2. + + REAKSI SUBSTITUSI Y menggantikan tempat X (Substitusi ) Y “menggantikan” X Satu gugus menggantikan gugus yang lain Y R X R Y X
3. SUBSTITUSI NUKLEOFILIK produk PENGGANTIAN NUKLEOFILIK nukleofil “menggantikan” gugus lepas. Disebut reaksi substitusi: Nu menggantikan X (berganti tempat). nukleofil substrat gugus lepas
4. APA YANG MEMBUAT SUATU NUKLEOFIL BAIK? APA ITU NUKLEOFIL? BASA? NUKLEOFILISITAS
5.
6. NUKLEOFIL DAN BASA PERBEDAAN DASAR Basa baik belum tentu Nukleofil baik, begitu sebaliknya HOWEVER : Parameter kinetik (kecepatan) Parameter thermodinamika (keseimbangan) Nukleofilisitas kebasaan Semua nukleofil adalah basa..... dan semua basa adalah nukleofil.
7.
8. REAKSI SUBSTITUSI NUKLEOFILIK REAKSI ASAM-BASA (substitusi pada atom karbon) (Substitusi pada atom Hidrogen) Dapat dibandingkan dengan ….. REAKSI PENGGANTIAN
9. basa asam Asam konyugasi Basa kanyugasi nukleofil substrat produk Gugus lepas PERBANDINGAN SUBSTITUSI PENGGANTIAN PADA ATOM C PENGGANTIAN PADA ATOM H
10. R O R R ' C C R R ' C O O R NUKLEOFIL PEMILIHAN NUKLEOFIL UNTUK SINTESIS BERBAGAI SENYAWA ORGANIK: Nukleofil Produk R X R O H C N R R S H alkyl halides alcohols ethers nitriles esters alkynes thiols Senyawa ‘ ‘ R-Y + Nu R-Nu + Y
11. R ' N H R O R R NUKLEOFIL YANG TIDAK BERMUATAN Nukleofil Produk alcohols Senyawa O R H ethers R N H 2 amines amines O H H + R B r O H H R + + B r O H R O H H + H 3 O + + B r - - Under some circumstances water will react. ‘ ‘
12. Kedua reaksi kelihatan identik Dan mengikuti pola di atas Dua reaksi berikut.... Kenyataan, keduanya berbeda ! REAKSI “MIRIP” RBr + NaOH ROH + NaBr
13. DUA REAKSI MIRIP 1) 2) ( + some alkene by E1,E2 ) 55 o C 55 o C NaOH kons tinggi NaOH kons rendah KEC = k 2 [RBr] [NaOH] KEC = k 1 [RBr] RBr + NaOH ROH + NaBr
18. lambat cepat 2 tahap; unimolekular 55 o C k 1 = 0.010 liter/mole-sec substitusi nukleofilik unimolekular alkene (via E1) also kecepatan = k 1 [RBr] S N 1
19. pereaksi produk Ea 1 Ea 2 H intermediet TS 2 TS 1 E N E R G Y step 1 step 2 karbokation REAKSI DUA TAHAP S N 1
20. 55 o C Alkil halida primer Two similar reactions, different kinetics. RBr + NaOH ROH + NaBr Kecepatan = k 2 [RBr] [NaOH] S N 2 1) Kasus pertama
21. 55 o C Alkil halida tersier Kecepatan = k 1 [RBr] S N 1 2) Kasus kedua
22. S N 2 conditions S N 1 conditions [OH-] tinggi [OH-] rendah enantiomer Campuran resemat R-(-)-2-bromooktana S-(+)-2-octanol Inversion sempurna Rasemisasi sempurna PERUBAHAN STEREOKIMIA [ ] D = +10.3 o [ ] D = - 36.0 o [ ] D = 0 o + R S R S
23. enantiomer MEKANISME S N 1 karbokation planar (S) (R) (R) 50% 50% campuran racemat serangan atas dan bawah secara bersamaan + sp2 - RASEMISASI
24. MEKANISME S N 2 Serangan Belakang Serangan nukleofilik Konfigurasi (R) Konfigurasi (S) C R H CH 3 H O : .. .. : O .. H .. INVERSI C H Br R CH 3 : : .. ..
