Chapter 15 Alcohols, Diols and Thiols

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1 3 : methanol, toxic (wood alcohol) hapter 15 Alcohols, Diols and Thiols 3 2 : ethanol, non-toxic but inebriating (surprise...) Nomenclature: prefix parent suffix (1) for alcohols, the suffix is -ol (2) longest chain containing the - group has the highest priority (3) lowest numbering (4) write the name in alphabetical order propan- -ol = propanol = 2 butanol parent = 6 carbons = hexane 2,4 diol and 5-methyl 3 5 methyl-2,4 hexanediol 3 (5) - has a higher priority than -S As a substituent: (a) - is hydroxy (b) -S is mercapto

2 5 6 4 S methyl-1,2-cyclohexanediol 6-mercapto-4-cyclohexene-1,3-diol S 2-mercapto-4,4-dimethylcyclohexanol phenyl-2-butanol (3-hydroxybutylbenzene) ydrogen Bonding: like water, alcohols have very polar bonds (a) alcohols are capable of hydrogen bonding (b) lower molecular weight alcohols boil higher than expected based on molecular weight (recall: boiling means separation of molecules from liquid phase to vapor phase; the more tightly held to the liquid implies a higher boiling point)

3 δ δ δ + δ δ + δ + δ δ + δ δ + δ δ + δ water (-) alcohols (-) F 3 2 b.p. ( ) dipole moment (Debye) Alcohols can act as proton donors and acceptors Solubility: 3, 3 2, ( 3 ) 2 -, ( 3 ) 3 - are water soluble Acidity and Basicity: alcohol can act as bases (lone pairs) or acids (+ donor) B B- ethoxide in general: "alkoxide" methoxide ethoxide propoxide tert-butoxide

4 from S N 2 chapter: is a poor leaving group, but 2 is a better leaving group X 2 2 X 2 X + 2 Acidity of Alcohols in Water (pk a ): "activated" leaving group a more positive pk a implies a less acidic alcohol Alcohol ( 3 ) F (F 3 ) 3 - pk a the more stabilized that we can make, then the easier it will be for - to lose a + (i.e. - will be a strong acid) (a) is very charge dense so hydroxide is well -bonded in 2 (b) t-bu (( 3 ) 3 ) is greasier and less -bonded in 2 so t-bu is less acidic than 2 (c) also can have an inductive effect; electronegative atoms will help to withdraw electron density and can help to stabilize the negative charge on the anion (alkoxide) F F 2 F net =

5 Alcohols (and thiols) can therefore donate + in reactions with strong bases (Na, NaN 2, -Li, -MgBr) δ + δ Na- Na + δ δ + δ - 2 -Mg-Br MgBr + Preparation of Alcohols: (1) Addition of 2 to alkenes: proceeds by Markovnikov addition , (2) ydroboration/xidation: anti-markovnikov addition of - across the double bond 3 3

6 (3) xymercuration: Markovnikov addition of - across the double bond 2 1) g(ac) 2, 2 2) NaB 4 3 (4) Di-hydroxylation: 2 Alcohols from Aldehydes and Ketones: aldehyde ' (, ' ) ketone 3 acetaldehyde (ethanaldehyde) 3 2 propanaldehyde propanone (acetone) butanone

7 (1) atalytic eduction (ydrogenation) 2, catalyst high pressure 2, catalyst low pressure 2, catalyst high pressure 2) ydride educing Agents: : (hydride) can act as a base or a nucleophile; reactivity depends on coordination (a) Sodium Borohydride (NaB 4 ) Na B (i) a good source of : ; one can reduce aldehydes and ketones to alcohols (ii) NaB 4 is safe and easy to handle (iii) one can do NaB 4 reductions in water or alcohol solution (iv) this source of : is not very basic

8 δ δ + δ + B δ B 3 B 3 2 B Na 2 2 B Na B() 3 + Na (b) Lithium Aluminum ydride (LiAl 4 ): LA for short (i) great source of : (ii) need to be careful in handling; LA reacts violently with acidic protons ( 2, Me, and so on); must use ether (non-protic) solvents (Et 2 and TF) (iii) LA reduces all carbonyl (=) groups, i.e. LA is more reactive than NaB 4 (iv) this source of : is both basic and reductive

9 NaB 4 LiAl 4 aldehydes YES YES ketones YES YES esters slowly YES acids N YES 3 2 1) NaB 4, Et 2) ) LiAl 4, Et 2 2) ) NaB 4, Et 2) 3 + 1) LiAl 4, Et 2 2) 2 3

10 3 Al Li Li LiAl 4 2 hydrides get added to carbonyl carbon of the initial ester 2 Li NaB 4 is more selective but also less reactive than LiAl 4 α β 1) NaB 4, Et 2) ) LiAl 4, Et 2 2) 2 α,β-unsaturated enones can be reduced at the = group with selectively

