1. Chapter 3. Functional Group Interconversion
Advanced Org Chem-Carey B
Fall 2002
Chapter 3. Functional Group Interconversion
Conversion of alcohols to alkylating agents
Alcohols to sulfonates: R-OH  R-O-SO2-R’
R-OH + ClSO2R’/O(SO2R’)2 + R”3N  R-OSO2R’
R’: Me (mesylate, Ms), p-MePh (tosylate, Ts), CF3 (triflate, Tf)
RO-Li: more reactive;  216 middle
no rearrangement or racemization with 1o & 2o alcohols
reversible ionization possible with allylic/benzylic alcohols
elimination with 3o alcohols to alkenes
Carey B-Chap3-5ed
Chapter 3

2. Conversion of Alcohols to Sulfonates
Advanced Org Chem-Carey B
Fall 2002
Conversion of Alcohols to Sulfonates
Carey B-Chap3-5ed
Chapter 3

3. Conversion of Alcohols (I)
Advanced Org Chem-Carey B
Fall 2002
Conversion of Alcohols (I)
Alcohols to halides: R-OH  R-X
simple 1o alcohols: R-OH + HBr/HCl-ZnCl2  R-Br/Cl
SOCl2: inversion/retention,  217 middle; PCl3
ready transformation with Bt(z) [pKa 8.37]:  218 top
PBr3: racemization & rearrangement;  top
Ph3P+–X Y- for acid-labile compounds:  219 middle
X=Br: inversion via R’3P+–OR;  219 bot &  220 top
X=Cl: Y=Cl/CCl3/CCl2C(O)CCl3;  220 middle
X=I/Br, imidazole & Y=I/Br: for R–I/Br
Carey B-Chap3-5ed
Chapter 3

4. Chlorination with SOCl2: Inversion/Retention
Advanced Org Chem-Carey B
Fall 2002
Chlorination with SOCl2: Inversion/Retention
inversion
retention
Carey B-Chap3-5ed
Chapter 3

5. Halogenation with R3P+–X•Y-: Milder
Advanced Org Chem-Carey B
Fall 2002
Halogenation with R3P+–X•Y-: Milder
Carey B-Chap3-5ed
Chapter 3

6. Halogenation with R3P+–X•Y-: Cl / I
Advanced Org Chem-Carey B
Fall 2002
Halogenation with R3P+–X•Y-: Cl / I
Carey B-Chap3-5ed
Chapter 3

7. Chlorination of Alcohols: Xanthate Esters
Advanced Org Chem-Carey B
Fall 2002
Chlorination of Alcohols: Xanthate Esters
March’s Advanced Organic Chemistry (5th ed), p. 760
Carey B-Chap3-5ed
Chapter 3

8. Conversion of Alcohols (II)
Advanced Org Chem-Carey B
Fall 2002
Conversion of Alcohols (II)
Alcohols to halides:  222 Scheme 3.1
Ph2PCl, imidazole & I2: reactive;  220 bottom
Ph2P(O)H: removable with basic workup
Mitsunobu reaction: mild conditions;  221 top
activation of Ph3P with DEAD & iodination with MeI
allylic alcohols: R–OH  R–OMs  R–X;  221 mid
mild & basic conditions (SN2 type): no rearrangement
oxazolium ions as activators: R–Cl;  221 bottom
for R–Br/I: use of RN+Br-/I-
Carey B-Chap3-5ed
Chapter 3

9. Introduction of FGs at sp3-Carbons: SN2
Advanced Org Chem-Carey B
Fall 2002
Introduction of FGs at sp3-Carbons: SN2
Reactivity of electrophiles (E+): R-L
leaving groups (L); R’SO3  I > Br > Cl
structure of R: O=C-C-L > PhCH2/allylic > 1o > 2o >> 3o
Reactivity of nucleophiles (Nu): Nu-M
solvents: polar aprotic solvents;  Chapter 1
additives: crown ethers as a catalyst:  225 top
phase-transfer catalysts (PTC): R4N+(R4P+)X-
PTC transfers Nu in aqueous solvent to E+ in organic solvent & enhanced reactivity of Nu due to poor solvation
Carey B-Chap3-5ed
Chapter 3