25. Menemukan secara eksperiment bahwa: HUGHES AND INGOLD ca. 1940 Kebanyakan alkil halida primer bereaksi SN2 dengan orde reaksi kedua Kebanyakan alkil halida tersier bereaksi SN1 dengan orde reaksi pertama
26. Nu: C X Nu: + C X + X Nu C E R rate = k S N 2 = Substitusi Nukleofilik orde kedua Mekanisme Reaksi SN2
27. Nu: C X E R Nu: + C X + X Nu C rate = k S N 2 = Substitusi Nukleofilik orde kedua Mekanisme Reaksi SN2
28. C Nu X E R Nu: + C X + X Nu C rate = k S N 2 = Substitusi Nukleofilik orde kedua Mekanisme Reaksi SN2
29. C Nu X E R Nu: + + X Nu C Terjadi inversi pada karbon “ serangan belakang” C X S N 2 = Substitusi Nukleofilik orde kedua Mekanisme Reaksi SN2
30. Nu: Review: S N 2 = Substitusi Nukleofilik Orde ke 2 C X Nu: + C X + X Nu C E R reaktan produk
31. Nu: C X E R Nu: + C X + X Nu C Review: Keadaan transisi reaktan produk S N 2 = Substitusi Nukleofilik Orde ke 2
32. C Nu X E R Nu: + C X + X Nu C Review: ΔG ‡ ΔG ° (equilibria) (rates) Keadaan transisi reaktan produk S N 2 = Substitusi Nukleofilik Orde ke 2
33. LIKE POOL OR BILLIARDS 1) two balls at rest and touching 2) forceful shot directly on axis 3) straight-on collision 4) momentum transfer Nu Nu Nu X X X X CONCEPTUAL ANALOGY 1 Similar in concept to an attack from the back forcing the nucleophile to leave.
34. INVERSION OF AN UMBRELLA IN THE WIND Inversion of the umbrella is similar in concept to the inversion of an S N 2 atom. CONCEPTUAL ANALOGY 2
35. C H CH 3 R Br HO activated complex is trigonal planar (sp 2 ) (R)-configuration (S)-configuration configuration is inverted Ea HO C B partial bonding 2p THE INVERSION PROCESS sp 3 sp 3 sp 2 C R H CH 3 Br : C R H CH 3 HO : H O : .. ..
36. ACTIVATED COMPLEX FOR S N 2 C R H CH 3 Br HO trigonal planar (sp 2 ) 5 bonds to Carbon breaking forming … but the bonds to Br and OH are only half-formed and are not full bonds. NOT A STABLE SPECIES MIDPOINT OF THE REACTION
37. FAKTOR YANG MEMPENGARUHI SUBSTITUSI NUKLEOFILIK
38. NUCLEOPHILIC SUBSTITUTION Banyak Faktor Berpengaruh Terhadap Reaksi S N 1 dan S N 2 a) struktur b) atom yg digunakan c) konsentrasi d) Kekuatan basa a) struktur R, stereochemistry a) Keadaan X b) konsentrasi a) Pelarut b) Suhu c) pH SOME PARAMETERS : b) atom yg digunakan c) Kekuatan basa c) Kekuatan ikatan a) Kekuatan ikatan e) kelarutan f) ukuran d) H
43. If the atom type changes then nucleophilicity may not be determined by basicity.
44. If the atom type changes then nucleophilicity may not be determined by basicity. basicity basicity nucleophilicity nucleophilicity
45. Why are some species, such as H-S and I weak bases and strong nucleophiles. basicity nucleophilicity
46. Sulfur has polarizable electrons and can form strong bonds at long distances. The S N 2 Reaction is very sensitive to steric effects.
47.
