves with two bonding electrons, the carbon it leaves behind now has only three bonds (six electrons), giving it a net positive (+) charge Recall: carbocation rearrangements Note: carbocation rearrangements lead to carbocations of equal or greater stability NOT the other way around! 2 o 3 o
2 o 2 o
Chap. 9 complete conversion partial conversion 13 Be aware that unintentional cationic rearrangements (alkyl & hydride shifts) can occur during acid-cat. dehydration of alcohols Example (practice mechanism problem): Q: how can you tell that a rearr. has occurred? A: focus on carbon skeleton & look at the position of alkyl groups on longest chain ALCOHOLS reactions: Chap. 9 14 Dehydration of 1 o alcohols cant occur via an E1 mech. since 1 carbocations are highly unstable; thus, 1 alcohols undergo dehydration via an E2 mech. E2 Dehydration of 1 o Alcohols ALCOHOLS reactions: a 1 o carbon E2 mech. (avoids a high-energy 1 o carbocation formed via an E1 mechanism!) NO!! NO!! _____ Chap. 9 15 Some organic compounds decompose in the presence of strong acid, so other methods have been developed to convert alcohols to alkenes.
A common method uses phosphorus oxychloride (POCl 3 ) and pyridine (an amine base) in place of H 2 SO 4 or TsOH POCl 3 converts OH into a good leaving group
Dehydration then proceeds by an E2 mechanism Dehydration of Alcohols Using POCl 3 : same result as strong acid but MILDER conditions ALCOHOLS reactions: OH H H 2 O Chap. 9 16 ALCOHOLS reactions: E2 S N 2 Chap. 9 17 (b) conversion of ALCOHOLS to ALKYL HALIDES ALCOHOLS reactions: poor LG in S N reactions: OH - is conj. base of a weak acid (HOH); thus, must convert hydroxyl (OH) group into a good LG before an S N reaction can occur! 3 o ROH 2 o ROH 1 o ROH H + X - H + X - H + X - Againin mechanisms involving carbocations (S N 1/E1), unintended rearrangements can occur: see p 348 in your textbook for mechanism Chap. 9 use of HX (X = Cl, Br, I) (review, chap. 7) 18 ALCOHOLS reactions: What alkyl halide products would be afforded in the following reactions? Include all stereoisomers where appropriate, and mechanistically explain your answers. (a) (c) (b) (d) Show how to convert 1-propanol to each of the synthetic targets shown below. Use any necessary reactants or reagents, show the product of each synthetic step, and indicate any necessary reaction conditions. (i) (ii) (iii) (iv) (v) (vi) Practice synthesis/reaction problems (S) (R) Chap. 9 19 ALCOHOLS reactions: Propose reasonable mechanisms for the following reactions. Use arrows correctly to indicate bond making and bond breaking (i.e., movement of electrons), show all mechanistic intermediates, and indicate any formal charges on atoms. (a) (b) (c) (d) (e) (f) (g) (h) (i) OMG!... sequential cationic rearrangements must be involved in this problem!! Practice mechanism problems Chap. 9 challenge problem 20 1 o & 2 R-OH are converted to R-Cl using SOCl 2 (thionyl chloride) & to R-Br using PBr 3 (phosphorus tribromide)
both reagents convert OH into a good leaving group in situ (directly in the reaction mixture) and provide the nucleophile (either Cl or Br) to displace the leaving group via an S N 2 reaction
since NO strong acid (HX) is present, use of SOCl 2 & PBr 3 avoids: unwanted cationic rearrangements of the carbon skeleton unwanted reaction of other acid-reactive FGs in the substrate molecule conversion of alcohols to ALKYL HALIDES with SOCl 2 and PBr 3 ALCOHOLS reactions: Chap. 9 R-OH R-X SOCl 2 or PBr 3 X = Cl (SOCl 2 ) Br (PBr 3 ) (1 o & 2) (1 o & 2) (S N 2 reaction) Conversion of 1 o or 2 o alcohols to alkyl chlorides with SOCl 2 1 o alcohol 2 o alcohol NOTE: SAME result is obtained with HCl, but SOCl 2 avoids use of HCl & is S N 2 rxn S N 2 S N 2 21 Chap. 9 22 Conversion of 1 o or 2 o alcohols to alkyl bromides with PBr 3 ALCOHOLS reactions: 1 o alcohol 2 o alcohol S N 2 S N 2 Chap. 9 23 Indicate an appropriate reagent for each of the following transformations: (a) (b) (c) (d) (e) ALCOHOLS reactions: Practice synthesis/reaction problems Chap. 9 24 use for chemoselective & stereoselective conversion of ROH RX use for chemoselective & stereoselective conversion of ROH RX ALCOHOLS reactions: HCl HBr Hl SOCl 2 PBr 3 Chap. 9 25 Alcohols can be converted into ALKYL TOSYLATES: R-OTs acts like R-X; X = halide An alkyl tosylate is composed of two parts: 1. alkyl group R, derived from R-OH 2. the tosylate group (short for p-toluenesulfonate), which is a v. good LG