10. Nitriles & Azides:  235 Scheme 3.2 A & B
Advanced Org Chem-Carey B
Fall 2002
Nitriles & Azides:  235 Scheme 3.2 A & B
Nitriles: R-CN  -CO2R, -CHO, -CH2NH2
Na-/KCN: reactive in DMSO / with PTC:  226 top
Azides: R-N=N+=N-  R-NH2, N-intermediates
NaN3: usually in DMSO/DMF;  231 bottom top
direct preparation from alcohols: R-OH  R-N3
2-fluoropyridinium salt & LiN3:  232 middle
HN3/Ph2P(O)N3, Ph3P & DEAD:  232 middle
Ph2P(O)N3/(p-NO2-Ph)2P(O)N3 & DBU:  232 bottom
tetrametylguanidinium azide: soluble in CHCl3/CH2Cl2
Carey B-Chap3-5ed
Chapter 3

11. Formation of C-O Bonds:  Scheme 3.2 D & E
Advanced Org Chem-Carey B
Fall 2002
Formation of C-O Bonds:  Scheme 3.2 D & E
Oxygen nucleophiles: HO-, RO- & RCO2-
substitution vs elimination: alcohols/ethers;  227 top
MeI & BnX as alkylating agents: no elimination
AcO-: equivalent to HO- after hydrolysis
esterification under non-acidic conditions
use of CH2N2 or Ar-N=N-NHR’:  227 mid & section F
SN2 reactions: RCO2M + R’-X in polar aprotic solvents
reactivity of M: Cs > Rb > K > Na; section G
inversion of alcohols: Mitsunobu reactions;  228 top
sulfates & mixed phosphites:  228 bottom & 229 top
Carey B-Chap3-5ed
Chapter 3

12. Advanced Org Chem-Carey B
Fall 2002
Formation of C-N Bonds
Nitrogen nucleophiles:  236 section C
aryl/alkyl amines: multiple alkylation;  229 middle
selective alkylation of amines
Gabriel synthesis: phthalimide;  229 bot &  230 top
amide alkylation:  230 middle (1st)
O-alkylation: hard E+ (Me3O+BF4-);  230 mid (2nd)
amides under Mitsunobu conditions:  230 bottom
mild C-N bond formation:  231
reductive amination with carbonyls: 
Carey B-Chap3-5ed
Chapter 3

13. Nitrogen Nucleophiles (I)
Advanced Org Chem-Carey B
Fall 2002
Nitrogen Nucleophiles (I)
Carey B-Chap3-5ed
Chapter 3

14. Advanced Org Chem-Carey B
Fall 2002
Formation of C-S Bonds
Sulfur nucleophiles:  237 section J
RS-: better Nu than RO-;  233 top
R2S & thioamides: good Nu;  233 top
alkylation of R2S=O:  233 middle
Formation of C-P Bonds
phosphorus nucleophiles:  237 section I
R3P & R2P-: good Nu;  233 bottom
Michaelis-Arbuzov reaction: mechanism
Carey B-Chap3-5ed
Chapter 3

15. Phosphorus Nucleophiles
Advanced Org Chem-Carey B
Fall 2002
Phosphorus Nucleophiles
Carey B-Chap3-5ed
Chapter 3

16. Cleavage of C-O Bonds in Ethers & Esters
Advanced Org Chem-Carey B
Fall 2002
Cleavage of C-O Bonds in Ethers & Esters
Reagents for mild cleavage:  241 Scheme 3.3
Lewis acids: BX3;  239 top
BX3 & Me2S: effective for cleaving aryl methyl ethers
SN2 mechanism for Me, Bn; SN1 for tBu
Me3SiI: more reactive;  239 middle
in-situ generation of Me3SiI:  239 bottom
H2SiI2: effective for cleaving 2o alkyls
cleavage of esters:  240 middle
Ac2O & Lewis acids (BF3, FeCl3, MgBr2):  240 mid
Carey B-Chap3-5ed
Chapter 3

17. C-O Bond Cleavage: BBr3 & Me3SiI
Advanced Org Chem-Carey B
Fall 2002
C-O Bond Cleavage: BBr3 & Me3SiI
Carey B-Chap3-5ed
Chapter 3