48. The S N 2 Reaction is very sensitive to steric effects.
49. 1. nucleophilicity of the nucleophile. Factors that affect the rate of S N 2 reactions E R G ‡
50. Factors that affect the rate of S N 2 reactions 1. basicity (nucleophilicity) of the nucleophile. E R G ‡ G ‡
51. Weak bases are good leaving groups in substitution reactions. pK a X
52. The Halides. Nucleophilicity and leaving group abilities. increasing acidity increasing nucleophilicity increasing reactivity (substitution)
53. The Halides Iodine is both a good leaving group and a good nucleophile! increasing nucleophilicity increasing reactivity (substitution)
54. Factors that affect the rate of S N 2 reactions 1. nucleophilicity of the nucleophile. 2. stability of the leaving group. E R G ‡
55. Factors that affect the rate of S N 2 reactions 1. basicity (nucleophilicity) of the nucleophile. 2. stability of the leaving group. E R G ‡
56. Factors that affect the rate of S N 2 reactions 1. basicity (nucleophilicity) of the nucleophile. 2. stability of the leaving group. stronger bond G ‡ E R G ‡
61. S N 1 - SUBSTRAT DAN KARBOKATION R-X R + + X - lambat R + + Nu - R-Nu cepat The better ion will have the lower energy pathway. Energi intermediet karbokation faktor penting untuk reaksi S N 1 3 o < 2 o < 1 o
63. 1935: Hughes & Ingold SOLVOLYSIS t-BUTYL BROMIDA + H 3 O + + Br - tertiary
64. kecepatan relatif 1.0 1.7 45 RBr + H 2 O ROH + HBr 100% HCOOH kecepatan meningkat rel rate = rate CH 3 Br rate PENGARUH PENINGKATAN SUBSTITUSI - S N 1 methyl primary secondary tertiary Guess ? PENGARUH SUBSTRAT PADA KECEPATAN 10 8
66. STABILITAS KARBOKATION HIPERKONYJUGASI C C H .. H H + R R elektron yang berdekatan ikatan C-H membantu menstabilkan Muatan positif karbokation tertiary secondary primary << < Energi terendah Energi tertinggi REVIEW
68. S N 2 - SUBSTRAT C R Br : H O : .. .. R R large groups introduce steric hindrance C H Br : H H easy access no steric hindrance H O : .. ..
69. decreasing rate EFFECT OF DEGREE OF SUBSTITUTION - S N 2 methyl primary secondary tertiary EFFECT OF SUBSTRATE ON RATE 150 1 0.01 0.001 rel rate = rate EtBr rate
70. decreasing rate EFFECT OF BULKY SUBSTITUENTS - S N 2 NEOPENTYL slower than t -butyl ALL ARE PRIMARY ! ( substitution on the carbon ) 17 1 0.03 3 x 10 -6 rel rate = rate EtBr rate
77. S N 1 S N 2 tertiary methyl ** benzyl benzyl allyl allyl secondary primary primary secondary tertiary neopentyl Notice that benzyl and allyl are good for both S N 1 and S N 2 BEST WORST (fastest) (slowest) bridgehead bridgehead (bicyclic) (bicyclic) APPROXIMATE RATE ORDERS BEST (fastest) WORST (slowest) SUMMARY ** In S N 2 reactions benzyl is actually better than methyl, but allyl is not. For illustration purposes benzyl and allyl were grouped in the yellow box.
78. AND DON’T FORGET: S N 1 and S N 2 reactions occur only at sp 3 (tetrahedral) carbon atoms. yes no sp 3 sp 2 sp (attempted S N 2 reaction) (attempted S N 1 solvolysis) CH 3 CH 2 -C=CH-Br + H 2 O no reaction + NaCN no reaction acetone
80. Nucleophiles are unimportant in an S N 1 reaction; they are not involved in the rate-determining step. S N 1 rate = K 1 [RX] The nature of a nucleophile is only important to an S N 2 reaction. S N 2 rate = K 2 [RX][Nu] NUCLEOPHILES IMPORTANCE IN S N 1 AND S N 2 REACTIONS
82. C R Br : R R WHAT IS THE IDEAL NUCLEOPHILE ? no way ! bad STERIC PROBLEMS Smaller is better ! LARGE SMALL S N 2 REACTIONS For an S N 2 reaction the nucleophile must find the back lobe of the sp 3 hybrid orbital that the leaving group is bonded to. good Y : : .. .. : .. .. X : -
83. :C N: SMALL SPHERES ROD OR SPEAR SHAPED EXPECTED “IDEAL” NUCLEOPHILES :N N N: - - - - - + etc. These types should be able to find the target ! azide cyanide Generally this idea is correct. .. :F: .. :Cl: .. ..