11 Grignard eagents: -Mg-X -X + Mg Et 2 δ δ + δ Mg X Br Mg Et 2 MgBr Polarity? (a) Mg is electropositive as compared to halogens or carbon, so -Mg-X (Grignard reagents) are carbon anions complexed (stabilized) by coordination to Mg as a metal (b) carbon anions are relatively unstable, but when coordinated to a metal (such as Mg2+ or Li+), one can make a variety of 1, 2, 3, vinyl or aryl carbon anions Br Mg Et Br Mg Et 2 ne can reduce carbonyl compounds to alcohols 1) -Mg-X, Et 2 2) 3 + Mg X δ δ + δ 3 +

12 (1) effective addition of and across carbonyl group (in separate steps) MgBr 1) Et 2 2) 3 + MgBr 1) 2 2) N 4 l Et 2 2 1) Et MgBr 2) 3 + 1) 3 2 -MgBr Et 2 2) 3 + (2) with esters, of Grignard reagent adds to carbonyl center 3 1) 2 3 MgBr, Et 2 2)

13 (3) with acids, acid-base reaction occurs and one gets no addition to carbonyl group 3 MgBr Et Grignard reagents (stabilized carbon anions) are nucleophiles and also bases! (i) need to be careful about acidic s that can quench the carbon anion (Grignard reactions are not compatible with functional groups like, S, 2, etc) (ii) must use dry solvents (no 2 can be present) ow would you prepare: 3 (a) 3 MgBr reduction of (b) MgBr reduction of (c) 2 reduction (NaB 4 ) of

14 eactions of Alcohols (1) dehydration (loss of water) a b b 3 2 a (a) Zaitsev s rule: most substituted double bond is favored (b) proceeds via carbocation (E1 mechanism) (c) 3 alcohols dehydrate well; 2 and 1 alcohols dehydrate less well; use Pl 3 with pyridine as an alternative for 1 and 2 alcohols

15 Pl 3 pyridine l P l l loss of + N l P l proceeds by E2 mechanism; need to make good leaving group (2) onversion into alkyl halides: X X = l, Br, I (a) 3 alcohols react with l, Br or I (via a carbocation intermediate) (b) 2 and 1 alcohols react with Sl 2 (for X=l) or PBr 3 (for X=Br)

16 2 l S l S l l S l 2 l + S 2 + l make good leaving group and then favor S N 2 (avoid carbocation formation) (3) onversion into tosylates (-Ts): + N S 3 Ts group (good leaving group)

17 (4) xidation of alcohols to carbonyl compounds (a) oxidation of 3 alcohols gives no reaction 3 3 r 3, 2 S 4 2, acetone (b) oxidation of 1 alcohols yields carboxylic acids or aldehydes depending on reagents 3 ( 2 ) 8 2 Jones' reagent r 3, 2 S 4 2, acetone 3 ( 2 ) 8 3 ( 2 ) 8 2 P 2 l 2 3 ( 2 ) 8 P = pyridinium chlorochromate N r 3 l

18 (c) oxidation of 2 alcohols yields ketones r 3, 2 S 4 2, acetone P 2 l 2 Na 2 r 2 7 2, 3 2, (d) the mechanism is the same for these oxidations; E2 mechanism after good leaving group is made r 3 r 3 Base + r 3 2

19 Alcohol Protection: Why? ne reason: 3 2 1) 3 2 MgBr 2) MgBr MgBr 2 2 Br Mg 2 2 Et So need to mask (protect) the to do chemistry with the Br Si Et 3 N l Si Et 3 N l 3 TMS-l: trimethylsilyl chloride Trimethylsilyl ethers ( Si 3 ) are very useful as they are unreactive under basic conditions; silyl ethers are easily made by S N 2 reaction as Si bond lengths are long and Si is not very hindered

20 TMS TMS TMS-l Et 3 N Mg Et 2 Br Br MgBr De-Protection? Silyl ethers are readily cleaved with acid TMS TMS-l Et 3 N 3 + Thiols: X + S S + X good nucleophile 3 ( 2 ) 6 2 Br Na S 3 ( 2 ) 6 2 S + Na Br + 3 ( 2 ) 6 2 S 2

21 X + S S S + + X S + X thioether or sulfide So, to avoid this problem of double-addition : X S N N S N 2 N X 2 thiourea 2, S + 2 N N 2 urea Biological systems: very common to have disulfide bridges S S (cysteine residues) Br 2 2 S S S (oxidation) Zn, 3 + (reduction)

ALCOHOLS: Properties & Preparation

ALCOHOLS: Properties & Preparation ALLS: Properties & Preparation General formula: R-, where R is alkyl or substitued alkyl. Ar-: phenol - different properties. Nomenclature 1. ommon names: Name of alkyl group, followed by word alcohol.