18. Carboxylic Acid Derivatives (I)
Advanced Org Chem-Carey B
Fall 2002
Carboxylic Acid Derivatives (I)
Active acylating agents:  250 Scheme 3.4
acyl (acid) chlorides/bromides: R-C(O)-Cl/Br
SOCl2 or PCl5:for acid-stable carboxylic acids
(COCl)2 & Ph3P+Br:  243 middle &  244 top
catalyzed by pyridine or DMAP:  244 middle
acid anhydride & MgBr2, i-Pr2NEt: 3o/hindered R-OH
ScTf3, Sc[TFSI]3, BiTf3, TMS-Tf:   246
R-C(O)-imid.: stable & produced with CDI;  247 top
less N-C=O delocalization & activated by protonation
Carey B-Chap3-5ed
Chapter 3

19. Esters & Anhydrides with Acid Halides
Advanced Org Chem-Carey B
Fall 2002
Esters & Anhydrides with Acid Halides
Carey B-Chap3-5ed
Chapter 3

20. Activation of Acid Chlorides/Anhydrides (I)
Advanced Org Chem-Carey B
Fall 2002
Activation of Acid Chlorides/Anhydrides (I)
Carey B-Chap3-5ed
Chapter 3

21. Activation of Acid Chlorides/Anhydrides (IV)
Advanced Org Chem-Carey B
Fall 2002
Activation of Acid Chlorides/Anhydrides (IV)
Carey B-Chap3-5ed
Chapter 3

22. Carboxylic Acid Derivatives (II)
Advanced Org Chem-Carey B
Fall 2002
Carboxylic Acid Derivatives (II)
In situ activation of HO-C(O)-R:  250 Scheme 3.4
DCC activation: catalyzed by DMAP;  247 middle
2-Chloropyridinium ion:  248 top (cf.  232 middle)
2,2’-dipyridyl disulfide: reactive thioesters;  248 middle
useful for macrolactonization:  248 bottom &  249 top
Yamaguchi method: 2,4,6-trichloro-PhCOCl;  249 middle
Acid-catalyzed activation:  253 Scheme 3.5
Fischer esterification: RCO2H+R’OH RCO2R’+H2O
equilibrium-controlled: excess R’OH, removal of H2O
Carey B-Chap3-5ed
Chapter 3

23. Activation of Carboxylic Acid (I)
Advanced Org Chem-Carey B
Fall 2002
Activation of Carboxylic Acid (I)
Carey B-Chap3-5ed
Chapter 3

24. Advanced Org Chem-Carey B
Fall 2002
Preparation of Amides
Amides: RCO-Y + R’R”NH  RCONR’R” + HY
acyl halides (Y=Cl/Br): amines or NaOH (Schotten-Bauman process,  252 bottom);  257 Scheme 3.6
active esters: Y = O-succinimide ( 253), O-Ph-p-NO2
in situ activation: DCC & HOBt ( 254 bottom), (PhO)2P(O)N3 ( 255 top), BOP-Cl ( 255 middle)
activation of esters with Lewis acids:  255 bottom
from nitriles: acidic/basic conditions;  256 middle
Carey B-Chap3-5ed
Chapter 3

25. In Situ Synthesis of Amides from Acids (I)
Advanced Org Chem-Carey B
Fall 2002
In Situ Synthesis of Amides from Acids (I)
Carey B-Chap3-5ed
Chapter 3

26. In Situ Synthesis of Amides from Acids (II)
Advanced Org Chem-Carey B
Fall 2002
In Situ Synthesis of Amides from Acids (II)
BOP-Cl [N,N’-bis(2-oxo-3-oxazolidinyl)-
phosphinic chloride]
BOP [benzotriazol-1-yloxytris(dimethylamino)-
phosphonium hexafluorophosphate]
(S.-Y. Han Tetrahedron 2004, 60, )
Carey B-Chap3-5ed
Chapter 3

27. Advanced Org Chem-Carey B
Fall 2002
Amides from Nitriles
Carey B-Chap3-5ed
Chapter 3

28. Protecting Groups & Deprotection
Advanced Org Chem-Carey B
Fall 2002
Protecting Groups & Deprotection
strategy of using protecting groups
Carey B-Chap3-5ed
Chapter 3