84. F Cl Br I 1.36 A 1.81 A 1.95 A 2.16 A - - - - smallest ion and we would expect the smallest one (fluoride) to be the best nucleophile, … .. however, that is not usually the case. OUR NAÏVE EXPECTATION We would expect the halides to be good nucleophiles: ionic radii:
85. F - 5 x 10 2 Cl - 2.3 x 10 4 Br - 6 x 10 5 I - 2 x 10 7 slowest fastest k CH 3 -I + NaX CH 3 -X + NaI Rate = k [CH 3 I] [X - ] RELATIVE RATES OF REACTION FOR THE HALIDES MeOH * MeOH solvates like water but dissolves everything better. EXPERIMENTAL RESULTS S N 2
87. F - 120 Kcal / mole - gas phase F - H O H water solution H O H HEAT OF SOLVATION H O H H O H F - (g) F - (aq) HEAT OF SOLVATION SOLVATED ION ENERGY IS RELEASED WHEN AN ION IS PLACED IN WATER The interaction between the ion and the solvent is a type of weak bond. Energy is released when it occurs. Solvation lowers the potential energy of the nucleophile making it less reactive.
88. F Cl Br I 1.36 A 1.81 A 1.95 A 2.16 A HALIDE IONS Heats of solvation in H 2 O - 120 - 90 Kcal / mole - 65 - - - - increasing solvation - 75 SMALL IONS SOLVATE MORE THAN LARGE IONS smallest ion larger n smaller n IONIC RADIUS X(H 2 O) n -
89. WATER AS A SOLVENT polar OH bonds Water is a polar molecule. Negative on the oxygen end, and positive on the hydrogen end. It can solvate both cations and anions.
90. SMALL IONS SOLVATE MORE HEAVILY THAN LARGE ONES solvent shell - - ...smaller solvent shell ...escapes easily … more potential energy BETTER NUCLEOPHILE I F - - “ Effective size” is larger. H O H H O H H O H H O H H O H H O H H O H H O H H O H H O H Heavy solvation lowers the potential energy of the nucleophile. It is difficult for the solvated nucleophile to escape the solvent shell. This ion is less reactive.
91. PROTIC SOLVENTS water methanol ethanol amines Water is an example of a “protic” solvent. Protic solvents are those that have Protic solvents can form hydrogen bonds and can solvate both cations and anions. O-H, N-H or S-H bonds.
92. In protic solvents the larger ions are solvated less (smaller solvent shell) and they are, therefore, effectively smaller in size and have more potential energy. Since the solvent shell is smaller in a larger ion it can more easily “escape” from the surrounding solvent molecules during reaction. There is more potential energy. LARGER IONS ARE BETTER NUCLEOPHILES IN PROTIC SOLVENTS THREE FACTORS ARE INVOLVED : 1 2 3 The larger ions are thought ( by some ) to be more “polarizable”. see the next slide …..