A tosyl group, CH 3 C 6 H 4 SO 2 , is abbreviated Ts, so an alkyl tosylate becomes R-OTs formation & reaction of ALKYL TOSYLATES; tosylate (OTs - ) as a great leaving group (LG)
ALCOHOLS reactions: O O Chap. 9 Why? 26 Tosylate is a good LG because its conjugate acid, p-toluenesulfonic acid (CH 3 C 6 H 4 SO 3 H, TsOH), is a strong acid (pK a = ~ 3)thus, its conjugate base (CH 3 C 6 H 4 SO 3 - , TsO - ) is a weak base (i.e., happy anion, good LG) formation and use of tosylates
ALCOHOLS reactions: Stereochemistry of tosylate formation
(2S)-2-Butanol is converted to its tosylate with retention of configuration at the stereogenic center since the C-O bond of the alcohol is not broken in the process Chap. 9 27 formation and use of tosylates
ALCOHOLS reactions: Step [1], formation of tosylate, proceeds with retention of configuration at a stereogenic center Step [2] is an S N 2 reaction, so it proceeds with inversion of configuration because the nucleophile attacks from the backside Overall there is a net inversion of configuration at a stereogenic center Overall Inversion of Stereochemistry in REACTION of alkyl tosylates
Br: - Br
the HX-free R-OH R-X conversion shown above can also be done by direct rxn with PBr 3 or SOCl 2 however, alkyl tosylates are useful since they can react with OTHER nucleophiles besides halides!...
Chap. 9 Nu: - = halide, CN - , N 3 - , etc. 28 Because alkyl tosylates have good leaving groups, they undergo both nucleophilic substitution and elimination, exactly as alkyl halides do
Generally, alkyl tosylates are treated with strong nucleophiles and bases, in which case the mechanism of substitution is S N 2, and the mechanism of elimination is E2 formation and use of tosylates
ALCOHOLS reactions: Chap. 9 29 Note: since R-OTs behaves like R-X, S N 1 & E1 rxns are also possible.
Provide a mechanism to explain the following rxn: formation and use of tosylates
ALCOHOLS reactions: Chap. 9 30 formation and use of tosylates
ALCOHOLS reactions: (a) Provide the products of the following reactions. (b) Propose reasonable mechanisms for the following reactions. (i) (ii) Practice problems Chap. 9 31 Summary of ALCOHOL preparation & reactions discussed in lecture I recommend that you come up with your own FG preparation/reaction summaries (like the one above) for each new FG discussed in lecture
its one good way to (i) collect your thoughts, (ii) organize the material for review & for USE IN SOLVING PROBLEMS (iii) learn how FGs can be converted to one another (important for solving synthesis problems) Chap. 9 32 R = alkyl, aryl ETHERS structure & nomenclature (9.1, 9.2, 9.3B, 9.5)
preparation (9.6) (A) Williamson ether synthesis (p 334) (B) acid-cat. add'n of ROH's to C=C's (10.12; p 395)
reactions cleavage by conc. HX (9.14) (Chap. 9) ALCOHOLS, ETHERS & EPOXIDES Chap. 9 (refer to textbook) common abbrev. = ROR 33 ETHERS preparation: complementary methods (a) Williamson ether synthesis (S N 2 rxn) (b) acid-cat. addition of ROH to alkenes (C=C elec. addn rxn) our synthetic target molecule (a) Williamson ether synth. (S N 2 rxn): used to prepare O-C(1 o ) bond: must use 1 o R-X (X = halide, OTs) as E + 1 o
2 o
(2 reactions) Chap. 9 34 ETHERS preparation: complementary methods (a) Williamson ether synthesis (S N 2 rxn) (b) acid-cat. addition of ROH to alkenes (C=C elec. addn rxn) our synthetic target molecule (b) acid-cat. addn of ROH to C=C: used to prepare O-C(2 o or 3 o ) bond; its an alkene electrophilic addn rxn analogous to alkene hydration!...use ROH instead of HOH in the rxn.