29. Requirements for Ideal Protecting Groups
Advanced Org Chem-Carey B
Fall 2002
Requirements for Ideal Protecting Groups
Quantitative protection under mild conditions
Stable under the reaction conditions
Quantitative deprotection under mild conditions
Orthogonal protection: inert to deprotection conditions of other protecting groups
references: (1) P. G. M. Wuts & T. W. Greene, ‘Greene’s Protective Groups in Organic Synthesis’ 4th ed., Wiley, (2) P. J. Kocienski, ‘Protecting Groups’, Thieme, 3rd ed
Carey B-Chap3-5ed
Chapter 3

30. Alcohols (I): R-OH R-O-P
Advanced Org Chem-Carey B
Fall 2002
Alcohols (I): R-OH R-O-P
Acetals: R-O-C-O-R’; stable to bases, oxidants
THP: mild acidic hydrolysis, new chiral center;  259 mid
EE & MOP (x 20): faster deprotection;  260 top
MOM: rather stable, ready protection;  260 middle
MEM: cleaved with Lewis acids; orthogonality,  260 bot
MTM: quite stable with H+, removed with Hg2+, Ag+ & MeI in moist acetone;  261 top
ROCH2OCH2CCl3: labile with Zn, SmI2, Na(Hg);  261 mid
SEM: deprotected with F-, MgBr2;  261 bottom
Carey B-Chap3-5ed
Chapter 3

31. Hydroxy-Protecting Groups (I): THP
Advanced Org Chem-Carey B
Fall 2002
Hydroxy-Protecting Groups (I): THP
DHP
(dihydropyran)
Carey B-Chap3-5ed
Chapter 3

32. Hydroxy-Protecting Groups (II): EE & MOP
Advanced Org Chem-Carey B
Fall 2002
Hydroxy-Protecting Groups (II): EE & MOP EE
(ethoxyethyl)
MOP
(methoxypropyl)
Carey B-Chap3-5ed
Chapter 3

33. Hydroxy-Protecting Groups (III): MOM & MEM
Advanced Org Chem-Carey B
Fall 2002
Hydroxy-Protecting Groups (III): MOM & MEM
(methoxymethyl)
(methoxyethoxymethyl)
Carey B-Chap3-5ed
Chapter 3

34. Hydroxy-Protection (IV): Cl3CH2OCH2-OR
Advanced Org Chem-Carey B
Fall 2002
Hydroxy-Protection (IV): Cl3CH2OCH2-OR
Carey B-Chap3-5ed
Chapter 3

35. Alcohols (II): R-OH R-O-P
Advanced Org Chem-Carey B
Fall 2002
Alcohols (II): R-OH R-O-P
Ethers: R-O-R’; stable to bases, oxidants
R (alkyl): very stable but hard to remove
Me, allyl, benzyl (Bn), p-methoxybenzyl (PMB)
t-Bu: TFA, acidic hydrolysis;  262 middle
Tr: faster deprotection than t-Bu; < MMTr < DMTr < TMT
SiR3: versatile & orthogonal protection;  264 – 265
Esters: R-O-C(O)-R’;  265 – 266
Common OH protecting groups:  267 Table 3.2
Carey B-Chap3-5ed
Chapter 3

36. Protection of Alcohols (R-OH) (I)
Advanced Org Chem-Carey B
Fall 2002
Protection of Alcohols (R-OH) (I)
ether formation: R-O-R’
stable under neutral/basic conditions & to oxidations
1. RO-CH3 / RO-CH2CH3: alkyl ethers
2. RO-CH2CH=CH2: allyl ethers
Carey B-Chap3-5ed
Chapter 3

37. Protection of Alcohols (R-OH) (II)
Advanced Org Chem-Carey B
Fall 2002
Protection of Alcohols (R-OH) (II)
ether formation: R-O-R’
3. RO-CH2Ph (Bn): benzyl ethers; RO-CH2Ph-p-OMe (PMB)
Carey B-Chap3-5ed
Chapter 3

38. Protection of Alcohols (R-OH) (III)
Advanced Org Chem-Carey B
Fall 2002
Protection of Alcohols (R-OH) (III)
ether formation: R-O-R’
4. RO-CPh3 (Tr): trityl ethers, selective for 1o alcohols
5. RO-CMe3 (RO-tBu): tert-butyl ethers, stable & bulky
Carey B-Chap3-5ed
Chapter 3