93. POLARIZABILITY Polarizability assumes larger ions are able to easily distort the electons in their valence shell, and that smaller ions cannot. C Br The distortion of large ions is easier because the orbital clouds are more diffuse. The nucleophile “flows” into the reactive site. VERY HYPOTHETICAL
94. If everything else is equal, the stronger base is the better nucleophile . BASICITY This principle shows up in a period, where atoms do not vary appreciably in size, and solvate to similar extents. OH - is a better nucleophile than F -
96. OBSERVED NUCLEOPHILICITY TRENDS H 2 O OR OTHER “ PROTIC ” SOLVENTS CH 3 - NH 2 - OH - F - PH 2 - SH - Cl - Br - I - increasing nucleophilicity (ROWS) increasing nucleophilicity (COLUMNS) GROUP IV V VI VII basicity more solvation, larger effective size, lower potential energy basicity
97. MeOH RELATIVE RATES OF SOME NUCLEOPHILES CH 3 -I + Nu: CH 3 -Nu + I - Rate = k [CH 3 I] [X - ] F- 5 x 10 2 CH 3 COO- 2 x 10 4 Cl- 2.3 x 10 2 C 6 H 5 O- 5.6 x 10 5 N 3 - 6 x 10 5 Br- 6 x 10 5 CH 3 O- 2 x 10 6 CN- 5 x 10 6 I- 2 x 10 7 C 6 H 5 S- 8 x 10 9 CH 3 OH 1.0 NH 3 3.2 x 10 5 (CH 3 ) 2 S 3.5 x 10 5 C 6 H 5 NH 2 5 x 10 5 C 6 H 5 SH 5 x 10 5 these are the good nucleophiles, but watch out, some are strong bases (solvolysis is faster) S N 2 CHARGED NEUTRAL
99. APROTIC SOLVENTS dimethylsulfoxide dimethylformamide hexamethylphosphoramide acetone acetonitrile if scrupulously free of water + - - + APROTIC SOLVENTS DO NOT HAVE OH, NH, OR SH BONDS “ DMSO” “ DMF” “ HMPA” They do not form hydrogen bonds.
100. APROTIC SOLVENTS SOLVATE CATIONS, BUT NOT ANIONS (NUCLEOPHILES) The nucleophile is “ free” (unsolvated), and therefore is small and not hindered by a solvent shell. - - + + crowded
101. S O H H DIMETHYLSUFOXIDE density - electrostatic potential plot space-filling
103. OBSERVED NUCLEOPHILICITY APROTIC SOLVENTS CH 3 - NH 2 - OH - F - PH 2 - SH - Cl - Br - I - increasing nucleophilicity (ROWS) increasing nucleophilicity (COLUMNS) GROUP IV V VI VII The direction of the red arrow ( COLUMNS ) represents a different order than in protic solvents. basicity decreasing ionic size
104. WHY NOT ALWAYS USE APROTIC SOLVENTS FOR S N 2 ? Mostly, it is a matter of expense. Water, ethanol, methanol and acetone are much cheaper, especially water. Water “free” Methanol $14.70 / L Ethanol $15.35 / L Acetone $16.60 / L DMSO $47.50 / L DMF $33.75 / L HMPA $163.40 / L Cheapest grades available, Aldrich Chemical Co., 2000.
106. S N 1 reactions prefer polar-protic solvents that can solvate the anion and cation formed in the rate-determining step. R-X R + + X - rate-determining step solvation of both ions speeds the ionization S N 1 SOLVENTS = POLAR Carbocation ions
107. S N 2 reactions prefer “non-polar” solvents, or polar-aprotic solvents that do not solvate the nucleophile. C R Br : : .. .. R R X : smaller is better ! SMALL, UNSOLVATED S N 2 SOLVENTS = NONPOLAR OR POLAR-APROTIC
108. overall polarity NONPOLAR POLAR POLAR PROTIC SOLVENTS POLAR APROTIC SOLVENTS S N 2 NONPOLAR SOLVENTS S N 1
110. SOLVENT MIXTURES ARE VERY COMMON Alkyl halides don’t dissolve in water, but dissolve in most organic solvents. Nucleophile salts don’t dissolve in most organic solvents, but dissolve in water. RX NaX soluble in EtOH soluble in H 2 O miscible solvents Both dissolve in a mixed solvent.
111. EXCEPTIONS NaX Dissolve in polar-aprotic organic solvents: DMF, DMSO, HMPA. NaI and NaCN dissolve in acetone, but NaCl and NaBr do not
112. CARBOCATIONS REACT WITH ALL NUCLEOPHILES EQUALLY S N 1 S N 2 BETTER NUCLEOPHILES REACT FASTER GIVING MORE PRODUCT THE BOTTOM LINE The nucleophile is not involved in the rate-determining step. The nucleophile is involved in the rate-determining step.