1 o
2 o
(2 reactions) Chap. 9 35 cleavage of ethers with strong acids such as conc. HBr and conc. HI via successive S N rxns
ETHERS reactions: example: a proposed mechanism: (1 reaction) Chap. 9 36 R = alkyl, aryl EPOXIDES structure, nomenclature & general reactivity (9.1, 9.2, 9.3C, 9.5)
preparation (9.6; 12.8) (A) intramolecular Williamson ether synthesis using halohydrins (10.15) (later well see a more straightforward & common method described in chap. 12.8) reactions (9.15) (A) nucleophilic ring opening with strong nucleophiles under basic/neutral conditions (B) nucleophilic ring opening under acidic conditions (Chap. 9) ALCOHOLS, ETHERS & EPOXIDES Chap. 9 (refer to textbook) 37 (intramolecular Williamson ether synthesis) (A) Intramolecular Williamson ether synthesis using VICINAL HALOHYDRINS EPOXIDES preparation: Chap. 9 38 Epoxide structure affects its chemical reactivity Chap. 9 Nu: nuc. attack leads to ring opening (A) NEUTRAL/BASIC rxn conditions (w/strong Nuc.) (B) ACIDIC rxn conditions Note: all epoxide rxns you will see involve ring opening
but rxn outcomes (& mechanisms) change under diff. rxn conditions (A) vs. (B) 39 EPOXIDES reactions: epoxide as E + Well examine nucleophilic ring opening under: Chap. 9 think of the oxygen as a LG in an S N rxn EPOXIDES reactions: please note: rxn of unsymmetrically substituted epoxides (e.g., monosubstituted epoxides) with nucleophiles under any conditions can potentially afford one or both constitutional isomers (regioisomers) of alcohol product shown below: new bond new bond 40 Chap. 9 a monosubstituted epoxide constitutional isomers (regioisomers) of alcohol products 41 (A) Nucleophilic ring opening under NEUTRAL/BASIC conditions w/strong nucleophiles:
S N 2 mechanism (least hindered carbon is attacked preferentially) * *
= asymm. (stereogenic )center: optically active epoxide would afford optically active product w/retention of stereochem. at asymm. center since rxn occurs at other epoxide carbon * think of the oxygen as a LG in an S N rxn * Chap. 9 EPOXIDES reactions: 42 Note: achiral (optically inactive) reactants yield optically inactive products even if products are chiral
Mechanistic explanation for racemic mixture: at equal rates 50% A : 50% B Chap. 9 43 Chap. 9 (a) Provide the major organic products of the following reactions. EPOXIDES reactions: (i) (ii) 44 Chap. 9 (b) Provide a reasonable mechanism for the following reaction. Use arrows correctly to indicate bond making and bond breaking, show all mechanistic intermediates and clearly indicate any charged atoms with appropriate symbols. EPOXIDES reactions: new bond 45 (B) Nucleophilic ring opening under ACIDIC conditions nuc. attack @ MOST substituted carbon (S N 1-like) inversion of configuration @ carbon being attacked (S N 2-like) rxn proceeds via a borderline S N 2 mech. Mechanism proposed to explain the above results: Chap. 9 46 Regioselectivity of epoxide ring opening w/nucleophiles - SUMMARY
EPOXIDES reactions: examples from the chemical literature: ACIDIC conditions BASIC conditions Long, F. A., Pritchard, J. G. J. Am. Chem. Soc. 1956, 78, 2663 BASIC/NEUTRAL conditions ACIDIC conditions Chap. 9 47 (1) Prepare compounds (i)-(vi) from 4-methyl-1-pentene as your only organic starting reactant. Use any necessary reagents & as many molecules of 4-methyl-1-pentene as you need. Show the product of each synthetic step (do NOT include any mechanistic details; i.e., arrow pushing, cationic/anionic intermediates, etc.). (i) (ii) (iii) (iv) (vi) (v) (2) The epoxide ring can also open by an acid-catalyzed rearrangement reaction, like the one shown below. Propose a reasonable mechanism for the following rearrangement reaction. Use arrows correctly to indicate bond making and bond breaking (i.e., movement of electrons), show all mechanistic intermediates, and indicate any formal charges on atoms. Ether & epoxide practice problems: Chap. 9