39. Protection of Alcohols (R-OH) (IV)
Advanced Org Chem-Carey B
Fall 2002
Protection of Alcohols (R-OH) (IV)
ether formation: R-O-R’;
6. RO-SiR’3 (RO-TMS): trimethylsilyl ether
TMS: unstable in acid, TBDMS: rather stable, TBDPS & TPS: bulky & very stable, TIPS: bulky & stable, SEM: orthogonal deprotection
Carey B-Chap3-5ed
Chapter 3

40. Protection of Alcohols (R-OH) (V)
Advanced Org Chem-Carey B
Fall 2002
Protection of Alcohols (R-OH) (V)
ester formation: R-O-CO-R’;  265
stable under mild acidic conditions & to oxidations
Carey B-Chap3-5ed
Chapter 3

41. Protection of 1,2- / 1,3-Diols
Advanced Org Chem-Carey B
Fall 2002
Protection of 1,2- / 1,3-Diols
acetals: stable under basic conditions;  266
reagents: ArCHO / ketones or PhCH(OMe)2 / Me2C(OMe)2
carbonates: stable under mild acidic conditions; R=R’=O
reagents: COCl2, (RO)2C=O, (Cl3CO)2C=O, CDI
Carey B-Chap3-5ed
Chapter 3

42. Protection of Aldehydes & Ketones (I)
Advanced Org Chem-Carey B
Fall 2002
Protection of Aldehydes & Ketones (I)
acetals / thioacetals:  273 – 275
Y = W = O; stable to bases, deprotection with acids
(TMSOCH2)2 & cat. TMS-triflate: under neutral conditions by Noyori
Y = W = S; stable to acids & bases, deprotection with HgO, F3B•OEt2
Y =O, W = S; intermediate between acetals & thioacetals
Carey B-Chap3-5ed
Chapter 3

43. Protection of Aldehydes & Ketones (II)
Advanced Org Chem-Carey B
Fall 2002
Protection of Aldehydes & Ketones (II)
Carey B-Chap3-5ed
Chapter 3

44. Deprotection of Aldehydes & Ketones (III)
Advanced Org Chem-Carey B
Fall 2002
Deprotection of Aldehydes & Ketones (III)
Carey B-Chap3-5ed
Chapter 3

45. Protection of Amines (I)
Advanced Org Chem-Carey B
Fall 2002
Protection of Amines (I)
alkylamines: similar to alcohols (Bn, SEM, allyl);  269
Carey B-Chap3-5ed
Chapter 3

46. Protection of Amines (II)
Advanced Org Chem-Carey B
Fall 2002
Protection of Amines (II)
amides/imides: rather stable;  270 – 271
less basic/nucleophilic N & more acidic H
Carey B-Chap3-5ed
Chapter 3

47. Protection of Amines (III)
Advanced Org Chem-Carey B
Fall 2002
Protection of Amines (III)
Imides: Gabriel synthesis;  270
less basic/nucleophilic N (more acidic H)
Carey B-Chap3-5ed
Chapter 3

48. Protection of Amines (IV)
Advanced Org Chem-Carey B
Fall 2002
Protection of Amines (IV)
disilylimides/sulfonamides:  271
less basic/nucleophilic N (more acidic H)
Carey B-Chap3-5ed
Chapter 3

49. Protection of Amines (V)
Advanced Org Chem-Carey B
Fall 2002
Protection of Amines (V)
Carbamates:  272 Table 3.2
R-NH-Troc
R-NH-Boc
R-NH-Fmoc
R-NH-Teoc
Carey B-Chap3-5ed
Chapter 3

50. Protection of Carboxylic Acids (RCO2H) (I)
Advanced Org Chem-Carey B
Fall 2002
Protection of Carboxylic Acids (RCO2H) (I)
ester formation: RC(O)-O-R’; similar to alcohols
esterification with alcohols, CH2N2, or SN2 reaction
orthoester formation: RC(OR’)3, acid labile;  276
Carey B-Chap3-5ed
Chapter 3

51. Protection of Carboxylic Acids (RCO2H) (II)
Advanced Org Chem-Carey B
Fall 2002
Protection of Carboxylic Acids (RCO2H) (II)
dithioorthoester formation:  276
oxazoline formation:  275
Carey B-Chap3-5ed
Chapter 3

52. Deprotection of Carboxylic Esters
Advanced Org Chem-Carey B
Fall 2002
Deprotection of Carboxylic Esters
Carey B-Chap3-5ed
Chapter 3